Ultra-large library docking for discovering new chemotypes.

Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC ß-lactamase (AmpC) and the D4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D4 dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D4 dopamine receptor.

Long-term HIV care outcomes under universal HIV treatment guidelines: A retrospective cohort study in 25 countries.

BACKGROUND: While national adoption of universal HIV treatment guidelines has led to improved, timely uptake of antiretroviral therapy (ART), longer-term care outcomes are understudied. There is little data from real-world service delivery settings on patient attrition, viral load (VL) monitoring, and viral suppression (VS) at 24 and 36 months after HIV treatment initiation. METHODS AND FINDINGS: For this retrospective cohort analysis, we used observational data from 25 countries in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium's Asia-Pacific, Central Africa, East Africa, Central/South America, and North America regions for patients who were ART naïve and aged ≥15 years at care enrollment between 24 months before and 12 months after national adoption of universal treatment guidelines, occurring 2012 to 2018. We estimated crude cumulative incidence of loss-to-clinic (CI-LTC) at 12, 24, and 36 months after enrollment among patients enrolling in care before and after guideline adoption using competing risks regression. Guideline change-associated hazard ratios of LTC at each time point after enrollment were estimated via cause-specific Cox proportional hazards regression models. Modified Poisson regression was used to estimate relative risks of retention, VL monitoring, and VS at 12, 24, and 36 months after ART initiation. There were 66,963 patients enrolling in HIV care at 109 clinics with ≥12 months of follow-up time after enrollment (46,484 [69.4%] enrolling before guideline adoption and 20,479 [30.6%] enrolling afterwards). More than half (54.9%) were females, and median age was 34 years (interquartile range [IQR]: 27 to 43). Mean follow-up time was 51 months (standard deviation: 17 months; range: 12, 110 months). Among patients enrolling before guideline adoption, crude CI-LTC was 23.8% (95% confidence interval [95% CI] 23.4, 24.2) at 12 months, 31.0% (95% CI [30.6, 31.5]) at 24 months, and 37.2% (95% [CI 36.8, 37.7]) at 36 months after enrollment. Adjusting for sex, age group, enrollment CD4, clinic location and type, and country income level, enrolling in care and initiating ART after guideline adoption was associated with increased hazard of LTC at 12 months (adjusted hazard ratio [aHR] 1.25 [95% CI 1.08, 1.44]; p = 0.003); 24 months (aHR 1.38 [95% CI 1.19, 1.59]; p < .001); and 36 months (aHR 1.34 [95% CI 1.18, 1.53], p < .001) compared with enrollment before guideline adoption, with no before-after differences among patients with no record of ART initiation by end of follow-up. Among patients retained after ART initiation, VL monitoring was low, with marginal improvements associated with guideline adoption only at 12 months after ART initiation. Among those with VL monitoring, VS was high at each time point among patients enrolling before guideline adoption (86.0% to 88.8%) and afterwards (86.2% to 90.3%), with no substantive difference associated with guideline adoption. Study limitations include lags in and potential underascertainment of care outcomes in real-world service delivery data and potential lack of generalizability beyond IeDEA sites and regions included in this analysis. CONCLUSIONS: In this study, adoption of universal HIV treatment guidelines was associated with lower retention after ART initiation out to 36 months of follow-up, with little change in VL monitoring or VS among retained patients. Monitoring long-term HIV care outcomes remains critical to identify and address causes of attrition and gaps in HIV care quality.

Prediction Under Interventions: Evaluation of Counterfactual Performance Using Longitudinal Observational Data.

Predictions under interventions are estimates of what a person's risk of an outcome would be if they were to follow a particular treatment strategy, given their individual characteristics. Such predictions can give important input to medical decision-making. However, evaluating the predictive performance of interventional predictions is challenging. Standard ways of evaluating predictive performance do not apply when using observational data, because prediction under interventions involves obtaining predictions of the outcome under conditions that are different from those that are observed for a subset of individuals in the validation dataset. This work describes methods for evaluating counterfactual performance of predictions under interventions for time-to-event outcomes. This means we aim to assess how well predictions would match the validation data if all individuals had followed the treatment strategy under which predictions are made. We focus on counterfactual performance evaluation using longitudinal observational data, and under treatment strategies that involve sustaining a particular treatment regime over time. We introduce an estimation approach using artificial censoring and inverse probability weighting that involves creating a validation dataset mimicking the treatment strategy under which predictions are made. We extend measures of calibration, discrimination (c-index and cumulative/dynamic AUCt) and overall prediction error (Brier score) to allow assessment of counterfactual performance. The methods are evaluated using a simulation study, including scenarios in which the methods should detect poor performance. Applying our methods in the context of liver transplantation shows that our procedure allows quantification of the performance of predictions supporting crucial decisions on organ allocation.

