Humans can navigate complex graph structures acquired during latent learning.

Humans appear to represent many forms of knowledge in associative networks whose nodes are multiply connected, including sensory, spatial, and semantic. Recent work has shown that explicitly augmenting artificial agents with such graph-structured representations endows them with more human-like capabilities of compositionality and transfer learning. An open question is how humans acquire these representations. Previously, it has been shown that humans can learn to navigate graph-structured conceptual spaces on the basis of direct experience with trajectories that intentionally draw the network contours (Schapiro, Kustner, & Turk-Browne, 2012; Schapiro, Turk-Browne, Botvinick, & Norman, 2016), or through direct experience with rewards that covary with the underlying associative distance (Wu, Schulz, Speekenbrink, Nelson, & Meder, 2018). Here, we provide initial evidence that this capability is more general, extending to learning to reason about shortest-path distances across a graph structure acquired across disjoint experiences with randomized edges of the graph - a form of latent learning. In other words, we show that humans can infer graph structures, assembling them from disordered experiences. We further show that the degree to which individuals learn to reason correctly and with reference to the structure of the graph corresponds to their propensity, in a separate task, to use model-based reinforcement learning to achieve rewards. This connection suggests that the correct acquisition of graph-structured relationships is a central ability underlying forward planning and reasoning, and may be a core computation across the many domains in which graph-based reasoning is advantageous.

Increased and biased deliberation in social anxiety.

A goal of computational psychiatry is to ground symptoms in basic mechanisms. Theory suggests that avoidance in anxiety disorders may reflect dysregulated mental simulation, a process for evaluating candidate actions. If so, these covert processes should have observable consequences: choices reflecting increased and biased deliberation. In two online general population samples, we examined how self-report symptoms of social anxiety disorder predict choices in a socially framed reinforcement learning task, the patent race, in which the pattern of choices reflects the content of deliberation. Using a computational model to assess learning strategy, we found that self-report social anxiety was indeed associated with increased deliberative evaluation. This effect was stronger for a particular subset of feedback ('upward counterfactual') in one of the experiments, broadly matching the biased content of rumination in social anxiety disorder, and robust to controlling for other psychiatric symptoms. These results suggest a grounding of symptoms of social anxiety disorder in more basic neuro-computational mechanisms.

Quality of Life and Symptom Management in Advanced Biliary Tract Cancers.

Biliary tract carcinomas (BTCs) account for less than 1% of all cancers but are increasing in incidence. Prognosis is poor for BTC patients, with 5-year survival rates of less than 10%. While chemotherapy has been the mainstay treatment for patients with advanced BTC, immunotherapy and targeted therapies are being evaluated in numerous clinical trials and rapidly incorporated into clinical practice. As patients with BTC have reduced health-related quality of life (HRQoL) due to both tumor- and treatment-related symptoms, it is important for clinicians to recognize and manage these symptoms early. This review will highlight the anticipated complications from BTC and its systemic treatment, as well as their effects on HRQoL.

Context-sensitive valuation and learning.

A variety of behavioral and neural phenomena suggest that organisms evaluate outcomes not on an absolute utility scale, but relative to some dynamic and context-sensitive reference or scale. Sometimes, as in foraging tasks, this results in sensible choices; in other situations, like choosing between options learned in different contexts, irrational choices can result. We argue that what unites and demystifies these various phenomena is that the brain's goal is not assessing utility as an end in itself, but rather comparing different options to choose the better one. In the presence of uncertainty, noise, or costly computation, adjusting options to the context can produce more accurate choices.

Vitamin D deficiency cardiomyopathy in Scotland: a retrospective review of the last decade.

