Clinical utility of family history of depression for prognosis of adolescent depression severity and duration assessed with predictive modeling.

BACKGROUND: Family history of depression (FHD) is a known risk factor for the new onset of depression. However, it is unclear if FHD is clinically useful for prognosis in adolescents with current, ongoing, or past depression. This preregistered study uses a longitudinal, multi-informant design to examine whether a child's FHD adds information about future depressive episodes and depression severity applying state-of-the-art predictive out-of-sample methodology. METHODS: We examined data in adolescents with current or past depression (age 11-17 years) from the National Institute of Mental Health Characterization and Treatment of Adolescent Depression (CAT-D) study. We asked whether a history of depression in a first-degree relative was predictive of depressive episode duration (72 participants) and future depressive symptom severity in probands (129 participants, 1,439 total assessments). RESULTS: Family history of depression, while statistically associated with time spent depressed, did not improve predictions of time spent depressed, nor did it improve models of change in depression severity measured by self- or parent-report. CONCLUSIONS: Family history of depression does not improve the prediction of the course of depression in adolescents already diagnosed with depression. The difference between statistical association and predictive models highlights the importance of assessing predictive performance when evaluating questions of clinical utility.

Accurate Simulation of Both Sensitivity and Variability for Amazonian Photosynthesis: Is It Too Much to Ask?

Estimates of Amazon rainforest gross primary productivity (GPP) differ by a factor of 2 across a suite of three statistical and 18 process models. This wide spread contributes uncertainty to predictions of future climate. We compare the mean and variance of GPP from these models to that of GPP at six eddy covariance (EC) towers. Only one model's mean GPP across all sites falls within a 99% confidence interval for EC GPP, and only one model matches EC variance. The strength of model response to climate drivers is related to model ability to match the seasonal pattern of the EC GPP. Models with stronger seasonal swings in GPP have stronger responses to rain, light, and temperature than does EC GPP. The model to data comparison illustrates a trade-off inherent to deterministic models between accurate simulation of a mean (average) and accurate responsiveness to drivers. The trade-off exists because all deterministic models simplify processes and lack at least some consequential driver or interaction. If a model's sensitivities to included drivers and their interactions are accurate, then deterministically predicted outcomes have less variability than is realistic. If a GPP model has stronger responses to climate drivers than found in data, model predictions may match the observed variance and seasonal pattern but are likely to overpredict GPP response to climate change. High or realistic variability of model estimates relative to reference data indicate that the model is hypersensitive to one or more drivers.

Probing infants' sensitivity to pupil size when viewing eyes.

Sensitive responding to eye cues plays a key role in human social interactions. Pupil size provides subtle cues regarding a social interaction partner's arousal states. The current study assessed infants' sensitivity to and preference for differences in pupil size. Specifically, we examined White 14-month-old infants' pupillary responses when viewing own-race and other-race (Asian) eyes with dilating, constricting, and static medium-sized pupils. Our results show that, independent of race, infants' pupils dilated more when viewing eyes with dynamically changing (dilating and constricting) pupils than when viewing eyes with non-changing, static, and medium-sized pupils. We also measured infants' looking preferences, showing that, independent of race, infants preferentially attended to eyes with dilated pupils. Moreover, our results show that infants orient more quickly to pupillary changes in own-race eyes than in other-race eyes. These findings demonstrate that infants detect, but do not mimic, changes in pupil size in others and show a preference for eyes with dilated pupils.

Beyond ecosystem modeling: A roadmap to community cyberinfrastructure for ecological data-model integration.

In an era of rapid global change, our ability to understand and predict Earth's natural systems is lagging behind our ability to monitor and measure changes in the biosphere. Bottlenecks to informing models with observations have reduced our capacity to fully exploit the growing volume and variety of available data. Here, we take a critical look at the information infrastructure that connects ecosystem modeling and measurement efforts, and propose a roadmap to community cyberinfrastructure development that can reduce the divisions between empirical research and modeling and accelerate the pace of discovery. A new era of data-model integration requires investment in accessible, scalable, and transparent tools that integrate the expertise of the whole community, including both modelers and empiricists. This roadmap focuses on five key opportunities for community tools: the underlying foundations of community cyberinfrastructure; data ingest; calibration of models to data; model-data benchmarking; and data assimilation and ecological forecasting. This community-driven approach is a key to meeting the pressing needs of science and society in the 21st century.