Emergent constraint on equilibrium climate sensitivity from global temperature variability.

Equilibrium climate sensitivity (ECS) remains one of the most important unknowns in climate change science. ECS is defined as the global mean warming that would occur if the atmospheric carbon dioxide (CO2) concentration were instantly doubled and the climate were then brought to equilibrium with that new level of CO2. Despite its rather idealized definition, ECS has continuing relevance for international climate change agreements, which are often framed in terms of stabilization of global warming relative to the pre-industrial climate. However, the 'likely' range of ECS as stated by the Intergovernmental Panel on Climate Change (IPCC) has remained at 1.5-4.5 degrees Celsius for more than 25 years. The possibility of a value of ECS towards the upper end of this range reduces the feasibility of avoiding 2 degrees Celsius of global warming, as required by the Paris Agreement. Here we present a new emergent constraint on ECS that yields a central estimate of 2.8 degrees Celsius with 66 per cent confidence limits (equivalent to the IPCC 'likely' range) of 2.2-3.4 degrees Celsius. Our approach is to focus on the variability of temperature about long-term historical warming, rather than on the warming trend itself. We use an ensemble of climate models to define an emergent relationship between ECS and a theoretically informed metric of global temperature variability. This metric of variability can also be calculated from observational records of global warming, which enables tighter constraints to be placed on ECS, reducing the probability of ECS being less than 1.5 degrees Celsius to less than 3 per cent, and the probability of ECS exceeding 4.5 degrees Celsius to less than 1 per cent.

Observation of others' actions during limb immobilization prevents the subsequent decay of motor performance.

There is rich clinical evidence that observing normally executed actions promotes the recovery of the corresponding action execution in patients with motor deficits. In this study, we assessed the ability of action observation to prevent the decay of healthy individuals' motor abilities following upper-limb immobilization. To this end, upper-limb kinematics was recorded in healthy participants while they performed three reach-to-grasp movements before immobilization and the same movements after 16 h of immobilization. The participants were subdivided into two groups; the experimental group observed, during the immobilization, the same reach-to-grasp movements they had performed before immobilization, whereas the control group observed natural scenarios. After bandage removal, motor impairment in performing reach-to-grasp movements was milder in the experimental group. These findings support the hypothesis that action observation, via the mirror mechanism, plays a protective role against the decline of motor performance induced by limb nonuse. From this perspective, action observation therapy is a promising tool for anticipating rehabilitation onset in clinical conditions involving limb nonuse, thus reducing the burden of further rehabilitation.

Observational analysis of the immunogenicity and safety of various types of spinal muscular atrophy vaccines.

BACKGROUND: This study aimed to evaluate the immunogenicity and safety of different types of poliovirus vaccines. METHODS: A randomized, blinded, single-center, parallel-controlled design was employed, and 360 infants aged ≥ 2 months were selected as study subjects. They were randomly assigned to bOPV group (oral Sabin vaccine) and sIPV group (Sabin strain inactivated polio vaccine), with 180 infants in each group. Adverse reaction events in the vaccinated subjects were recorded. The micro-neutralization test using cell culture was conducted to determine the geometric mean titer (GMT) of neutralizing antibodies against poliovirus types I, II, and III in different groups, and the seroconversion rates were calculated. RESULTS: Both groups exhibited a 100% seropositivity rate after booster immunization. The titers of neutralizing antibodies for the three types were predominantly distributed within the range of 1:128 to 1:512. The fold increase of type I antibodies differed markedly between the two groups (P < 0.05). Moreover, the fold increase of type II and type III antibodies for poliovirus differed slightly between the two groups (P > 0.05). The fourfold increase rate in sIPV group was drastically superior to that in bOPV group (P < 0.05). When comparing the post-immunization GMT levels of type I antibodies in individuals who completed the full course of spinal muscular atrophy vaccination, bOPV group showed greatly inferior levels to sIPV group (P < 0.05). For type II and type III antibodies, individuals in bOPV group demonstrated drastically superior post-immunization GMT levels to those in sIPV group (P < 0.05). The incidence of adverse reactions between the bOPV and sIPV groups differed slightly (P > 0.05). CONCLUSION: These findings indicated that both the oral vaccine and inactivated vaccine had good safety and immunogenicity in infants aged ≥ 2 months. The sIPV group generated higher levels of neutralizing antibodies in serum, particularly evident in the post-immunization GMT levels for types II and III.