OBJECTIVE: To determine the incidence, demography and prognosis of vitamin D deficiency dilated cardiomyopathy (DCM) in Scotland over the last decade. STUDY DESIGN: A retrospective review of cases of vitamin D deficiency DCM presenting to a national paediatric cardiac centre between 1 January 2008 and 1 January 2018. The departmental database and electronic and paper case notes were used to identify patients and extract data. RESULTS: Six patients were identified (three male), three of whom were Caucasian. Median age at presentation was 206 days (range 2-268.) All six patients had high serum parathyroid hormone levels (median 45 pmol/L, range 27-120 pmol/L), a sensitive marker of total body calcium deprivation secondary to vitamin D deficiency. All patients demonstrated clinical and echocardiographic improvement following high dose vitamin D treatment. No patients required cardiac transplant, and only one patient required extracorporeal life support as a bridge to recovery. After an initial improvement, one child died at 5 months as a result of respiratory infection. Three patients lived within some of the most deprived areas in Scotland. CONCLUSIONS: This case series demonstrates a previously unreported demographic in Scotland, as 50% of cases presented in Caucasian children. Although vitamin D deficiency DCM is relatively rare, it is wholly preventable. Our study confirms that vitamin D deficiency cardiomyopathy is reversible with prompt identification and supplementation. The current implementation of public health policy in the UK is failing to prevent children from developing the most severe manifestation of vitamin D deficiency.

First-line pembrolizumab therapy in a cisplatin-ineligible patient with plasmacytoid urothelial carcinoma: A case report.

BACKGROUND: Plasmacytoid urothelial carcinoma (PUC) is a rare but aggressive variant of transitional cell carcinoma. In patients with unresectable disease, cisplatin-based combination chemotherapy is the most commonly used treatment. However, many patients are cisplatin-ineligible due to poor performance status or other comorbidities. We report a case of a cisplatin-ineligible patient with metastatic PUC who was treated with pembrolizumab. CASE REPORT: A 71-year-old man with 30 pack-year smoking history and schizoaffective disorder was found to have multiple right-sided lung nodules after presenting with atypical chest pain. Staging CT showed bilateral adrenal masses and a large soft tissue mass in the right iliac fossa. Tissue pathology and immunohistochemical staining was consistent with PUC. As the patient was cisplatin-ineligible due to poor performance status and multiple medical comorbidities, the decision was made to treat with pembrolizumab. Repeat CT chest and abdomen showed partial response at three months and stable disease at six months. DISCUSSION: The KEYNOTE-052 study found that first-line pembrolizumab in cisplatin-ineligible patients with urothelial cancer resulted in complete or partial response in 24% of patients with few adverse effects. However, it is unclear if patients with plasmacytoid variant were included. To our knowledge, this is the first case report of a patient with metastatic PUC not only treated with pembrolizumab but shown to have clinical response. CONCLUSION: Given our patient's clinical response, pembrolizumab is a promising first-line agent for treating cisplatin-ineligible patients with metastatic PUC. Further evaluation is warranted to confirm the benefit of treating this patient population with pembrolizumab.

Stimulus generalization as a mechanism for learning to trust.

How do humans learn to trust unfamiliar others? Decisions in the absence of direct knowledge rely on our ability to generalize from past experiences and are often shaped by the degree of similarity between prior experience and novel situations. Here, we leverage a stimulus generalization framework to examine how perceptual similarity between known individuals and unfamiliar strangers shapes social learning. In a behavioral study, subjects play an iterative trust game with three partners who exhibit highly trustworthy, somewhat trustworthy, or highly untrustworthy behavior. After learning who can be trusted, subjects select new partners for a second game. Unbeknownst to subjects, each potential new partner was parametrically morphed with one of the three original players. Results reveal that subjects prefer to play with strangers who implicitly resemble the original player they previously learned was trustworthy and avoid playing with strangers resembling the untrustworthy player. These decisions to trust or distrust strangers formed a generalization gradient that converged toward baseline as perceptual similarity to the original player diminished. In a second imaging experiment we replicate these behavioral gradients and leverage multivariate pattern similarity analyses to reveal that a tuning profile of activation patterns in the amygdala selectively captures increasing perceptions of untrustworthiness. We additionally observe that within the caudate adaptive choices to trust rely on neural activation patterns similar to those elicited when learning about unrelated, but perceptually familiar, individuals. Together, these findings suggest an associative learning mechanism efficiently deploys moral information encoded from past experiences to guide future choice.

