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Hip pain in children is common, with causes ranging from the benign to destructive. This article reviews slipped capital femoral epiphysis (SCFE), one of the most common hip pathologies in preadolescents and adolescents, which often is missed or delayed in diagnosis because of its vague, atypical presentation.

People who identify as African Americans, Latinos, or from indigenous backgrounds, are dramatically underrepresented in the U.S. physician workforce. It is critical for academic health centers to recognize racial and ethnic diversity at the residency level and implement changes to enhance diversity among trainees.The Office of Graduate Medical Education (GME) at the University of Pennsylvania Health System (UPHS) developed a multipronged approach to enhance diversity and inclusion (DI) among residency trainees. The approach included the development of an underrepresented in medicine (UIM) professional network; UIM-focused visiting clerkship programs; holistic review implementation by selection committees; and targeted outreach to UIM candidates, overseen by an associate designated institutional official for UIM Affairs. The authors reported demographic data on residency applicants invited for interviews and matching for all programs at UPHS from 2014-2015 (baseline) to 2020-2021. They also reported data on maximum ranking number programs reached to fill their positions and the average United States Medical License Examination (USMLE) Step 1 scores of matched candidates. Finally, they discussed the implications for leaders who wish to enhance DI at academic health centers.During the baseline year (2014-2015), UIMs represented 12.1% of interviewees and 8.7% of all matched candidates into UPHS residency programs. Over the successive 6 years after incremental implementation of the approach, UIM representation steadily increased. In 2020-2021, UIMs represented 23.2% of interviewees and 26.4% of matched candidates. Programs' maximum rank number to fill and USMLE Step 1 scores of matched candidates remained relatively unchanged.The UPHS Office of GME incorporated a purposeful approach to enhance the DI of its residents. Across 6 years of implementation, UIM representation among resident matches tripled while quantitative program and candidate metrics remained unchanged. Similar efforts should be given further consideration for implementation and evaluation nationwide.

This article addresses a fundamental question of multiagent knowledge distribution: what information should be sent to whom and when with the limited resources available to each agent? Communication requirements for multiagent systems can be rather high when an accurate picture of the environment and the state of other agents must be maintained. To reduce the impact of multiagent coordination on networked systems, for example, power and bandwidth, this article introduces two concepts for the partially observable Markov decision processes (POMDPs): 1) action-based constraints that yield constrained-action POMDPs (CA-POMDPs) and 2) soft probabilistic constraint satisfaction for the resulting infinite-horizon controllers. To enable constraint analysis over an infinite horizon, an unconstrained policy is first represented as a finite-state controller (FSC) and optimized with policy iteration. The FSC representation then allows for a combination of the Markov chain Monte Carlo and discrete optimization to improve the probabilistic constraint satisfaction of the controller while minimizing the impact on the value function. Within the CA-POMDP framework, we then propose intelligent knowledge distribution (IKD) which yields per-agent policies for distributing knowledge between agents subject to interaction constraints. Finally, the CA-POMDP and IKD concepts are validated using an asset tracking problem where multiple unmanned aerial vehicles (UAVs) with heterogeneous sensors collaborate to localize a ground asset to assist in avoiding unseen obstacles in a disaster area. The IKD model was able to maintain asset tracking through multiagent communications while only violating soft power and bandwidth constraints 3% of the time, while greedy and naive approaches violated constraints more than 60% of the time.

Supplementary Figures S1-S7 and Tables S1 and S2

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location.Significance:Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known.See related commentary by De Dominici and DeGregori, p. 227.This article is highlighted in the In This Issue feature, p. 211

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.