Tummy Time Tracking: Examining Agreement Between Parent Recall and Direct Observation in Infants.

IMPORTANCE: Parent recall is the primary method for measuring positioning practices such as tummy time in infants. Concerns regarding the accuracy of parent recall have been raised in the literature. To date, no study has examined the agreement of tummy time recall measures with gold-standard methods. OBJECTIVE: To assess the agreement between parental recall versus direct observation of tummy time in infants, and to explore the impact of prematurity on this relationship. DESIGN: Cross-sectional observational study, spanning 1 yr. SETTING: Participants' homes Participants: Thirty-two infant-parent dyads (19 full-term, 13 preterm), with infants ages 3 to 6 mo and caregivers ages older than 18 yr. OUTCOME AND MEASURES: Home-recorded videos of infant play across 3 days were used as a proxy for direct observation of tummy time and compared with a 12-item parent recall survey. RESULTS: Parent recall had a significant moderate correlation (ρ = .54, p = .002) with direct observation in full-term infants but was not correlated (p = .23) with direct observation in preterm infants. On average, parents of preterm infants overestimated tummy time by 2.5 times per day compared with direct observation. CONCLUSIONS AND RELEVANCE: For full-term infants, parent recall measures of tummy time exhibit an acceptable level of agreement with direct observation and can be reliably used over shorter periods. Parents of preterm infants may display a bias in recalling tummy time, leading to overestimations. To accurately assess tummy time in this population, a combination of subjective and objective measures should be explored. Plain-Language Summary: Tummy time is an essential movement experience for infants, especially for preterm infants, who are at a higher risk for motor delays. The most common way to track tummy time is through parent reports, or recall, versus a practitioner directly observing tummy time in the home. Despite the widespread use of parent recall to track tummy time, no study has examined the accuracy of parent recall versus direct observation in the home. Accurately assessing tummy time is crucial for improving and supporting health outcomes for infants. This study found that prematurity may affect the accuracy of parent recall for assessing tummy time in young infants. The authors discuss the implications of this finding and provide suggestions to guide the selection of appropriate methods to measure tummy time in clinical practice and research studies.

Using automated active infrared counters to estimate footfall on urban park footpaths: behavioural stability and validity testing.

BACKGROUND: Using infrared counters is a promising unobtrusive method of assessing footfall in urban parks. However, infrared counters are susceptible to reliability and validity issues, and there is limited guidance for their use. The aims of this study were to (1) determine how many weeks of automated active infrared count data would provide behaviourally stable estimates of urban park footfall for each meteorological season, and (2) determine the validity of automated active infrared count estimates of footfall in comparison to direct manual observation counts. METHODS: Three automated active infrared counters collected daily footfall counts for 365 days on three footpaths in an urban park within Northampton, England, between May 2021 - May 2022. Intraclass correlation coefficients were used to compare the behavioural stability of abbreviated data collection schedules with total median footfall within each meteorological season (Spring, Summer, Autumn, Winter). Public holidays, events, and extreme outliers were removed. Ten one-hour manual observations were conducted at the site of an infrared counter to determine the validity of the infrared counter. RESULTS: At least four-weeks (28 days) of infrared counts are required to provide 'good' to 'excellent' (Intraclass correlation > 0.75, > 0.9, respectively) estimates of median daily footfall per meteorological season in an urban park. Infrared counters had, on average, -4.65 counts per hour (95% LoA -12.4, 3.14; Mean absolute percentage error 13.7%) lower counts compared to manual observation counts during one-hour observation periods (23.2 ± 15.6, 27.9 ± 18.9 counts per hour, respectively). Infrared counts explained 98% of the variance in manual observation counts. The number of groups during an observation period explained 78% of the variance in the difference between infrared and manual counts. CONCLUSIONS: Abbreviated data collection schedules can still obtain estimates of urban park footfall. Automated active infrared counts are strongly associated with manual counts; however, they tend to underestimate footfall, often due to people in groups. Methodological and practical recommendations are provided.