Case Report of Dual-Site Neurostimulation and Chronic Recording of Cortico-Striatal Circuitry in a Patient With Treatment Refractory Obsessive Compulsive Disorder.

Psychiatric disorders are increasingly understood as dysfunctions of hyper- or hypoconnectivity in distributed brain circuits. A prototypical example is obsessive compulsive disorder (OCD), which has been repeatedly linked to hyper-connectivity of cortico-striatal-thalamo-cortical (CSTC) loops. Deep brain stimulation (DBS) and lesions of CSTC structures have shown promise for treating both OCD and related disorders involving over-expression of automatic/habitual behaviors. Physiologically, we propose that this CSTC hyper-connectivity may be reflected in high synchrony of neural firing between loop structures, which could be measured as coherent oscillations in the local field potential (LFP). Here we report the results from the pilot patient in an Early Feasibility study (https://clinicaltrials.gov/ct2/show/NCT03184454) in which we use the Medtronic Activa PC+ S device to simultaneously record and stimulate in the supplementary motor area (SMA) and ventral capsule/ventral striatum (VC/VS). We hypothesized that frequency-mismatched stimulation should disrupt coherence and reduce compulsive symptoms. The patient reported subjective improvement in OCD symptoms and showed evidence of improved cognitive control with the addition of cortical stimulation, but these changes were not reflected in primary rating scales specific to OCD and depression, or during blinded cortical stimulation. This subjective improvement was correlated with increased SMA and VC/VS coherence in the alpha, beta, and gamma bands, signals which persisted after correcting for stimulation artifacts. We discuss the implications of this research, and propose future directions for research in network modulation in OCD and more broadly across psychiatric disorders.

Spring enhancement and summer reduction in carbon uptake during the 2018 drought in northwestern Europe.

We analysed gross primary productivity (GPP), total ecosystem respiration (TER) and the resulting net ecosystem exchange (NEE) of carbon dioxide (CO2) by the terrestrial biosphere during the summer of 2018 through observed changes across the Integrated Carbon Observation System (ICOS) network, through biosphere and inverse modelling, and through remote sensing. Highly correlated yet independently-derived reductions in productivity from sun-induced fluorescence, vegetative near-infrared reflectance, and GPP simulated by the Simple Biosphere model version 4 (SiB4) suggest a 130-340 TgC GPP reduction in July-August-September (JAS) of 2018. This occurs over an area of 1.6 × 106 km2 with anomalously low precipitation in northwestern and central Europe. In this drought-affected area, reduced GPP, TER, NEE and soil moisture at ICOS ecosystem sites are reproduced satisfactorily by the SiB4 model. We found that, in contrast to the preceding 5 years, low soil moisture is the main stress factor across the affected area. SiB4's NEE reduction by 57 TgC for JAS coincides with anomalously high atmospheric CO2 observations in 2018, and this is closely matched by the NEE anomaly derived by CarbonTracker Europe (52 to 83 TgC). Increased NEE during the spring (May-June) of 2018 (SiB4 -52 TgC; CTE -46 to -55 TgC) largely offset this loss, as ecosystems took advantage of favourable growth conditions. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.

Surface-Atmosphere Coupling Scale, the Fate of Water, and Ecophysiological Function in a Brazilian Forest.

Tropical South America plays a central role in global climate. Bowen ratio teleconnects to circulation and precipitation processes far afield, and the global CO2 growth rate is strongly influenced by carbon cycle processes in South America. However, quantification of basin-wide seasonality of flux partitioning between latent and sensible heat, the response to anomalies around climatic norms, and understanding of the processes and mechanisms that control the carbon cycle remains elusive. Here, we investigate simulated surface-atmosphere interaction at a single site in Brazil, using models with different representations of precipitation and cloud processes, as well as differences in scale of coupling between the surface and atmosphere. We find that the model with parameterized clouds/precipitation has a tendency toward unrealistic perpetual light precipitation, while models with explicit treatment of clouds produce more intense and less frequent rain. Models that couple the surface to the atmosphere on the scale of kilometers, as opposed to tens or hundreds of kilometers, produce even more realistic distributions of rainfall. Rainfall intensity has direct consequences for the "fate of water," or the pathway that a hydrometeor follows once it interacts with the surface. We find that the model with explicit treatment of cloud processes, coupled to the surface at small scales, is the most realistic when compared to observations. These results have implications for simulations of global climate, as the use of models with explicit (as opposed to parameterized) cloud representations becomes more widespread.