This is the Supplemental Materials document for the article published in MDPI - Microorganisms by Jessica Halfen, Nathaly Ana Carpinelli, Sergio D. Lasso, Tainara Cristina Michelotti, Emily C. Fowler, Benoit St-Pierre, Erminio Trevisi, and Johan S. Osorio. Physiological conditions leading to maternal subclinical ketosis in Holstein dairy cows can impair the offspring's postnatal growth and gut microbiome development

Salmonella enterica is a diverse species of bacterial pathogens comprised of >2,500 serovars with variable host ranges and virulence properties. Accumulating evidence indicates that two AB5-type toxins, typhoid toxin and ArtAB toxin, contribute to the more severe virulence properties of the Salmonella strains that encode them. It was recently discovered that there are two distinct types of artAB-like genetic elements in Salmonella: those that encode ArtAB toxins (artAB elements) and those in which the artA gene is degraded and the ArtB homolog, dubbed PltC, serves as an alternative delivery subunit for typhoid toxin (pltC elements). Here, we take a multifaceted approach to explore the evolutionary diversification of artAB-like genetic elements in Salmonella. We identify 7 subtypes of ArtAB toxins and 4 different PltC sequence groups that are distributed throughout the Salmonella genus. Both artAB and pltC are encoded within numerous diverse prophages, indicating a central role for phages in their evolutionary diversification. Genetic and structural analyses revealed features that distinguish pltC elements from artAB and identified evolutionary adaptations that enable PltC to efficiently engage typhoid toxin A subunits. For both pltC and artAB, we find that the sequences of the B subunits are especially variable, particularly amongst amino acid residues that fine tune the chemical environment of their glycan binding pockets. This study provides a framework to delineate the remarkably complex collection of Salmonella artAB/pltC-like genetic elements and provides a window into the mechanisms of evolution for AB5-type toxins.

While the Early Neolithic chambered tombs of the Isle of Man are well known and the Late Neolithic has been clearly defined with reference to a distinctive suite of artefacts, little is known about the Middle Neolithic. This article reports on 17 new Neolithic radiocarbon dates from cremated human remains from the Isle of Man. These identify five burials in cists as Middle Neolithic and indicate new sequences of activity at cemeteries starting in the Middle Neolithic. Each of these sites is examined in detail. The dates also spur a reconsideration of the development of Ronaldsway pottery and the integration of Grooved Ware pottery and motifs into early 3rd millennium practice on the island. The paper ends with a consideration of the changing effects of mortuary practices throughout the Neolithic on the Isle of Man and a discussion of connections with Middle and Late Neolithic activity in Ireland and Britain.

Background Preoperative goals of care (GOC) and code status (CS) discussions are important in achieving an in-depth understanding of the patient's care goals in the setting of a serious illness, enabling the clinician to ensure patient autonomy and shared decision making. Past studies have shown that anesthesiologists are not formally trained in leading these discussions and may lack the necessary skill set. We created an innovative online video curriculum designed to teach these skills. This curriculum was compared to a traditional method of learning from reading the medical literature. Methods In this bi-institutional randomized controlled trial at 2 major academic medical centers, 60 anesthesiology trainees were randomized to receive the educational content in 1 of 2 formats: (1) the novel video curriculum (video group) or (2) journal articles (reading group). Thirty residents were assigned to the experimental video curriculum group, and 30 were assigned to the reading group. The content incorporated into the 2 formats focused on general preoperative evaluation of patients and communication strategies pertaining to GOC and CS discussions. Residents in both groups underwent a pre- and postintervention objective structured clinical examination (OSCE) with standardized patients. Both OSCEs were scored using the same 24-point rubric. Score changes between the 2 OSCEs were examined using linear regression, and interrater reliability was assessed using weighted Cohen's kappa. Results Residents receiving the video curriculum performed significantly better overall on the OSCE encounter, with a mean score of 4.19 compared to 3.79 in the reading group. The video curriculum group also demonstrated statistically significant increased scores on 8 of 24 rubric categories when compared to the reading group. Conclusions Our novel video curriculum led to significant increases in resident performance during simulated GOC discussions and modest increases during CS discussions. Further development and refinement of this curriculum are warranted.

