Search

In species with vocal learning, acquiring species-typical vocalizations relies on early social orienting. In songbirds, for example, learning song requires dynamic social interactions with a “tutor” during an early sensitive period. Here, we hypothesized that the attentional and motivational processes that support song learning recruit the oxytocin system, which is well-understood to play a role in social orienting in other species. Juvenile male zebra finches naïve to song were each tutored by two unfamiliar adult males. Before exposure to one tutor, juveniles were injected subcutaneously with oxytocin receptor antagonist (OTA; ornithine vasotocin) and before exposure to the other, saline (control). Treatment with OTA reduced behaviors associated with approach and attention during tutoring sessions. Using a novel operant paradigm to measure preference while balancing exposure to the two tutor songs, we showed that the juveniles preferred to hear the song of the control tutor. Their adult songs more closely resembled the control tutor’s song, and the magnitude of this difference was predicted by early preference for control over OTA song. Overall, oxytocin antagonism during exposure to a tutor seemed to bias juveniles against that tutor and his song. Our results suggest that oxytocin receptors are important for socially-guided vocal learning.

Significance Increased rates of smoking cessation will be essential to maximize the population benefit of low-dose CT screening for lung cancer. The NCI’s Smoking Cessation at Lung Examination (SCALE) Collaboration includes eight randomized trials, each assessing evidence-based interventions among smokers undergoing lung cancer screening (LCS). We examined predictors of trial enrollment to improve future outreach efforts for cessation interventions offered to older smokers in this and other clinical settings. Methods We included the six SCALE trials that randomized individual participants. We assessed demographics, intervention modalities, LCS site and trial administration characteristics, and reasons for declining. Results Of 6285 trial- and LCS-eligible individuals, 3897 (62%) declined and 2388 (38%) enrolled. In multivariable logistic regression analyses, Blacks had higher enrollment rates (OR 1.5, 95% CI 1.2,1.8) compared to Whites. Compared to “NRT Only” trials, those approached for “NRT + prescription medication” trials had higher odds of enrollment (OR 6.1, 95% CI 4.7,7.9). Regarding enrollment methods, trials using “Phone + In Person” methods had higher odds of enrollment (OR 1.6, 95% CI 1.2,1.9) compared to trials using “Phone Only” methods. Some of the reasons for declining enrollment included “too busy” (36.6%), “not ready to quit” (8.2%), “not interested in research” (7.7%), and “not interested in the intervention offered” (6.2%). Conclusion Enrolling smokers in cessation interventions in the LCS setting is a major priority that requires multiple enrollment and intervention modalities. Barriers to enrollment provide insights that can be addressed and applied to future cessation interventions to improve implementation in LCS and other clinical settings with older smokers. Implications We explored enrollment rates and reasons for declining across six smoking cessation trials in the lung cancer screening setting. Offering multiple accrual methods and pharmacotherapy options predicted increased enrollment across trials. Enrollment rates were also greater among Blacks compared to Whites. The findings offer practical information for the implementation of cessation trials and interventions in the lung cancer screening context and other clinical settings, regarding intervention modalities that may be most appealing to older, long-term smokers.

As one of the Arctic Council’s permanent observer states, South Korea has implemented various policies related to the Arctic despite its significant geographical and cultural distance from the Arct...

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

We investigated efficacy of in ovo application of epidermal growth factor (EGF) on intestinal expression of EGF receptor (EGFR) during embryogenesis (experiment 1) and posthatch growth performance and gastrointestinal development in broiler chickens (experiment 2). In experiment 1, 450 fertile Ross 708 eggs were allocated to 3 groups (150 eggs/group): 1) control, 2) 160 μg EGF/kg of egg, and 3) 640 μg of EGF/kg of egg. Eggs were candled for live embryos on day 16 and injected with the respective treatment solutions on day 17 and sampled for jejunal tissue from day 17 to hatch for EGFR analyses. There was no effect of EGF (P > 0.05) on EGFR expression on day 17 to 20; however, on day 21, EGF increased (P < 0.05) EGFR expression in EGF birds relative to control birds. In experiment 2, 600 fertile Ross 708 eggs were allocated to 5 treatments: 1) intact, no puncture or injection, 2) punched but not injected, 3) control, no EGF, 4) 80 μg of EGF/kg of egg, and 5) 160 μg of EGF/kg of egg. The eggs were incubated and candled for live embryos on D 19, treated, and subsequently transferred to the hatcher. Upon hatching, chicks were weighed, and 90 chicks per treatment placed in cages (15 birds/cage) and allowed free access to a standard antibiotic-free corn-soybean diet for 21 D. Feed intake and body weight were monitored on a weekly basis. Samples of birds were necropsied on D 0, 7, 14, and 21 for measurements of intestinal weight and jejunal histomorphology and excreta samples taken on D 3 to 5 and 17 to 19 for apparent retention of dry matter. There was no EGF effect (P > 0.05) on any posthatch response criteria. In conclusion, in ovo application of EGF increased EGFR expression but had no effect on posthatch growth performance, DM retention, and intestinal development. The lack of EGF effect on posthatch response was surprising but suggested in ovo application of EGF may not be a viable approach.