Toe Walking: A Neurological Perspective After Referral From Pediatric Orthopaedic Surgeons.

BACKGROUND: Toe walking (TW) in children is often idiopathic in origin. Our purpose was to determine the incidence of a neurological etiology for TW in patients seen in the neurology clinic after referral from pediatric orthopaedic surgeons. METHODS: We performed an Institutional Review Board approved retrospective review of 174 patients referred to the neurology clinic from orthopaedic surgeons at an academic pediatric tertiary care center between January 2010 and September 2015. Medical records were reviewed and data recorded including pertinent family history, birth history, age of initial ambulation, physical examination findings, and workup results including neuroimaging, neurophysiological studies, and findings of genetic testing and tissue biopsy. RESULTS: Sixty-two percent (108/174) of patients were found to have a neurological etiology for TW. Final pathologic diagnoses were: 37% (40/108) previously undiagnosed cerebral palsy (CP), 16.7% (18/108) peripheral neuropathy, 15.7% (17/108) autism spectrum disorder, 13.9% (15/108) hereditary spastic paraparesis, 8.3% (9/108) attention deficit hyperactivity disorder, 5.6% (6/108) syndromic diagnosis, and 2.8% (3/108) spinal cord abnormality. Ankle equinus contractures were noted in idiopathic and neurological patients and did not indicate a pathologic origin. Seventy-one percent of unilateral toe walkers and 32% of bilateral but asymmetric toe walkers were diagnosed with CP (P<0.001). Twenty-six percent of 145 brain magnetic resonance imaging studies diagnosed CP. Of the 125 (72%) with spinal imaging, 3 had spinal pathology to account for TW. Fourteen percent of 87 subjects with an electromyography/nerve conduction study had abnormal results indicating a peripheral polyneuropathy. CONCLUSIONS: An underlying pathologic diagnosis was found in 62% of patients referred to neurology for TW. A concerning birth history, delayed initial ambulation, unilateral TW, upper or lower motor neuron signs on examination, or behavioral features may suggest a pathologic diagnosis. Ankle contracture is not predictive of an abnormal diagnosis and can be found in idiopathic patients. CP, peripheral neuropathy, autism spectrum disorder, and hereditary spastic paraparesis are the most common pathologic diagnoses identified in our population. LEVEL OF EVIDENCE: Level III-retrospective cohort.

Rationale and design of the Multicenter Medication Reconciliation Quality Improvement Study (MARQUIS).

BACKGROUND: Unresolved medication discrepancies during hospitalization can contribute to adverse drug events, resulting in patient harm. Discrepancies can be reduced by performing medication reconciliation; however, effective implementation of medication reconciliation has proven to be challenging. The goals of the Multi-Center Medication Reconciliation Quality Improvement Study (MARQUIS) are to operationalize best practices for inpatient medication reconciliation, test their effect on potentially harmful unintentional medication discrepancies, and understand barriers and facilitators of successful implementation. METHODS: Six U.S. hospitals are participating in this quality improvement mentored implementation study. Each hospital has collected baseline data on the primary outcome: the number of potentially harmful unintentional medication discrepancies per patient, as determined by a trained on-site pharmacist taking a "gold standard" medication history. With the guidance of their mentors, each site has also begun to implement one or more of 11 best practices to improve medication reconciliation. To understand the effect of the implemented interventions on hospital staff and culture, we are performing mixed methods program evaluation including surveys, interviews, and focus groups of front line staff and hospital leaders. DISCUSSION: At baseline the number of unintentional medication discrepancies in admission and discharge orders per patient varies by site from 2.35 to 4.67 (mean=3.35). Most discrepancies are due to history errors (mean 2.12 per patient) as opposed to reconciliation errors (mean 1.23 per patient). Potentially harmful medication discrepancies averages 0.45 per patient and varies by site from 0.13 to 0.82 per patient. We discuss several barriers to implementation encountered thus far. In the end, we anticipate that MARQUIS tools and lessons learned have the potential to decrease medication discrepancies and improve patient outcomes. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01337063.