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location. Significance: Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known. See related commentary by De Dominici and DeGregori, p. 227. This article is highlighted in the In This Issue feature, p. 211

Effective methods for engaging clinicians in continuing education for learning-based practice improvement remain unknown.To determine whether a smartphone-based app using spaced education with retrieval practice is an effective method to increase evidence-based practice.A prospective, unblinded, single-center, crossover randomized clinical trial was conducted at a single academic medical center from January 6 to April 24, 2020. Vanderbilt University Medical Center clinicians prescribing intravenous fluids were invited to participate in this study.All clinicians received two 4-week education modules: 1 on prescribing intravenous fluids and 1 on prescribing opioid and nonopioid medications (counterbalancing measure), over a 12-week period. The order of delivery was randomized 1:1 such that 1 group received the fluid management module first, followed by the pain management module after a 4-week break, and the other group received the pain management module first, followed by the fluid management module after a 4-week break.The primary outcome was evidence-based clinician prescribing behavior concerning intravenous fluids in the inpatient setting and pain medication prescribing on discharge from the hospital.A total of 354 participants were enrolled and randomized, with 177 in group 1 (fluid then pain management education) and 177 in group 2 (pain management then fluid education). During the overall study period, 16 868 questions were sent to 349 learners, with 11 783 (70.0%) being opened: 10 885 (92.4%) of those opened were answered and 7175 (65.9%) of those answered were answered correctly. The differences between groups changed significantly over time, indicated by the significant interaction between educational intervention and time (P = .002). Briefly, at baseline evidence-concordant IV fluid ordered 7.2% less frequently in group 1 than group 2 (95% CI, -19.2% to 4.9%). This was reversed after training at 4% higher (95% CI, -8.2% to 16.0%) in group 1 than group 2, a more than doubling in the odds of evidence-concordant ordering (OR, 2.56, 95% CI, 0.80-8.21). Postintervention, all gains had been reversed with less frequent ordering in group 1 than group 2 (-9.5%, 95% CI, -21.6% to 2.7%). There was no measurable change in opioid prescribing behaviors at any time point.In this randomized clinical trial, use of smartphone app learning modules resulted in statistically significant short-term improvement in some prescribing behaviors. However, this effect was not sustained over the long-term. Additional research is needed to understand how to sustain improvements in care delivery as a result of continuous professional development at the institutional level.ClinicalTrials.gov Identifier: NCT03771482.

Repeated serosurveys are an important tool for understanding trends in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination. During 1 September 2020–20 March 2021, the NYC Health Department conducted a population-based SARS-CoV-2 antibody prevalence survey of 2096 NYC adults who either provided a blood specimen or self-reported the results of a previous antibody test. The serosurvey, the second in a series of surveys conducted by the NYC Health Department, aimed to estimate SARS-CoV-2 antibody prevalence across the city and for different groups at higher risk for adverse health outcomes. Weighted citywide prevalence was 23.5% overall (95% confidence interval (CI) 20.1–27.4) and increased from 19.2% (95% CI 14.7–24.6) before coronavirus disease 2019 vaccines were available to 31.3% (95% CI 24.5–39.0) during the early phases of vaccine roll-out. We found no differences in antibody prevalence by age, race/ethnicity, borough, education, marital status, sex, health insurance coverage, self-reported general health or neighbourhood poverty. These results show an overall increase in population-level seropositivity in NYC following the introduction of SARS-CoV-2 vaccines and highlight the importance of repeated serosurveys in understanding the pandemic's progression.

DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G2 phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G1 phase and non-cycling quiescent (G0) cells where DSBs are predominately repaired by non-homologous end joining (NHEJ). Unexpectedly, we uncovered extensive MRE11- and CtIP-dependent DNA end resection at DSBs in G0 murine and human cells. A whole genome CRISPR/Cas9 screen revealed the DNA-dependent kinase (DNA-PK) complex as a key factor in promoting DNA end resection in G0 cells. In agreement, depletion of FBXL12, which promotes ubiquitylation and removal of the KU70/KU80 subunits of DNA-PK from DSBs, promotes even more extensive resection in G0 cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in proliferating cells at the G1 or G2 phase of the cell cycle was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G0, but not in G1 or G2 phase cells, which has important implications for DNA DSB repair in quiescent cells.

During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.