The effect of Eimeria challenge on standardized ileal digestibility (SID) of amino acids (AA) in major poultry feed ingredients fed to broiler chickens was determined. A total of 840 male 9-day-old Ross 708 chicks were placed in 84 cages (10 birds/cage) and allocated to either a nitrogen-free diet (NFD) or one of the 6 test diets based on a single or mixture of feed ingredients as the sole source of AA (n = 12). Test diets were: 1) corn, 2) wheat, 3) soybean meal (SBM), 4) pork meal (PM), 5) corn, SBM, and PM (CSP), and 6) wheat, SBM, and PM (WSP). On d 10, birds in 6 cages/diet were orally gavaged with 1 mL of E. acervulina and E. maxima mixture and the other 6 cages with sham. On d 15, birds were bled for plasma AA and necropsied for intestinal lesion scores and ileal digesta samples. Challenge decreased (P0.05) plasma concentration of Arg, His, Thr, Asp, Gln, and Tyr and increased concentration of Lys, Ile, Leu, and Val. There was a diet by challenge interaction (P0.05) on intestinal lesion scores with birds fed mixed diets exhibiting more severe lesions than birds fed single ingredient diets. Diet by challenge interacted (P0.05) on ileal total endogenous flow (ITEF) of AA except for Arg, Met, Ala, Asp, and Cys, such that challenged birds fed the mixed, particularly WSP, had higher ITEF of AA compared to single ingredients birds. Diet and challenge interaction (P0.05) was observed for SID of Arg, Thr, Val, Glu, and Gly. Challenge decreased (P0.05) SID of most AA except for Met, Asp, and Cys with the largest impact seen on Lys, His, Ser, and Thr. With exception of Arg, Thr, Asp, and Cys, birds fed mixed diets had higher (P0.05) SID values compared to birds fed single ingredients. In conclusion, Eimeria reduced plasma availability and ileal digestibility of most AA. However, challenge interaction with diet composition on SID of some AA warrants further investigations.

Physical therapy is important for the treatment and prevention of musculoskeletal injuries, as well as recovery from surgery. In this paper, we explore techniques for automatically determining whether an exercise was performed correctly or not, based on camera images and wearable sensors. Classifiers were tested on data collected from 30 patients during normally-scheduled physical therapy appointments. We considered two lower limb exercises, and asked how well classifiers could generalize to the assessment of individuals for whom no prior data were available. We found that our classifiers performed well relative to several metrics (mean accuracy: 0.76, specificity: 0.90), but often returned low sensitivity (mean: 0.34). For one of the two exercises considered, these classifiers compared favorably with human performance.

BACKGROUND Intraventricular brain tumors make up only 0.9–4.5% of all cases of metastatic brain cancer.1 Involvement of the choroid plexus (CP) is even rarer with only a handful of documented cases. 2,3 Here we describe a case of bilateral multifocal metastasis to the choroid plexus appearing 10 years after nephrectomy in a male with stage IV renal cell carcinoma (RCC). CASE PRESENTATION: Our patient is a 74-year-old male with stage IV RCC diagnosed in 2006 and treated with radical nephrectomy and immunotherapy in 2011. In 2020, he presented to the emergency department with altered mental status. Brain magnetic resonance imaging (MRI) revealed an enhancing hemorrhagic lesion in the trigone of the right lateral ventricle (LV) and nodular thickening in the center of the right LV and trigone of the left LV, suggestive of metastatic disease. In 2021, the patient developed refractory seizures, and serial MRIs showed disease progression. He underwent several craniotomies with pathology confirming metastatic clear cell carcinoma, consistent with a renal primary. In 2022, the patient again presented with altered mental status. MRI revealed new avidly enhancing subcentimeter solid nodules in the CP of both LVs consistent with metastatic disease. Per the wishes of the family, palliative measures were pursued, and the patient was discharged home. CONCLUSION RCC can reappear several years after nephrectomy. 4 Metastatic RCC appears to have a unique propensity to spread to the ventricular system and the CP, which indicates late progression of disease. 1,5,6 While surgery may be viable if tumor burden is low, therapeutic options are limited in the advanced disease stages, as in our patient. Palliative care should be offered early to maximize remaining quality of life.