Altered pupillary light response scales with disease severity in migrainous photophobia.

Background Autonomic dysfunction and light sensitivity are core features of the migraine attack. Growing evidence also suggests changes in these parameters between attacks. Though sensory and autonomic responses likely interact, they have not been studied together across the spectrum of disease in migraine. Methods We performed digital infrared pupillometry while collecting interictal photophobia thresholds (PPT) in 36 migraineurs (14 episodic; 12 chronic; 10 probable) and 24 age and sex-matched non-headache controls. Quantitative pupillary light reflexes (PLR) were assessed in a subset of subjects, allowing distinction of sympathetic vs parasympathetic pupillary function. A structured questionnaire was used to ascertain migraine diagnosis, headache severity, and affective symptoms. Results Photophobia thresholds were significantly lower in migraineurs than controls, and were lowest in chronic migraine, consistent with a disease-related gradient. Lower PPT correlated with smaller dark-adapted pupil size and larger end pupil size at PPT, which corresponded to a reduced diameter change. On PLR testing, measures of both parasympathetic constriction and sympathetic re-dilation were reduced in migraineurs with clinically severe migraine. Conclusions In summary, we show that severity of photophobia in migraine scales with disease severity, in association with shifts in pupillary light responses. These alterations suggest centrally mediated autonomic adaptations to chronic light sensitivity.

Episodic memories predict adaptive value-based decision-making.

Prior research illustrates that memory can guide value-based decision-making. For example, previous work has implicated both working memory and procedural memory (i.e., reinforcement learning) in guiding choice. However, other types of memories, such as episodic memory, may also influence decision-making. Here we test the role for episodic memory-specifically item versus associative memory-in supporting value-based choice. Participants completed a task where they first learned the value associated with trial unique lotteries. After a short delay, they completed a decision-making task where they could choose to reengage with previously encountered lotteries, or new never before seen lotteries. Finally, participants completed a surprise memory test for the lotteries and their associated values. Results indicate that participants chose to reengage more often with lotteries that resulted in high versus low rewards. Critically, participants not only formed detailed, associative memories for the reward values coupled with individual lotteries, but also exhibited adaptive decision-making only when they had intact associative memory. We further found that the relationship between adaptive choice and associative memory generalized to more complex, ecologically valid choice behavior, such as social decision-making. However, individuals more strongly encode experiences of social violations-such as being treated unfairly, suggesting a bias for how individuals form associative memories within social contexts. Together, these findings provide an important integration of episodic memory and decision-making literatures to better understand key mechanisms supporting adaptive behavior.

Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus.

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

Comparing the Clinical Utility of the Infant Developmental Inventory With the Ages and Stages Questionnaire at 9-Month Well-Child Visits.

OBJECTIVE: The purpose of our study was to compare the clinical utility of administering 2 recommended developmental screening instruments, the Infant Developmental Inventory (IDI) and the Ages and Stages Questionnaire (ASQ), at 9-month well-child visits in paper format. METHODS: Outcomes of the 2 screens, including correct completion and interpretation by clinician, time of visit, and screen outcome were compared. RESULTS: Out of 33 children administered the ASQ and with documented scores, 12 (36.4%) did not receive passing scores, while 5 (12.2%) of the 41 children administered the IDI did not receive passing scores (P = .014). Out of 41 IDI screens, 12 (29.3%) were completed incorrectly, while there were no ASQ screens completed incorrectly (P < .001) by caregivers. CONCLUSION: In our pilot study, the ASQ is more often completed correctly by caregivers and identifies more children at risk for delay as compared with the IDI. Additional larger scale studies are needed to evaluate the usefulness of developmental screening tools when used within primary care practice.

Acute and subacute complications of pediatric and adolescent knee arthroscopy.