Typhoid toxin is an A2B5 protein toxin and an important virulence factor for the human-adapted bacterial pathogen Salmonella enterica serovar Typhi, the causative agent of typhoid fever. Typhoid toxin contains two enzymatic subunits, PltA and CdtB, which dock onto a pentameric delivery platform composed of the protein PltB. It was recently reported that the same enzymatic subunits can assemble with a different delivery platform composed of the protein PltC, forming a distinct version of typhoid toxin. However, the differences in structure and receptor specificity between the PltC and PltB typhoid toxins remain unknown. Here, we determined atomic-level structures of the pentameric PltC subunit, the fully assembled PltC typhoid toxin, and the PltC pentamers in complex with glycan receptors. Biochemical and structural analyses indicate that PltB and PltC are unable to form heteromeric delivery complexes due to electrostatic repulsion at the subunit interface and thus form separate toxins only. We further observed that, despite low sequence similarity between PltB and PltC, they interact with PltA in a similar manner but that PltC exhibits stronger electrostatic interactions with PltA, enabling it to outcompete PltB in toxin assembly. The ligand-bound atomic structures of PltC show an additional glycan binding site not found in PltB and glycan array analysis indicates that PltB and PltC exhibit significant differences in glycan binding specificity. Collectively, this study offers atomic-level insights into how S. Typhi produces two distinct versions of typhoid toxin, thereby generating functional diversity in this key virulence factor.

Epithelial stem cells accumulate mutations throughout life. Some of these mutants increase competitive fitness and may form clones that colonize the stem cell niche and persist to acquire further genome alterations. After a transient expansion, mutant stem cells must revert to homeostatic behavior so normal tissue architecture is maintained. Some positively selected mutants may promote cancer development, whereas others inhibit carcinogenesis. Factors that shape the mutational landscape include wild-type and mutant stem cell dynamics, competition for the niche, and environmental exposures. Understanding these processes may give new insight into the basis of cancer risk and opportunities for cancer prevention. Significance: Recent advances in sequencing have found somatic mutations in all epithelial tissues studied to date. Here we review how the mutational landscape of normal epithelia is shaped by clonal competition within the stem cell niche combined with environmental exposures. Some of the selected mutant genes are oncogenic, whereas others may be inhibitory of transformation. Discoveries in this area leave many open questions, such as the definition of cancer driver genes, the mechanisms by which tissues constrain a high proportion of oncogenic mutant cells, and whether clonal fitness can be modulated to decrease cancer risk.

This study describes the process used by the US Food and Drug Administration to review potential generic drugs for Competitive Generic Therapy (CGT) designation and marketing exclusivity as well as the characteristics and outcomes of products that have sought CGT designation and exclusivity from 2017-2020.

The Muller muscle-conjunctival resection is a common technique used to treat blepharoptosis, but there is variability with the target surgical resection and expected postoperative outcomes measured by marginal reflex distance-1 (MRD1). A Levator-Mullerectomy is a novel surgical approach described by Morris et al to incorporate the levator palpebrae superioris in the same incision as the classic Muller muscle-conjunctival resection in the treatment of blepharoptosis. This a retrospective study of patients who underwent Levator-Mullerectomy for ptosis repair showing the clinical outcomes based on MRD1. Statistical analysis was performed using analysis of variance and a nonparametric Kruskal-Wallis test. One hundred-twelve eyes of 83 patients (29 bilateral cases) with a mean age 64.6 years (7-92 years) were included. The types and prevalence of blepharoptosis were involutional (83%), neurogenic (8.0%), traumatic (3.6%), apraxia (2.7%), and congenital (2.7%). There was no significant difference in clinical outcome based on type of blepharoptosis (P = 0.7). Target resection lengths of 8 mm, 10 mm, and 12 mm were compared with postoperative MRD1 change. The mean change in MRD 1 between 8 mm and 10 mm was found to be statistically significant (P = 0.001 for both) but was not statistically significant for the 12 mm resection (P = 0.8). In patients with blepharoptosis and a positive response to 2.5% phenylephrine can benefit from Levator-Mullerectomy with either an 8 mm or 10 mm resection. This novel surgical approach allows surgeons to produce a more predictable and consistent clinical outcome.

DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G2 phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G1 phase and non-cycling quiescent (G0) cells where DSBs are predominately repaired by non-homologous end joining (NHEJ). Unexpectedly, we uncovered extensive MRE11- and CtIP-dependent DNA end resection at DSBs in G0 mammalian cells. A whole genome CRISPR/Cas9 screen revealed the DNA-dependent kinase (DNA-PK) complex as a key factor in promoting DNA end resection in G0 cells. In agreement, depletion of FBXL12, which promotes ubiquitylation and removal of the KU70/KU80 subunits of DNA-PK from DSBs, promotes even more extensive resection in G0 cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in proliferating cells at the G1 or G2 phase of the cell cycle was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G0, but not in G1 or G2 phase cells, and has important implications for DNA DSB repair in quiescent cells.

DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G

DNA double-strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to the expression of HR proteins, including BRCA1, BRCA2, PALB2, and RAD51, and promotes DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection in LIN37-deficient G0 cells depends on BRCA1 and leads to RAD51 filament formation and HR. LIN37 is not required to protect DNA ends in cycling cells at G1-phase. Thus, LIN37 regulates a novel 53BP1-independent cell phase-specific DNA end protection pathway that functions uniquely in quiescent cells.

BACKGROUND: Research has demonstrated that active learning, spaced education, and retrieval-based practice can improve knowledge acquisition, knowledge retention, and clinical practice. Furthermore, learners prefer active learning modalities that use the testing effect and spaced education as compared to passive, lecture-based education. However, most research has been performed with students and residents rather than practicing physicians. To date, most continuing medical education (CME) opportunities use passive learning models, such as face-to-face meetings with lecture-style didactic sessions. The aim of this study was to investigate learner engagement, as measured by the number of CME credits earned, via two different learning modalities. METHODS: Diplomates of the American Board of Anesthesiology or candidates for certification through the board (referred to colloquially and for the remainder of this article as board certified or board eligible) were provided an opportunity to enroll in the study. Participants were recruited via email. Once enrolled, they were randomized into 1 of 2 groups: web-app–based CME (Webapp CME) or an online interface that replicated online CME (Online CME). The intervention period lasted 6 weeks and participants were provided educational content using one of the two approaches. As an incentive for participation, CME credits could be earned (without cost) during the intervention period and for completion of the postintervention quiz. The same number of CME credits was available to each group. RESULTS: Fifty-four participants enrolled and completed the study. The mean number of CME credits earned was greater in the Webapp group compared to the Online group (12.3 ± 1.4 h versus 4.5 ± 2.3 h, P < .001). Concerning knowledge acquisition, the difference in postintervention quiz scores was not statistically significant (Webapp 70% ± 7% versus Online 60% ± 11%, P = .11). However, only 29% of the Online group completed the postintervention quiz, versus 77% of the Webapp group (P < .001), possibly showing a greater rate of learner engagement in the Webapp group. CONCLUSION: In this prospective, randomized controlled pilot study, we demonstrated that daily spaced education delivered to learners through a smartphone web app resulted in greater learner engagement than an online modality. Further research with larger trials is needed to confirm our findings.

Two pigeons key pecked under a two-component multiple fixed-ratio (FR) FR schedule. Each component provided a different reinforcer magnitude (small or large) thatwhich was signaled by the color of the key light. Large- (rich) and small- (lean) reinforcer components randomly alternated to produce four different types of transitions between the size of the immediately preceding reinforcer and the size of the upcoming reinforcer: lean-to-lean, lean-to-rich, rich-to-lean, and rich-to-rich. During probe sessions, a mirror (which was covered during baseline sessions) was uncovered and attack responses toward the mirror were measured, along with the force of individual mirror attacks. The pigeons paused the longest, and attacked most frequently during the rich-to-lean transitions. The pigeons also exhibited some attacksh during lean-to-lean transitions, and pauses were longer during these transitions than during the lean-to-rich and rich-to-rich transitions. Pauses were short and attack infrequent during these last two transition types. In addition, attacks were more forceful during the rich-to-lean transitions thaen during the other transition types. These data are consistent with the view that rich-to-lean transitions function aversively and, as such, generate behavior patterns, including aggression, commonly produced by other aversive stimuli.

Collaborations and partnerships across disciplines are becoming increasingly recognized as valuable endeavors toward solving emerging global challenges in our rapidly changing world. Thus, it is cr...