Intersectoral Collaboration to Promote Child Development: The Contributions of the Actor-Network Theory.

An integrated intersectoral care model promises to meet complex needs to promote early child development and address health determinants and inequities. Nevertheless, there is a lack of understanding of actors' interactions in producing intersectoral collaboration networks. The present study aimed to analyze the intersectoral collaboration in the social protection network involved in promoting early child growth and development in Brazilian municipalities. Underpinned by the tenets of actor-network theory, a case study was conducted with data produced from an educational intervention, entitled "Projeto Nascente." Through document analysis (ecomaps), participant observation (in Projeto Nascente seminars), and interviews (with municipal management representatives), our study explored and captured links among actors; controversies and resolution mechanisms; the presence of mediators and intermediaries; and an alignment of actors, resources, and support. The qualitative analysis of these materials identified three main themes: (1) agency fragility for intersectoral collaboration, (2) attempt to form networks, and (3) incorporation of fields of possibilities. Our findings revealed that intersectoral collaboration for promoting child growth and development is virtually non-existent or fragile, and local potential is missed or underused. These results emphasized the scarcity of action by mediators and intermediaries to promote enrollment processes to intersectoral collaboration. Likewise, existing controversies were not used as a mechanism for triggering changes. Our research supports the need to mobilize actors, resources, management, and communication tools that promote processes of interessement and enrollment in favor of intersectoral collaboration policies and practices for child development.

Why We Learn Less from Observing Outgroups.

Humans are less likely to learn from individuals belonging to a different group (outgroup) than from individuals of their own group (ingroup), yet the source of this societally relevant deficit has remained unclear. Here we used neuroimaging and computational modeling to investigate how people learn from observing the actions and outcomes of ingroup and outgroup demonstrators. Politically left-wing male and female participants performed worse when observing computer-simulated actions they believed were from a right-wing outgroup member compared with those from a left-wing ingroup member. A control experiment in which participants observed choices from a nonhuman agent confirmed that this performance difference reflected an outgroup deficit, rather than an ingroup gain. Accounting for the outgroup deficit, a computational model showed that participants relied less on information from outgroup actions compared with ingroup actions, while learning from outgroup outcomes was not impaired. At the neural level, the differences in observational ingroup versus outgroup learning were reflected in lateral prefrontal activity. The stronger the activity in this region, the more strongly participants weighed ingroup compared with outgroup learning signals (action prediction errors), which formally captured deficits in outgroup learning. Together, our work provides a computational and neural account of why people learn less from observing outgroups.SIGNIFICANCE STATEMENT Learning from observing others is an efficient way to acquire knowledge. In our globalized world, "the others" often are people from a different social group (outgroup). There is evidence that people learn less from observing outgroup individuals compared with individuals from their own group (ingroup). However, the source of this outgroup deficit in observational learning remained unknown, which limits our chances to improve intergroup learning. Our results showed that participants rely less on observed outgroup actions compared with ingroup actions, while learning from outgroup outcomes is not impaired. On the neural level, this outgroup deficit was reflected in the activation of the inferior frontal gyrus. These findings imply that intergroup learning should rely on observing outcomes, rather than actions.

Price Equations for Understanding the Response of Ecosystem Function to Community Change.

AbstractThe relationship between biodiversity and ecosystem function (BEF) remains unclear in many natural ecosystems, partially for lack of theoretical and analytical tools that match common characteristics of observational community data. The ecological Price equation promises to meet this need by organizing many different species-level changes into a few ecologically meaningful categories that sum to total ecosystem function change. Current versions of the ecological Price equation focus on species richness and presence-absence. However, abundance and relative abundance are better estimated in samples and are likely showing a stronger response to global change. Here, we present a novel, abundance-based version of the ecological Price equation in both discrete and continuous forms and explain the similarities and differences between this method and a related, previously developed richness-based method. We also present new empirical techniques for applying the Price equation to ecological data. Our two demonstration analyses reveal how additive effects of increasing abundance on total function are modified by concurrent selection effects due to shifts in species' composition as well as intraspecific change in species' per capita function. The ecological Price equations derived here complement existing approaches and together offer BEF researchers analytical tools and a unifying framework for studying BEF in observational community data.