Von Hippel–Lindau disease (VHL) is a hereditary disorder associated with malignant tumors including clear cell renal cell carcinoma (ccRCC). Partial nephrectomy is complicated by multilocular tumor occurrence and a high recurrence rate. The aim of this study was to evaluate the potential of stereotactic body radiotherapy (SBRT) as an alternative treatment approach in VHL patients with multiple ccRCC. Patients with VHL and a diagnosis of ccRCC were enrolled. SBRT was conducted using five fractions of 10 Gy or eight fractions of 7.5 Gy. The primary endpoint was local control (LC). Secondary endpoints included alteration of renal function and adverse events. Seven patients with a total of eight treated lesions were enrolled. Median age was 44 years. Five patients exhibited multiple bilateral kidney cysts in addition to ccRCC. Three patients underwent at least one partial nephrectomy in the past. After a median follow-up of 43 months, 2-year LC was 100%, while 2-year CSS, 2-year PFS and 2-year OS was 100%, 85.7% and 85.7%, respectively. SBRT was very well tolerated with no acute or chronic toxicities grade ≥ 2. Mean estimated glomerular filtration rate (eGFR) at baseline was 83.7 ± 13.0 mL/min/1.73 m2, which decreased to 76.6 ± 8.0 mL/min/1.73 m2 after 1 year. Although the sample size was small, SBRT resulted in an excellent LC rate and was very well tolerated with preservation of kidney function in patients with multiple renal lesions and cysts.

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.

Lung cancer mortality can be reduced by 20% via low dose CT lung cancer screening (LCS) and treatment of early-stage disease. Providing tobacco use treatment to high risk cigarette smokers in the LCS setting may result in health benefits beyond the impact of LCS. As one of the nine trials in the National Cancer Institute's Smoking Cessation at Lung Examination (SCALE) collaboration, the goal of the Lung Screening, Tobacco, and Health (LSTH) trial is to develop a scalable and cost-effective cessation intervention for subsequent implementation by LCS programs. Guided by the RE-AIM Framework, the LSTH trial is a two-arm RCT ( N = 1330) enrolling English- and Spanish-speaking smokers registered for LCS at one of seven collaborating sites. Participants are randomly assigned to Usual Care (UC; three proactive telephone counseling sessions/two weeks of nicotine patches) vs. Intensive Telephone Counseling (ITC; eight proactive sessions/eight weeks of nicotine patches, plus discussion of the LCS results to increase motivation to quit). Telephone counseling is provided by tobacco treatment specialists. To increase continuity of care, referring physicians are notified of participant enrollment and smoking status following the intervention. Outcomes include: 1) self-reported 7-day, 30-day, and sustained abstinence, and biochemically-verified at 3-, 6-, and 12-months post-randomization, 2) reach and engagement of the interventions, and 3) cost-effectiveness of the interventions. The Cancer Intervention and Surveillance Modeling Network (CISNET) will model long-term impacts of six SCALE trials on the cost per life year saved, quality-adjusted life years saved, lung cancer mortality reduction, and population mortality. Clinical trials registration The trial is registered at clinical trials.gov : NCT03200236 .

Evolutionary theories of disease avoidance propose that humans have a set of universal psychological processes to detect environmental cues indicative of infectious disease. These processes then initiate cognitive, emotional, and behavioral responses that function to limit contact with harmful pathogens. Here, we study the conditions under which people exhibit behavioral avoidance of others with a contagious illness or a physical injury (i.e., a broken leg), and the potential mechanisms that underlie this behavior. Across three studies, participants were given the option of sitting at one of two workstations previously occupied by two confederates, one of whom either showed visible symptoms of a cold (contagion condition), wore a lower-leg orthopedic boot and used crutches (broken leg condition), or showed no signs of illness or physical injury (control). We found strong evidence that adults explicitly avoid contact with individuals who show symptoms of a contagious illness. Further, we provide some evidence that adults also avoid individuals with a physical injury, but that this behavior might be driven by implicit, unconscious processes. The findings are discussed in terms of implications for the healthy avoidance of contagion, and the risk for potential stigmatization of non-contagious groups.

How do different government mandates compare in their short and long-term efficacies in curbing COVID-19 infections? Does a mandate’s early adoption enhance its eventual efficacy? Using worldwide data on the daily evolution of government mandate adoptions and COVID-19 infections from January to July 2020, we found that, compared with five other commonly adopted mandates, early adoption of the mask mandate has the strongest short and long-term effect on curbing infections. Mass gathering bans and school closures have some effect but take more time to manifest their efficacy. Domestic lockdowns and restaurant closures have the least effect. When designing measures for curbing COVID-19 infections, governments must weigh the timing and relative efficacies of alternative policy instruments.