Introduction The extraction of salient information from the environment is modulated by the activation of dopamine receptors. Using rodent models, we previously reported that gating deficits caused by dopamine receptor activation - as measured by the prepulse inhibition (PPI) of startle - are effectively opposed by inhibitors of the steroidogenic enzyme 5α-reductase (5αR). The specific 5αR isoenzyme and steroids implicated in these effects, however, remain unknown. Methods The effects of the selective D1 dopamine receptor agonist SKF-82958 (SKF, 0.3 mg/kg, IP) and D2 receptor agonist quinpirole (QUIN, 0.5 mg/kg, IP) were tested in the startle reflex and PPI of knockout (KO) mice for either 5αR type 1 (5αR1) or type 2 (5αR2). Furthermore, we established whether these effects may be modified by the 5α-reduced steroids dihydroprogesterone (DHP), allopregnanolone (AP), dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol (3α-diol), or androsterone. To test the mechanisms whereby 5αR products may alter the PPI-disrupting properties of D1 agonists, we studied the involvement of GABA-A and PXR, two receptors targeted by neuroactive steroids. Specifically, we tested the effects of SKF in combination with the GABA-A antagonist bicuculline, as well as in KO mice for the GABA-A δ subunit and PXR. Results 5αR1, but not 5αR2, knockout (KO) mice were insensitive to the PPI-disrupting effects of SKF. This sensitivity was reinstated by AP (3 mg/kg, IP), but not other 5α-reduced steroids. The PPI deficits induced by SKF were not modified by bicuculline, δ-subunit KO mice and PXR KO mice. Conclusions These results collectively suggest that 5αR1 enables the negative effects of D1 dopamine receptor activation on information processing via production of AP. The contribution of AP to the PPI-disrupting mechanisms of D1 receptor agonists, however, do not appear to be mediated by either GABA-A or PXR receptors.

Acknowledgements. Funding for DIB was provided by NE/R018243/1 REBUS (Resolving Enthalpy Budget to Understand Surging). We present the first general theory of glacier surging that includes both temperate and polythermal glacier surges, based on coupled mass and enthalpy budgets. Enthalpy (in the form of thermal energy and water) is gained at the glacier bed from geothermal heating plus frictional heating (expenditure of potential energy) as a consequence of ice flow. Enthalpy losses occur by conduction and loss of meltwater from the system. Because enthalpy directly impacts flow speeds, mass and enthalpy budgets must simultaneously balance if a glacier is to maintain a steady flow. If not, glaciers undergo out-of-phase mass and enthalpy cycles, manifest as quiescent and surge phases. We illustrate the theory using a lumped element model, which parameterizes key thermodynamic and hydrological processes, including surface-to-bed drainage and distributed and channelized drainage systems. Model output exhibits many of the observed characteristics of polythermal and temperate glacier surges, including the association of surging behaviour with particular combinations of climate (precipitation, temperature), geometry (length, slope) and bed properties (hydraulic conductivity). Enthalpy balance theory explains a broad spectrum of observed surging behaviour in a single framework, and offers an answer to the wider question of why the majority of glaciers do not surge. Publisher PDF

Youth with a history of traumatic or non-traumatic acquired brain injury are at increased risk for long-lasting cognitive, emotional, behavioral, social, and physical sequelae post-injury. Such sequelae have great potential to negatively impact this population’s academic functioning. Consistently, poorer academic achievement and elevated need for educational supports have been well-documented among youth with a history of acquired brain injury. The current paper reviews the literature on neuropsychological, psychiatric, and academic outcomes of pediatric acquired brain injury. A discussion of special education law as it applies to this patient population, ongoing limitations within the field, and a proposal of solutions are also included.

SummaryHuman epithelial tissues accumulate cancer-driver mutations with age1–7, yet tumor formation remains rare. The positive selection of these mutations argues they alter the behavior and fitness of proliferating cells8–10. Hence, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less-competitive neighbors9–12. However, little is known about how such dynamic competition in normal epithelia impacts early tumorigenesis. Here we show that the majority of newly formed esophageal tumors are eliminated through competition with mutant clones in the surrounding normal epithelium. We followed the fate of microscopic tumors in a mouse model of esophageal carcinogenesis. Most neoplasms are rapidly lost despite no indication of tumor cell death, decreased proliferation, or an anti-tumor immune response. Deep-sequencing of 10-day and 1-year-old tumors shows evidence of genetic selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased tumor removal, while pharmacologically inhibiting clonal competition reduced tumor loss. The results are consistent with a model where survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the adjacent normal tissue. We have identified an unexpected anti-tumorigenic role for mutant clones in normal epithelium by purging early neoplasms through cell competition, thereby preserving tissue integrity.