Timescales for detection of trends in the ocean carbon sink.

The ocean has absorbed 41 per cent of all anthropogenic carbon emitted as a result of fossil fuel burning and cement manufacture. The magnitude and the large-scale distribution of the ocean carbon sink is well quantified for recent decades. In contrast, temporal changes in the oceanic carbon sink remain poorly understood. It has proved difficult to distinguish between air-to-sea carbon flux trends that are due to anthropogenic climate change and those due to internal climate variability. Here we use a modelling approach that allows for this separation, revealing how the ocean carbon sink may be expected to change throughout this century in different oceanic regions. Our findings suggest that, owing to large internal climate variability, it is unlikely that changes in the rate of anthropogenic carbon uptake can be directly observed in most oceanic regions at present, but that this may become possible between 2020 and 2050 in some regions.

Serendipity and Observations in Functional Neurosurgery: From James Parkinson's Stroke to Hamani's & Lozano's Flashbacks.

BACKGROUND: Serendipity and observations have a noble tradition in medicine, including neurology, and are responsible for many medical treatments (carbamazepine for tic douloureux, amantadine for Parkinson's disease, gabapentin for restless legs…). We aimed at examining the contribution of serendipity and observations to functional neurosurgery. Scholarly publications relevant to the history of functional neurosurgery for movement and psychiatric disorders were reviewed, starting from the pre-stereotactic era. The documents were scrutinized with respect to indications for surgery, surgical methods, and brain targets, in view of determining whether serendipitous discoveries and other observations contributed to various functional neurosurgical procedures. SUMMARY: James Parkinson's observation that tremors disappeared in the arm of a person with shaking palsy after a hemiparetic stroke encouraged neurosurgeons in the first half of the 20th century to perform ablative procedures on central motor pathways. Following a lobotomy performed by Browder that extended too far medially in a psychiatric patient with coexisting Parkinson's disease (PD), it was noted that the Parkinsonian signs improved. This encouraged Russel Meyers to carry out open surgery on the caudate nucleus and basal ganglia in PD. Cooper introduced ligation of the anterior choroidal artery as a treatment for PD following a surgical accident during a pedunculotomy. Cooper later started to perform stereotactic surgery on the ventrolateral thalamus following the pathological finding that an intended pallidal lesion had in fact targeted the thalamus. Leksell discovered the ideal location of a pallidal lesion being in the posteroventral area empirically, long before the advent of the basal ganglia model of PD. Modern Deep Brain Stimulation (DBS) that started in the thalamus for tremor was the result of an observation by Benabid that intraoperative high-frequency stimulation during a thalamotomy reduced tremor. Both the discoveries of the anterior limbic subthalamic nucleus as a DBS target for OCD and the medial forebrain bundle as a DBS target for depression occurred by chance. Hamani and Lozano observed memory flashbacks in a patient who was undergoing DBS for obesity, which led to the discovery of the fornix as a potential DBS target for Alzheimer's disease. KEY MESSAGES: In the history of functional neurosurgery, serendipity and observations have resulted in discoveries of several procedures, brain targets for lesioning or DBS as well as new clinical surgical indications. In this era of neuromodulation, this technology should be exquisite in allowing potential serendipitous discoveries, provided that clinicians remain both observant and prepared.

Evaluation of a COVID-19 emergency department observation protocol.