Prior research documents that analyst revisions are important information events and that some investors trade ahead of them. However, prior studies have been unable to show which investors trade ahead of analyst revisions, the aggregate benefits to trading ahead, and the costs borne by various investors from trading against investors that anticipate revisions. To address these questions, we exploit high-frequency trading information from the Korea Exchange (KRX) that characterizes all purchase and sale transactions of twenty different investor groups. We first validate that analyst revisions contain valuable private information: upgrades increase prices by 2.5% and downgrades decrease prices by 2.9%. We next document that asset managers who are geographically and socially close to analysts anticipate recommendations up to two days before they are released, while other institutions do not. Lastly, we show that this ability to anticipate analyst revisions enables these investors to trade profitably against domestic retail investors and foreign professional investors. Local hedge funds earn $2.5 million more than normal when trading against foreign professionals ahead of analyst revisions, which is more than all other investor groups combined. Notably, local asset managers typically lose money when trading against foreign professionals, who seem to earn profits by engaging in high-frequency market making. In sum, asset managers in Korea appear to receive tips from brokerages about upcoming revisions, which shifts the competitive balance between domestic institutions and skilled foreign market makers, and aggregate profits around revisions depend on investor sophistication, geographic proximity, and cultural affinity.

Transmetatarsal amputation (TMA) is performed in patients with nonhealing wounds of the forefoot. Compared with below-knee amputations, healing after TMA is less reliable, and often leads to subsequent higher-level amputation. The aim of this study was to evaluate the functional and patient-reported outcomes of TMA.A retrospective review of patients who underwent TMA from 2013 to 2021 at our limb-salvage center was conducted. Primary outcomes included postoperative complications, secondary proximal lower extremity amputation, ambulatory status, and mortality. Univariate and multivariate analyses were performed to evaluate independent risk factors for higher-level amputation after TMA. Patient-reported outcome measures for functionality and pain were also obtained.A total of 146 patients were identified. TMA success was achieved in 105 patients (72%), and 41 patients (28%) required higher-level amputation (Lisfranc: 31.7%, Chopart: 22.0%, below-knee amputations: 43.9%). There was a higher incidence of postoperative infection in patients who subsequently required proximal amputation (39.0 versus 9.5%,TMA healing remains variable, and many patients will eventually require a secondary proximal amputation. Multi-institutional studies are warranted to identify perioperative risk factors for higher-level amputation and to further evaluate patient-reported outcomes.

Introduction Changing demographics have created substantial unmet needs for mental health and physical disability services for immigrant and racial/ethnic minority elders. Workforce shortages can be reduced by task-shifting to community health workers (CHWs) who speak the same language and share the culture of these elders. Yet, implementation of interventions offered by CHWs requires adaptations of content and delivery, ideally under clinical supervision. Objective To culturally adapt two evidence-based interventions, offered in community settings, to address mental health and physical disability prevention for diverse minority elders. Methods We followed the Castro-Barrera stepped model for cultural adaptation of two evidence-based interventions into one combined program of disability management and prevention delivered by CHWs. We used feedback from key stakeholders, including four clinical supervisors, 16 CHWs, 17 exercise trainers, and 153 participants, collected at three time points to further adapt the intervention to a diverse population of elders. Results Adaptations for administration by CHWs/exercise trainers included: systematization of supervision process, increased flexibility in sessions offered per participants’ needs, inclusion of self-care content, modification of materials to better reflect elders’ daily life experiences, and greater focus on patient engagement in care. Areas for additional adaptation included enhancing examples with culturally relevant metaphors, incorporating visual aids, and training CHWs in the importance of building trust. Conclusion This study identifies key aspects of the cultural adaptation process that facilitates broader cultural sensitivity of service delivery by CHWs to diverse elders in community settings.