PURPOSE: The purposes of this study were to determine the frequency of acute and subacute complications (within 6 months) of arthroscopic knee procedures in patients aged 17 years or younger and to determine associated risk factors. METHODS: We identified all patients aged 17 years or younger who underwent arthroscopic knee procedures at our institution from 1997 to 2009. Patient demographic and surgical data were collected from the medical and surgical records, with specific focus on intraoperative and postoperative complications. RESULTS: During the study period, 1,002 knee arthroscopies were reviewed. The overall complication rate was 14.7%. Major complications occurred in 21 surgeries (2.1%) and included the following: septic arthritis (n = 3, 0.3%), wound complication requiring operative revision (n = 9, 0.9%), arthrofibrosis requiring manipulation (n = 4, 0.4%), other unplanned subsequent surgery (n = 4, 0.4%), and death (n = 1, 0.1%). Surgeries with an anesthesia time of 265 minutes or greater (P = .026), operative time of 220 minutes or greater (P = .013), or tourniquet time of 114 minutes or greater (P < .001) and surgeries with 3 or more Current Procedural Terminology codes (P = .003) had a statistically significant increase in risk of major complications. The incidence of minor complications was 12.6%, which included persistent effusion/hemarthrosis requiring arthrocentesis (n = 59, 5.9%) and superficial wound infection (n = 18, 1.8%). CONCLUSIONS: Major complications after knee arthroscopy in children and adolescents are rare, but minor complications are more common. If possible, surgeons should avoid prolonged anesthesia, surgery, and tourniquet times. The pediatric patient's medical and family history should be reviewed to identify important risk factors. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Facial shape and asymmetry in 5-year-old children with repaired unilateral cleft lip and/or palate: an exploratory study using laser scanning.

To investigate the feasibility of facial laser scanning in pre-school children and to demonstrate landmark-independent three-dimensional (3D) analyses for assessment of facial deformity in 5-year-old children with repaired non-syndromic unilateral cleft lip and/or cleft palate (UCL/P). Faces of twelve 5-year-old children with UCL/P (recruited from university hospitals in Cardiff and Swansea, UK) and 35 age-matched healthy children (recruited from a primary school in Cardiff) were laser scanned. Cleft deformity was assessed by comparing individual faces against the age and gender-matched average face of healthy children. Facial asymmetry was quantified by comparing original faces with their mirror images. All facial scans had good quality. In a group of six children with isolated cleft palate coincidence with the average norm ranged from 18.8 to 26.4 per cent. There was no statistically significant difference in facial asymmetry when compared with healthy children (P > 0.05). In a group of six children with UCL with or without cleft palate coincidence with the average norm ranged from 14.8 to 29.8 per cent. Forehead, midface and mandibular deficiencies were a consistent finding, ranging from 4 to 10mm. The amount of 3D facial asymmetry was higher in this group (P < 0.05). Facial laser scanning can be a suitable method for 3D assessment of facial morphology in pre-school children, provided children are well prepared. Landmark-independent methods of 3D analyses can contribute to understanding and quantification of facial soft tissue cleft deformity and be useful in clinical practice.

Effect of running retraining on pain, function, and lower-extremity biomechanics in a female runner with iliotibial band syndrome.