OBJECTIVES: Caring for patients with COVID-19 has resulted in a considerable strain on hospital capacity. One strategy to mitigate crowding is the use of ED-based observation units to care for patients who may have otherwise required hospitalization. We sought to create a COVID-19 Observation Protocol for our ED Observation Unit (EDOU) for patients with mild to moderate COVID-19 to allow emergency physicians (EP) to gather more data for or against admission and intervene in a timely manner to prevent clinical deterioration. METHODS: This was a retrospective cohort study which included all patients who were positive for SARS-CoV-2 at the time of EDOU placement for the primary purpose of monitoring COVID-19 disease. Our institution updated the ED Observation protocol partway into the study period. Descriptive statistics were used to characterize demographics. We assessed for differences in demographics, clinical characteristics, and outcomes between admitted and discharged patients. Multivariate logistic regression models were used to assess whether meeting criteria for the ED observation protocols predicted disposition. RESULTS: During the time period studied, 120 patients positive for SARS-CoV-2 were placed in the EDOU for the primary purpose of monitoring COVID-19 disease. The admission rate for patients in the EDOU during the study period was 35%. When limited to patients who met criteria for version 1 or version 2 of the protocol, this dropped to 21% and 25% respectively. Adherence to the observation protocol was 62% and 60% during the time of version 1 and version 2 implementation, respectively. Using a multivariate logistic regression, meeting criteria for either version 1 (OR = 3.17, 95% CI 1.34-7.53, p < 0.01) or version 2 (OR = 3.18, 95% CI 1.39-7.30, p < 0.01) of the protocol resulted in a higher likelihood of discharge. There was no difference in EDOU LOS between admitted and discharged patients. CONCLUSION: An ED observation protocol can be successfully created and implemented for COVID-19 which allows the EP to determine which patients warrant hospitalization. Meeting protocol criteria results in an acceptable admission rate.

Barriers to and facilitators of ethical encounters at the end of life in a nursing home: an ethnographic study.

BACKGROUND: Among a growing population of older persons, many affected by multiple diseases and complex needs, are cared for in nursing homes. Previous studies of nursing homes have highlighted the importance of personalised palliative care. Nevertheless, we know little about whether everyday care practice involving assistant nurses and frail older persons accomplishes ethical encounters, especially in assisted bodily care. Therefore, the aim of this study was to understand and conceptualize the encounter between residents and assistant nurses in bodily care-situations at the end of life in a nursing home. METHODS: Focused ethnographic design was used. Residents and assistant nurses from one nursing home in an urban Swedish area participated in this study. Data were collected for 6 months and consisted of 170 h of fieldwork, including participant observation and interviews. Observations and digitally recorded interviews were analysed thematically. Five public community stakeholders contributed to the analysis by discussing preliminary results and clinical implications in a focus group. RESULTS: Four themes, each encompassing both barriers to and facilitators of ethical encounters in assisted bodily care, were identified: Coping with the impact of workplace demands; Interacting in dialogue and communication; Experiencing involvement in the provision of assisted bodily care; and Adapting to good care and comfort. CONCLUSIONS: The findings suggest that accomplishing ethical encounters in assisted bodily care practice in a nursing home context has many barriers that are related to communication, relationships, and quality of care. Barriers included lack of resources, ineffective communication, and work values, which hinder ethical encounters. Nevertheless, moral sensitivity, genuine interest in resident engagement, and collaborative practices facilitated ethical encounters and are thus central to person-centred care. Uniquely, assistant nurses must be aware of their responsibility for performing their tasks in response to residents' vulnerability. We therefore suggest that moral deliberation over issues of communication, compassion, decision-making, and behavior, with particular consideration for the care relationship. To further improve the quality of care, organisations must provide resources for the building of relationships, as well as time for assistant nurses to recover after long shifts. Additional research is warranted, including implementation of ethically grounded palliative care.

Observation Versus Cast Treatment of Toddler's Fractures.