Protestants were more likely than non-Protestants to demonstrate phenomena consistent with the use of reaction formation. Lab experiments showed that when manipulations were designed to produce taboo attractions (to unconventional sexual practices), Protestants instead showed greater repulsion. When implicitly conditioned to produce taboo repulsions (to African Americans), Protestants instead showed greater attraction. Supportive evidence from other studies came from clinicians' judgments, defense mechanism inventories, and a survey of respondent attitudes. Other work showed that Protestants who diminished and displaced threatening affect were more likely to sublimate this affect into creative activities; the present work showed that Protestants who do not or cannot diminish or displace such threatening affect instead reverse it. Traditional individual difference variables showed little ability to predict reaction formation, suggesting that the observed processes go beyond what we normally study when we talk about self-control. (PsycINFO Database Record

In July 2019, the Trump administration began implementing its domestic gag rule to ban discussion of abortion in pregnancy options counseling and ensure physical separation of contraceptive and abortion services at clinical sites funded by the federal government's Title X Family Planning program. In this paper, we examine how organizational policy utilization correlated with organization-level protocols for discussing abortion in options counseling interactions while the domestic gag rule policy was under legal contest. From April 2018 to July 2019, we conducted in-depth interviews with 50 administrators in charge of setting clinical protocols regarding options counseling after a positive pregnancy test at 20 Title X-covered and 14 non-Title X-covered safety-net healthcare organizations in Ohio. We found that organizational characteristics and Title X policy utilization did not explain the heterogeneity in approaches to abortion referral that administrators reported. Administrators from 2 of 20 organizations covered by Title X policy requirements pre-emptively restricted discussion of abortion in their facilities in advance of policy enactment. Meanwhile, administrators from 10 of 14 non-Title X-covered organizations did not restrict discussion of abortion. Our analysis demonstrates how safety-net healthcare organizations' response to federal policy is shaped by administrators' institutional entrepreneurship within the abortion aversion complex: a pattern of policy miscomprehension and endorsed abortion stigma that facilitates the structural stigmatization of abortion within safety-net healthcare organizations. We conclude that current efforts to reverse the domestic gag rule will fail unless local abortion aversion complexes are targeted with intervention.

Significance Although it is a requirement that tobacco treatment is offered to cigarette smokers undergoing low-dose computed tomographic lung cancer screening (LCS), not all smokers engage in treatment. To understand the barriers to tobacco treatment in this setting, we evaluated predictors of attrition in a smoking cessation trial among individuals undergoing LCS. Methods Prior to LCS, 926 participants, 50–80 years old, completed the baseline (T0) phone assessment, including demographic, clinical, tobacco, and psychological characteristics. Following LCS and receipt of the results, participants completed the pre-randomization (T1) assessment. Results At the T1 assessment, 735 (79%) participants were retained and 191 (21%) dropped out. In multivariable analyses, attrition was higher among those who: smoked >1 pack per day (OR = 1.44, CI 1.01, 2.06) or had undergone their first (vs. annual) LCS scan (OR = 1.70, CI 1.20, 2.42). Attrition was lower among those with: more education (associates (OR = 0.67, CI = 0.46, 0.98) or bachelor's degree (OR = 0.56, CI 0.35, 0.91) vs. high school/GED), some (vs. none/a little) worry about lung cancer (OR = 0.60, CI 0.39, 0.92), or a screening result that was benign (OR = 0.57, CI 0.39, 0.82) or probably benign (OR = 0.38, CI 0.16, 0.90) vs. negative. Conclusions This study illuminated several LCS-related factors that contributed to trial attrition. Increasing tobacco treatment in this setting will require targeted strategies for those who. report little lung cancer worry, are undergoing their first LCS exam, and/or who have a negative LCS result. Addressing attrition and reducing barriers to tobacco treatment will increase. the likelihood of cessation, thereby reducing the risk of developing lung cancer.

Western culture has 2 contradictory images of creativity: the artist as intensely emotional versus the artist as sublimator, for whom work becomes the outlet for what is repressed and denied. We show that both images are correct, but that the routes to creativity are culturally patterned, such that Catholic creatives are relatively more likely to take the emotionally intense route and Protestant creatives relatively more likely to take the sublimating route. This pattern is consistent for both the Big-C creativity of historical eminents (Studies 1 and 1b) and small-c creativity of student samples (Studies 2 and 3). The student samples also highlighted the moderating role of Protestant asceticism, as Protestants who were high in asceticism and who also repressed or minimized troublesome emotions were particularly creative. Analyses of behavioral data in previous lab experiments (Studies 2b and 3b) provided conceptual validation of the findings reported in Studies 2 and 3. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

In this chapter, we will provide an overview of the development of fear across infancy and early childhood. First, we describe various theoretical accounts of emotion and their implications for studying fear across development. Next, we describe the perception of threat, including how infants and young children first come to recognize and differentiate a fearful face from other emotional expressions and when they begin to detect signals of threat in the environment. We then describe the developmental trajectory of fearful behavior starting with infancy. We discuss the most commonly experienced fears from infancy to adulthood and how these fears might be acquired. Finally, we describe the neurological underpinnings of fear learning throughout development and close with a few thoughts on future directions for studying fear over the life span.

Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.

von Hippel–Lindau (VHL) disease is an autosomal dominant syndrome caused by mutations in the VHL tumor-suppressor gene, leading to the dysregulation of many hypoxia-induced genes. Affected individuals are at increased risk of developing recurrent and bilateral kidney cysts and dysplastic lesions which may progress to clear cell renal cell carcinoma (ccRCC). Following the eponymous VHL gene inactivation, ccRCCs evolve through additional genetic alterations, resulting in both intratumor and intertumor heterogeneity. Genomic studies have identified frequent mutations in genes involved in epigenetic regulation and phosphoinositide 3-kinase–AKT–mechanistic target of rapamycin (mTOR) pathway activation. Currently, local therapeutic options include nephron-sparing surgery and alternative ablative procedures. For advanced metastatic disease, systemic treatment, including inhibition of vascular endothelial growth factor pathways and mTOR pathways, as well as immunotherapy are available. Multimodal therapy, targeting multiple signaling pathways and/or enhancing the immune response, is currently being investigated. A deeper understanding of the fundamental biology of ccRCC development and progression, as well as the development of novel and targeted therapies will be accelerated by new preclinical models, which will greatly inform the search for clinical biomarkers for diagnosis, prognosis, and response to treatment.

Sublimation is a process whereby forbidden thoughts and emotions are channeled into productive and often creative ends. Recent experiments and surveys have provided evidence for sublimation and have also suggested variation, such that Protestants (compared with Catholics and Jews) were more likely to minimize troublesome affect and displace it into creative work. Emotion per se did not induce sublimation among Protestants; rather, it was the forbidden or suppressed nature of the emotion that was important. Attending to the religious and cultural dimensions of thought and to dual-process theories of the mind can help us understand responses to the human predicament of encountering the forbidden.

BACKGROUND AND OBJECTIVE: Pediatric cervical spine injuries (CSIs) are rare and differ from adult CSIs. Our objective was to describe CSIs in a large, representative cohort of children. METHODS: We conducted a 5-year retrospective review of children RESULTS: A total of 540 children with CSIs were included in the study. CSI level was associated with both age and mechanism of injury. For children CONCLUSIONS: We demonstrated a high degree of variability of CSI patterns, treatments and outcomes in children. The rarity, variation, and morbidity of pediatric CSIs make prompt recognition and treatment critical.

It was hypothesized that students’ learning would be enhanced by an intervention getting them to elaborate on and restructure the notes they had taken in lecture. Students in a research methods course were randomly assigned to weeks in which they would turn in a copy of their restructured lecture notes along with a very brief summary of the class. This intervention required students to spend quality time-on-task. Subsequently, results of exam questions from weeks in which students completed the intervention were compared to weeks they did not do so. The intervention improved student performance by a full class grade (11 percent, effect size d = 1.1) and it improved performance equally for students at the top, bottom, and middle of the class.

Components of the KDM7 family of histone demethylases are implicated in neuronal development and one member, PHF8, is often found to be mutated in cases of X-linked mental retardation. However, how PHF8 regulates neurodevelopmental processes and contributes to the disease is still largely unknown. Here, we show that the catalytic activity of a PHF8 homolog in Caenorhabditis elegans, JMJD-1.2, is required non-cell-autonomously for proper axon guidance. Loss of JMJD-1.2 dysregulates transcription of the Hedgehog-related genes wrt-8 and grl-16, the overexpression of which is sufficient to induce the axonal defects. Deficiency of either wrt-8 or grl-16, or reduced expression of homologs of genes promoting Hedgehog signaling, restores correct axon guidance in jmjd-1.2 mutants. Genetic and overexpression data indicate that Hedgehog-related genes act on axon guidance through actin remodelers. Thus, our study highlights a novel function of jmjd-1.2 in axon guidance that might be relevant for the onset of X-linked mental retardation and provides compelling evidence of a conserved function of the Hedgehog pathway in C. elegans axon migration.