SummaryNOTCH1mutant clones occupy the majority of normal human esophagus by middle age, but are comparatively rare in esophageal cancers, suggestingNOTCH1mutations may promote clonal expansion but impede carcinogenesis1–3. Here we test this hypothesis. Visualizing and sequencingNOTCH1mutant clones in aging normal human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygousNotch1mutation confers a competitive advantage over wild type cells, an effect enhanced by loss of the second allele.Notch1loss alters transcription but has minimal effects on epithelial structure and cell dynamics. In a carcinogenesis model,Notch1mutations were less prevalent in tumors than normal epithelium. Deletion ofNotch1reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. We conclude thatNotch1mutations in normal epithelium are beneficial as wild typeNotch1promotes tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.

BackgroundSyndromic gastrointestinal multiplex polymerase chain reaction (PCR) panels (GMPPs) are used by an increasing number of clinical laboratories to identify enteric pathogens. Vibrio species are included on GMPPs, but because of the low prevalence of vibriosis, performance characteristics for these panels have been difficult to measure.MethodsAll Vibrio spp. cases identified by GMPPs in Minnesota during 2016–2018 (n = 100) were assessed to identify differences between culture-confirmed cases and those that were PCR-positive only.ResultsOverall, 47% of cases had Vibrio species recovered by culture. Two GMPPs were used in Minnesota, Verigene EPT and FilmArray GIP, and the recovery rate of Vibrio spp. was significantly different between these platforms (Verigene EPT 63%, compared with FilmArray GIP 28%). No distinct seasonality was identified among GMPP-positive, culture-negative cases, whereas culture-confirmed case incidence peaked during July and August. Among cases with no other pathogen detected by the GMPP, confirmed cases reported a lower rate of bloody diarrhea (odds ratio [OR], 0.7; P = .004) and were less likely to have a symptom duration >14 days (OR, 0.3; P = .04). Confirmed cases were also more likely to include reports of consuming food items typically associated with Vibrio spp. infection or to have another likely source of infection (eg, international travel or contact with an untreated body of fresh or salt water or marine life; OR, 9.6; P = .001).ConclusionsThe combined findings indicate that cases identified by GMPP that did not have culture confirmation were less likely to include symptoms or exposures consistent with vibriosis. These findings emphasize the need for improvements to testing platform specificity and the importance of combining clinical and exposure information when diagnosing an infection. This study underscores the importance of maintaining the ability to culture Vibrio species to aid in accurate diagnoses.

Teams of manned and unmanned active sensors can provide tactical military units, search and rescue teams, and emergency response units with timely information; however, limited numbers of these systems mean their tasking must be prioritized, and the information they provide needs to be synthesized to avoid overwhelming users. Automated methods can fuse a priori and real-time information to provide decision-makers with time- critical situational awareness and a basis for search prioritization and route planning. Previous work has shown how expected entropic information gain can be used as a measure of utility in motion planning, though in multi- target search scenarios not all information is equally valuable. This research investigates generating certainty grids for dynamic search prioritization using a time-dependent cell valuation that incorporates entropy as well as threat- and geography-specific importance of information relative to the mission. We compare two different approaches to calculating posterior probability and entropy: a Bayesian log odds method based on prior works on obstacle avoidance; and a Dempster-Shafer Theory approach using a plausibility measure. The resulting weighted certainty grid map is provided for dynamic search. We then demonstrate how this adaptive, integrated situational awareness approach performs in different simulated, small unit tactical scenarios.

DNA double strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to expression of HR proteins, including BRCA1, BRCA2, PALB2 and RAD51, and DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection in LIN37-deficient G0 cells depends on BRCA1 and leads to RAD51 filament formation and HR. LIN37 is not required to protect DNA ends in cycling cells at G1-phase. Thus, LIN37 regulates a novel 53BP1-independent cell phase-specific DNA end protection pathway that functions uniquely in quiescent cells.