BACKGROUND: Nondisplaced metaphyseal fractures of the distal tibia, or toddler's fractures, are one of the most common pediatric injuries. Healing typically occurs quickly without sequelae. Treatment ranges from long leg cast immobilization to observation. This study compares short-term clinical and radiographic outcomes of toddler's fractures treated with long leg casting versus observation. METHODS: Patients with toddler's fractures were offered enrollment and randomization at diagnosis. Because many families opposed randomization, a preference arm was added after one year. All subjects were analyzed as a prospective cohort. Radiographs were obtained at diagnosis and 4 weeks. A modified Oxford Ankle Foot Questionnaire for Children (OAFQ-C) and family satisfaction survey were collected at diagnosis, 4 and 8 weeks. Scores were analyzed using mixed effect models. Family satisfaction surveys were compared using a Wilcoxon rank sum test. RESULTS: Forty-four subjects participated in the study, 34 (77%) in the preference arm and 10 (23%) in the randomized cohort. The median patient age was comparable between the cast and the observation groups, 2.0 versus 1.8 years, respectively. Significant improvement in OAFQ-C scores was observed in both groups over 8 weeks (P<0.01). Patients in the observation group had a higher initial play score than the cast group (P=0.03). The observation group trended toward higher physical scores at all time points (P=0.11). There was no significant difference in emotional scores between groups (P=0.77). No displacement was observed in any patient. Casted patients had significantly more minor complications with 4 patients requiring cast change or removal compared with 0 in the observed group (P=0.01). At 8 weeks, 80% of parents in the cast group were likely or very likely to choose the same treatment compared with 95.6% in the observation group. Family satisfaction scores did not differ between groups (P=0.18). They demonstrated differences in perceived normal walking at 4 weeks, with 50% of casted patients walking normally compared with 92% of observed patients. Over 90% of patients in both groups were reportedly walking normally at week 8. CONCLUSION: Observation of toddler's fractures results in equivalent clinical and radiographic outcomes, high family satisfaction and fewer complications compared with treatment with a long leg cast. LEVEL OF EVIDENCE: Level II.

Comparison of Fine Arts- and Pathology-Based Observational Skills Training for Veterinary Students Learning Cytology.

Keen observational skills are essential for veterinarians; however, the development of these skills is not usually an explicit part of the veterinary curriculum. Fine arts-based (FAB) observation training has been shown to improve medical students' observational skills and might also improve veterinary students' observational skills. We compared FAB and pathology-based (PB) observation training in a veterinary cytology course. Students initially wrote a pre-test in which they described two cytology images and one art image, followed by participation in either FAB or PB observation training. Both groups completed a similar post-test immediately after training and a delayed post-test 4 weeks later following instruction in cytology. Differences between groups were noted only in the immediate post-test cytology descriptions. The PB group used significantly more specific vocabulary terms and significantly more accurate observations than the FAB group, suggesting an immediate benefit to the discipline-specific information gained in the PB observation training. In the delayed post-test, results for both groups were similar. The FAB group significantly increased their use of specific vocabulary terms and maintained but did not increase accurate observations following cytology instruction, while accurate observations decreased significantly for the PB group. The FAB group might have been able to generalize their observation skills to the discipline of cytology and to better retain these skills. Neither type of training resulted in both achievement and maintenance of the highest recorded scores for accurate observations. Both FAB and PB training led to improved observational skills, and explicit observation training may be useful for veterinary students.

Sensorimotor Expectations Bias Motor Resonance during Observation of Object Lifting: The Causal Role of pSTS.

Transcranial magnetic stimulation studies have highlighted that corticospinal excitability is increased during observation of object lifting, an effect termed "motor resonance." This facilitation is driven by movement features indicative of object weight, such as object size or observed movement kinematics. Here, we investigated in 35 humans (23 females) how motor resonance is altered when the observer's weight expectations, based on visual information, do not match the actual object weight as revealed by the observed movement kinematics. Our results highlight that motor resonance is not robustly driven by object weight but easily masked by a suppressive mechanism reflecting the correctness of weight expectations. Subsequently, we investigated in 24 humans (14 females) whether this suppressive mechanism was driven by higher-order cortical areas. For this, we induced "virtual lesions" to either the posterior superior temporal sulcus (pSTS) or dorsolateral prefrontal cortex (DLPFC) before having participants perform the task. Importantly, virtual lesion of pSTS eradicated this suppressive mechanism and restored object weight-driven motor resonance. In addition, DLPFC virtual lesion eradicated any modulation of motor resonance. This indicates that motor resonance is heavily mediated by top-down inputs from both pSTS and DLPFC. Together, these findings shed new light on the theorized cortical network driving motor resonance. That is, our findings highlight that motor resonance is not only driven by the putative human mirror neuron network consisting of the primary motor and premotor cortices as well as the anterior intraparietal sulcus, but also by top-down input from pSTS and DLPFC.SIGNIFICANCE STATEMENT Observation of object lifting activates the observer's motor system in a weight-specific fashion: Corticospinal excitability is larger when observing lifts of heavy objects compared with light ones. Interestingly, here we demonstrate that this weight-driven modulation of corticospinal excitability is easily suppressed by the observer's expectations about object weight and that this suppression is mediated by the posterior superior temporal sulcus. Thus, our findings show that modulation of corticospinal excitability during observed object lifting is not robust but easily altered by top-down cognitive processes. Finally, our results also indicate how cortical inputs, originating remotely from motor pathways and processing action observation, overlap with bottom-up motor resonance effects.