Study objective Cervical spine injuries in children are rare. However, immobilization and imaging for potential cervical spine injury after trauma are common and are associated with adverse effects. Risk factors for cervical spine injury have been developed to safely limit immobilization and radiography in adults, but not in children. The purpose of our study is to identify risk factors associated with cervical spine injury in children after blunt trauma. Methods We conducted a case-control study of children younger than 16 years, presenting after blunt trauma, and who received cervical spine radiographs at 17 hospitals in the Pediatric Emergency Care Applied Research Network (PECARN) between January 2000 and December 2004. Cases were children with cervical spine injury. We created 3 control groups of children free of cervical spine injury: (1) random controls, (2) age and mechanism of injury-matched controls, and (3) for cases receiving out-of-hospital emergency medical services (EMS), age-matched controls who also received EMS care. We abstracted data from 3 sources: PECARN hospital, referring hospital, and out-of-hospital patient records. We performed multiple logistic regression analyses to identify predictors of cervical spine injury and calculated the model's sensitivity and specificity. Results We reviewed 540 records of children with cervical spine injury and 1,060, 1,012, and 702 random, mechanism of injury, and EMS controls, respectively. In the analysis using random controls, we identified 8 factors associated with cervical spine injury: altered mental status, focal neurologic findings, neck pain, torticollis, substantial torso injury, conditions predisposing to cervical spine injury, diving, and high-risk motor vehicle crash. Having 1 or more factors was 98% (95% confidence interval 96% to 99%) sensitive and 26% (95% confidence interval 23% to 29%) specific for cervical spine injury. We identified similar risk factors in the other analyses. Conclusion We identified an 8-variable model for cervical spine injury in children after blunt trauma that warrants prospective refinement and validation.

Mutations of inversin cause type II nephronophthisis, an infantile autosomal recessive disease characterized by cystic kidney disease and developmental defects. Inversin regulates Wnt signaling and is required for convergent extension movements during early embryogenesis. We now show that Inversin is essential for Xenopus pronephros formation, involving two distinct and opposing forms of cell movements. Knockdown of Inversin abrogated both proximal pronephros extension and distal tubule differentiation, phenotypes similar to that of Xenopus deficient in Frizzled-8. Exogenous Inversin rescued the pronephric defects caused by lack of Frizzled-8, indicating that Inversin acts downstream of Frizzled-8 in pronephros morphogenesis. Depletion of Inversin prevents the recruitment of Dishevelled in response to Frizzled-8 and impeded the accumulation of Dishevelled at the apical membrane of tubular epithelial cells in vivo. Thus, defective tubule morphogenesis seems to contribute to the renal pathology observed in patients with nephronophthisis type II.

The aim of the current study was to examine the association between psychopathic features and various forms of relationship aggression in a non-clinical population. Additionally, exposure to media aggression was examined as a potential mediator of the relationship between psychopathy and aggression. Participants consisted of a total of 337 individuals who either reported on their current or most recent relationship. Results revealed that secondary psychopathy traits were related to both types of aggression measured in the current study (physical aggression and romantic relational aggression). Additionally, primary psychopathy traits were related to romantic relational aggression. Though exposure to media aggression (both physical and relational forms) was related to perpetration of relationship aggression, such exposure did not mediate the relationship between psychopathy and aggression.

Lmx1b is a LIM-homeodomain transcription factor that has dorsally restricted expression in limb mesoderm and is responsible for limb dorsalization. Mice lacking functional Lmx1b exhibit ventral-ven...

Purpose The effect of pharmacy students as primary pharmacy members on inpatient interdisciplinary mental health teams was investigated. Methods This retrospective study used Veterans Affairs data from veterans who were admitted to an inpatient mental health unit from January 1, 2010, through December 31, 2012. Eligible veterans had to have been hospitalized for at least five days and treated with at least five scheduled medications during the hospitalization. Information collected by the investigators included patient age, psychiatric diagnoses, accuracy of medication reconciliation on admission and at discharge, and readmission rates within six months and one year. Additional information collected included monitoring parameters for lithium, divalproex, first-generation antipsychotics, and second-generation antipsychotics. The primary outcome was the percentage of accurate medication reconciliations for treatment teams with a fourth-year pharmacy student and without a pharmacy student. Clinical monitoring and readmission rates were also compared. Results A total of 526 patients were eligible for study inclusion. Medication reconciliation was performed on admission for all patients followed by a team involving a pharmacy student (experimental group), but only 51% of patients in the control group had documented medication reconciliations in the medical chart. Of the medication reconciliations completed, 82% were performed correctly in the experimental group, compared with 61% when a pharmacy student was not involved ( p = 0.006). There were no significant differences between groups in psychotropic monitoring and readmission rates. Conclusion The presence of fourth-year pharmacy students on inpatient mental health interdisciplinary teams was associated with more frequent interventions, patient counseling, and medication reconciliation, compared with rates for teams without a pharmacy student. Medication reconciliation was performed more consistently and accurately when the teams had a pharmacy student than when they did not.