CONTEXT: Iliotibial-band syndrome (ITBS) is a common overuse running injury. There is inconclusive evidence to support current management strategies, and few advances have been made in the past few years. New management approaches should thus be developed and evaluated. OBJECTIVE: To assess the effects of a real-time running-retraining program on lower-extremity biomechanics, pain while running, and function. DESIGN: Single-subject experimental study. SETTING: University motion-analysis laboratory. PARTICIPANT: Female recreational runner with ITBS. INTERVENTION: Nine real-time running-retraining sessions were implemented based on the biomechanical alterations of the participant's symptomatic lower limb, including pelvic and knee movement in the transverse plane, as well as foot movement in the frontal plane. Real-time visual feedback of the pelvic-rotation angle was provided during the running-retraining sessions. MAIN OUTCOME MEASUREMENTS: 3-dimensional lower-extremity running kinematics, pain on a verbal analog scale while running on a treadmill, and the Lower Extremity Functional Scale (LEFS). RESULTS: Pelvic external rotation decreased, although the aim was to increase pelvic external rotation and knee rotation. The foot-progression angle improved after the intervention and at 1-mo follow-up. There was a 12.5% improvement in running time, and the pain score while running improved by 50% postintervention; these improvements were maintained at 1-mo follow-up. The mean LEFS score, indicative of function, improved by 8.75% and by 10% at the end of the intervention and at 1-mo follow-up, respectively. CONCLUSION: The real-time running-retraining program improved pain while running, as well as function, and was effective in addressing the lower-limb biomechanical alterations of the knee and foot in a female runner with ITBS. The application, effectiveness, and feasibility of real-time training should be addressed in larger studies in the future.

Impact of implementing mental health screening by mail with a primary care management model.

BACKGROUND: Early recognition and treatment of social and emotional disorders in children is significant for school preparation. These disorders are frequently underdetected without the use of standardized screening instruments. The purpose of our study is to describe the implementation of the Ages and Stages Questionnaire: Social-Emotional (ASQ:SE) in primary care practice by mail when children are 30 months old. METHODS: In this 4-month study, parents of all 30-month-old children who receive primary care at our study site were mailed the ASQ:SE. In children who did not pass screening or received a call from a registered nurse for parental concerns documented on the questionnaire, short-term clinical outcomes were obtained from the electronic medical record. During the last month of the study, the demographics variables of race and insurance type were analyzed for an association with questionnaire completion by mail. RESULTS: Of the 870 families mailed 30-month ASQ:SE screens, 507 (58.3%) were returned by mail. Out of the children with returned screens, 38 (7.5%) of parents were contacted for either elevated scores or concerning comments and 6 (1.2%) were referred to Early Intervention. Parents of children with government insurance returned the ASQ:SE questionnaire 34.2% (13/38) of the time compared with 65.5% (76/116) of those with private insurance (P < .001). CONCLUSION: Our results indicate that mental health screening can be effectively managed in primary care practice by a registered nurse using a follow-up protocol. Mailing the ASQ:SE is likely not an effective way to comprehensively screen most primary care populations.

Children's understandings and motivations surrounding novelty sweets: a qualitative study.

BACKGROUND: Novelty sweets resemble or can be used as toys, are brightly coloured, with striking imagery, and sold at pocket money prices. They encourage regular consumption as packaging can be resealed, leading to prolonged exposure of these high-sugar and low pH products to the oral tissues, risk factors for dental caries and erosion, respectively. AIM: To determine how children conceptualise novelty sweets and their motivations for buying and consuming them. DESIGN: Focus groups conducted using a brief schedule of open-ended questions, supported by novelty sweets used as prompts in the latter stages. Participants were school children (aged 9-10) from purposively selected state primary schools in Cardiff, UK. RESULTS: Key findings related to the routine nature of sweet eating; familiarity with and availability of novelty sweets; parental awareness and control; lack of awareness of health consequences; and the overall appeal of novelty sweets. CONCLUSIONS: Parents reported vagueness regarding consumption habits and permissiveness about any limits they set may have diluted the concept of treats. Flexible permissiveness to sweet buying applied to sweets of all kinds. Parents' reported lack of familiarity with novelty sweets combined with their low cost, easy availability, high sugar content, and acidity give cause for concern.

Protocol for "Seal or Varnish?" (SoV) trial: a randomised controlled trial to measure the relative cost and effectiveness of pit and fissure sealants and fluoride varnish in preventing dental decay.