Adjuvant Chemotherapy Versus Observation Following Resection for Patients With Nonmetastatic Poorly Differentiated Colorectal Neuroendocrine Carcinomas.

OBJECTIVE: The aim of this study was to determine whether adjuvant chemotherapy (AC) provides a survival benefit in patients with nonmetastatic poorly differentiated colorectal neuroendocrine carcinomas (CRNECs) following resection. BACKGROUND: There is little evidence to support the association between use of AC and improved overall survival (OS) in patients with CRNECs. METHODS: Patients with resected non-metastatic CRNECs were identified in the National Cancer Database (2004-2014). Inverse probability of treatment weighting (IPTW) method was used to reduce the selection bias. IPTW-adjusted Kaplan-Meier curves and Cox proportional hazards models were used to compare OS of patients in different treatment groups. RESULTS: A total of 806 patients diagnosed between 2004 and 2014 met the study entry criteria. Of these, 394 patients (48.9%) received AC. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for AC versus observation [57.4 (interquartile range, IQR, 14.8-153.8) vs 38.2 (IQR, 10.4-125.4) months; P = 0.007]. In IPTW-adjusted Cox proportional hazards regression analysis, AC was associated with a significant OS benefit [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.64-0.84; P < 0.001]. The results were consistent across subgroups stratified by pathologic T stage, pathologic N stage, and surgical margin status. Subgroup analysis according to tumor location demonstrated improved OS in the adjuvant therapy cohort among patients with left-sided neuroendocrine carcinomas (HR, 0.55; 95% CI, 0.44-0.68), but not in those with right-sided disease (HR, 0.89; 95% CI, 0.74-1.07). CONCLUSIONS: Patients with nonmetastatic CRNECs may derive survival benefit from AC. These findings support current guidelines recommending AC in patients with poorly differentiated neuroendocrine carcinomas in the colon and rectum. Efforts in education and adherence to national guidelines for NECs are needed.

Demographic, multi-morbidity and genetic impact on myocardial involvement and its recovery from COVID-19: protocol design of COVID-HEART-a UK, multicentre, observational study.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory illness, myocardial injury is increasingly reported and associated with adverse outcomes. However, the pathophysiology, extent of myocardial injury and clinical significance remains unclear. METHODS: COVID-HEART is a UK, multicentre, prospective, observational, longitudinal cohort study of patients with confirmed COVID-19 and elevated troponin (sex-specific > 99th centile). Baseline assessment will be whilst recovering in-hospital or recently discharged, and include cardiovascular magnetic resonance (CMR) imaging, quality of life (QoL) assessments, electrocardiogram (ECG), serum biomarkers and genetics. Assessment at 6-months includes repeat CMR, QoL assessments and 6-min walk test (6MWT). The CMR protocol includes cine imaging, T1/T2 mapping, aortic distensibility, late gadolinium enhancement (LGE), and adenosine stress myocardial perfusion imaging in selected patients. The main objectives of the study are to: (1) characterise the extent and nature of myocardial involvement in COVID-19 patients with an elevated troponin, (2) assess how cardiac involvement and clinical outcome associate with recognised risk factors for mortality (age, sex, ethnicity and comorbidities) and genetic factors, (3) evaluate if differences in myocardial recovery at 6 months are dependent on demographics, genetics and comorbidities, (4) understand the impact of recovery status at 6 months on patient-reported QoL and functional capacity. DISCUSSION: COVID-HEART will provide detailed characterisation of cardiac involvement, and its repair and recovery in relation to comorbidity, genetics, patient-reported QoL measures and functional capacity. CLINICAL TRIAL REGISTRATION: ISRCTN 58667920. Registered 04 August 2020.