Regulators of G protein signaling (RGS) constitute a family of proteins with a conserved RGS domain of approximately 120 amino acids that accelerate the intrinsic GTP hydrolysis of activated Galpha(i) and Galpha(q) subunits. The phosphorylation-dependent interaction of 14-3-3 proteins with a subset of RGS proteins inhibits their GTPase-accelerating activity in vitro. The inhibitory interaction between 14-3-3 and RGS7 requires phosphorylation of serine 434 of RGS7. We now show that phosphorylation of serine 434 is dynamically regulated by TNF-alpha. Cellular stimulation by TNF-alpha transiently decreased the phosphorylation of serine 434 of RGS7, abrogating the inhibitory interaction with 14-3-3. We examined the effect of 14-3-3 on RGS-mediated deactivation kinetics of G protein-coupled inwardly rectifying K(+) channels (GIRKs) in Xenopus oocytes. 14-3-3 inhibited the function of wild-type RGS7, but not that of either RSG7(P436R) or RGS4, two proteins that do not bind 14-3-3. Our findings are the first evidence that extracellular signals can modulate the activity of RGS proteins by regulating their interaction with 14-3-3.

Using dexfenfluramine as unconditional stimulus (US), the authors confirmed that sham-operated and area postrema (AP)-lesioned rats form comparable conditioned flavor avoidances. When lithium chloride (LiCI) was used as the US, AP-lesioned rats did not learn to avoid a drug-paired flavor conditional stimulus (CS+). Sham-operated, but not AP-lesioned, rats had low intakes of the placebo-paired flavor (CS-), which suggests that the lesions disrupted generalization of avoidance. Generalized avoidance in intact rats was similar when either sweetened milk or Polycose was used as the caloric vehicle for the CSs. When flavored gels of Polycose were used as CSs, C57BL/6J mice developed flavor avoidance with either LiCl or dexfenfluramine as US. Compared with rats, mice required higher doses of these agents, avoidance was not complete after many pairings, and there was no generalization to the CS-.

In this article, we review the history and progress of a large multicenter research network pertaining to emergency medical services for children. We describe the history, organization, infrastructure, and research agenda of the Pediatric Emergency Care Applied Research Network (PECARN), and highlight some of the important accomplishments since its inception. We also describe the network’s strategy to grow its research portfolio, train new investigators, and study how to translate new evidence into practice. This strategy ensures not only the sustainability of the network in the future, but the growth of research in emergency medical services for children in general.

The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes, PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase C (PKC) epsilon, a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N', N'-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC alpha and PKC epsilon, respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts.

The recently discovered family of regulators of G protein signaling (RGS) accelerates the intrinsic GTPase activity of certain Gα subunits, thereby terminating G protein signaling. Particularly high mRNA levels of one family member, RGS3, are found in the adult kidney. To establish the temporal and spatial renal expression pattern of RGS3, a polyclonal antiserum was raised against the COOH terminus of RGS3. Staining of mouse renal tissue at different gestational stages revealed high levels of RGS3 within the developing and mature tubular epithelial cells. We tested whether RGS3 can modulate tubular migration, an important aspect of tubular development, in response to G protein-mediated signaling. Several mouse intermedullary collecting duct (mIMCD-3) cell lines were generated that expressed RGS3 under the control of an inducible promoter. Lysophosphatidic acid (LPA) is a potent chemoattractant that mediates its effects through heterotrimeric G proteins. We found that induction of RGS3 significantly reduced LPA-mediated cell migration in RGS3-expressing mIMCD-3 clones, whereas chemotaxis induced by hepatocyte growth factor remained unaffected by RGS3. Our findings suggest that RGS3 modulates tubular functions during renal development and in the adult kidney.

Two distinct signaling pathways, involving Wnt signaling and polycystin, have been found to be critical for normal kidney development. Renal tubulogenesis requires the presence of certain Wnt proteins, whereas mutations in polycystin impede the terminal differentiation of renal tubular epithelial cells, causing the development of large cystic kidneys that characterize autosomal dominant polycystic kidney disease. Polycystin is an integral membrane protein, consisting of several extracellular motifs indicative of cell-cell and cell-matrix interactions, coupled through multiple transmembrane domains to a functionally active cytoplasmic domain. We report here that expression of the C-terminal cytoplasmic domain of polycystin stabilizes soluble endogenous β-catenin and stimulates TCF- dependent gene transcription in human embryonic kidney cells. Microinjection of the polycystin C-terminal cytoplasmic domain induces dorsalization in zebrafish. Our findings suggest that polycystin has the capacity to modulate Wnt signaling during renal development.

An inherited form of kidney disease results from defects in the cilium. Mouse knockout experiments now explore how cilia help guide the organ into the right shape—and hint that these tiny antennae may also help regulate food intake (pages 1490–1495).