BACKGROUND: Dental caries remains a significant public health problem, prevalence being linked to social and economic deprivation. Occlusal surfaces of first permanent molars are the most susceptible site in the developing permanent dentition. Cochrane reviews have shown pit and fissure sealants (PFS) and fluoride varnish (FV) to be effective over no intervention in preventing caries. However, the comparative cost and effectiveness of these treatments is uncertain. The primary aim of the trial described in this protocol is to compare the clinical effectiveness of PFS and FV in preventing dental caries in first permanent molars in 6-7 year-olds. Secondary aims include: establishing the costs and the relative cost-effectiveness of PFS and FV delivered in a community/school setting; examining the impact of PFS and FV on children and their parents/carers in terms of quality of life/treatment acceptability measures; and examining the implementation of treatment in a community setting. METHODS/DESIGN: The trial design comprises a randomised, assessor-blinded, two-arm, parallel group trial in 6-7 year old schoolchildren. Clinical procedures and assessments will be performed at 66 primary schools, in deprived areas in South Wales. Treatments will be delivered via a mobile dental clinic. In total, 920 children will be recruited (460 per trial arm). At baseline and annually for 36 months dental caries will be recorded using the International Caries Detection and Assessment System (ICDAS) by trained and calibrated dentists. PFS and FV will be applied by trained dental hygienists. The FV will be applied at baseline, 6, 12, 18, 24 and 30 months. The PFS will be applied at baseline and re-examined at 6, 12, 18, 24, and 30 months, and will be re-applied if the existing sealant has become detached/is insufficient. The economic analysis will estimate the costs of providing the PFS versus FV. The process evaluation will assess implementation and acceptability through acceptability scales, a schools questionnaire and interviews with children, parents, dentists, dental nurses and school staff. The primary outcome measure will be the proportion of children developing new caries on any one of up to four treated first permanent molars. DISCUSSION: The objectives of this study have been identified by the National Institute for Health Research as one of importance to the National Health Service in the UK. The results of this trial will provide guidance on which of these technologies should be adopted for the prevention of dental decay in the most susceptible tooth-surface in the most at risk children. TRIAL REGISTRATIONS: ISRCTN ref: ISRCTN17029222 EudraCT: 2010-023476-23 UKCRN ref: 9273.

Development, maturation, and necessity of transcription factors in the mouse suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the master mammalian circadian clock. The SCN is highly specialized because it is responsible for generating a near 24 h rhythm, integrating external cues, and translating the rhythm throughout the body. Currently, our understanding of the developmental origin and genetic program involved in the proper specification and maturation of the SCN is limited. Herein, we provide a detailed analysis of transcription factor (TF) and developmental-gene expression in the SCN from neurogenesis to adulthood in mice (Mus musculus). TF expression within the postmitotic SCN was not static but rather showed specific temporal and spatial changes during prenatal and postnatal development. In addition, we found both global and regional patterns of TF expression extending into the adult. We found that the SCN is derived from a distinct region of the neuroepithelium expressing a combination of developmental genes: Six3, Six6, Fzd5, and transient Rx, allowing us to pinpoint the origin of this region within the broader developing telencephalon/diencephalon. We tested the necessity of two TFs in SCN development, RORα and Six3, which were expressed during SCN development, persisted into adulthood, and showed diurnal rhythmicity. Loss of RORα function had no effect on SCN peptide expression or localization. In marked contrast, the conditional deletion of Six3 from early neural progenitors completely eliminated the formation of the SCN. Our results provide the first description of the involvement of TFs in the specification and maturation of a neural population necessary for circadian behavior.

Inverted impaction of a mandibular premolar associated with a dentigerous cyst: report of a case.

UNLABELLED: Inverted impaction of mandibular premolars is reported to be rare; its prevalence has not been quantified. Here we report a case in which a 12-year-old female presented with an inverted impacted manibular premolar associated with a dentigerous cyst. The likely aetiology and management of this condition is discussed. CLINICAL RELEVANCE: This case highlights the need for clinicians to be aware of the rarer causes of apparent absence of teeth from the arch and the importance of taking radiographs prior to treatment planning.