The chemokine receptors CXCR1 and CXCR2 couple to distinct G protein-coupled receptor kinases to mediate and regulate leukocyte functions.

The chemokine receptors, CXCR1 and CXCR2, couple to Gαi to induce leukocyte recruitment and activation at sites of inflammation. Upon activation by CXCL8, these receptors become phosphorylated, desensitized, and internalized. In this study, we investigated the role of different G protein-coupled receptor kinases (GRKs) in CXCR1- and CXCR2-mediated cellular functions. To that end, short hairpin RNA was used to inhibit GRK2, 3, 5, and 6 in RBL-2H3 cells stably expressing CXCR1 or CXCR2, and CXCL8-mediated receptor activation and regulation were assessed. Inhibition of GRK2 and GRK6 increased CXCR1 and CXCR2 resistance to phosphorylation, desensitization, and internalization, respectively, and enhanced CXCL8-induced phosphoinositide hydrolysis and exocytosis in vitro. GRK2 depletion diminished CXCR1-induced ERK1/2 phosphorylation but had no effect on CXCR2-induced ERK1/2 phosphorylation. GRK6 depletion had no significant effect on CXCR1 function. However, peritoneal neutrophils from mice deficient in GRK6 (GRK6(-/-)) displayed an increase in CXCR2-mediated G protein activation but in vitro exhibited a decrease in chemotaxis, receptor desensitization, and internalization relative to wild-type (GRK6(+/+)) cells. In contrast, neutrophil recruitment in vivo in GRK6(-/-) mice was increased in response to delivery of CXCL1 through the air pouch model. In a wound-closure assay, GRK6(-/-) mice showed enhanced myeloperoxidase activity, suggesting enhanced neutrophil recruitment, and faster wound closure compared with GRK6(+/+) animals. Taken together, the results indicate that CXCR1 and CXCR2 couple to distinct GRK isoforms to mediate and regulate inflammatory responses. CXCR1 predominantly couples to GRK2, whereas CXCR2 interacts with GRK6 to negatively regulate receptor sensitization and trafficking, thus affecting cell signaling and angiogenesis.

Pharmacists' recommendations to improve care transitions.

BACKGROUND: Increasingly, hospitals are implementing multifaceted programs to improve medication reconciliation and transitions of care, often involving pharmacists. OBJECTIVE: To assess pharmacists' views on their roles in hospital-based medication reconciliation and discharge counseling and provide their recommendations for improving care transitions. METHODS: Eleven study pharmacists at 2 hospitals participated in the Pharmacist Intervention for Low Literacy in Cardiovascular Disease (PILL-CVD) study and completed semistructured one-on-one interviews, which were coded systematically in NVivo. Pharmacists provided their perspectives on admission and discharge medication reconciliation, in-hospital patient counseling, provision of simple medication adherence aids (eg, pill box, illustrated daily medication schedule), and telephone follow-up. RESULTS: Pharmacists indicated that they considered medication reconciliation, although time consuming, to be their most important role in improving care transitions, particularly through detection of errors that required correction in the admission medication history. They also identified patients who required additional counseling because of poor understanding of their medications. Providing adherence aids was felt to be highly valuable for patients with low health literacy, although less useful for patients with adequate health literacy. Pharmacists noted that having trained administrative staff conduct initial postdischarge follow-up calls to screen for issues and triage which patients needed pharmacist follow-up was helpful and an efficient use of resources. Pharmacists' recommendations for improving care transitions included clear communication among team members, protected time for discharge counseling, patient and family engagement in discharge counseling, and provision of patient education materials. CONCLUSIONS: Pharmacists are well positioned to participate in hospital-based medication reconciliation, identify patients with poor medication understanding or adherence, and provide tailored patient counseling to improve transitions of care. Additional studies are needed to confirm these findings in other settings and to determine the efficacy and cost-effectiveness of different models of pharmacist involvement.

Building a science of partnership-focused research: forging and sustaining partnerships to support child mental health prevention and services research.

Building on growing interest in translational research, this paper provides an overview of a special issue of Administration and Policy in Mental Health and Mental Health Service Research, which is focused on the process of forging and sustaining partnerships to support child mental health prevention and services research. We propose that partnership-focused research is a subdiscipline of translational research which requires additional research to better refine the theoretical framework and the core principles that will guide future research and training efforts. We summarize some of the major themes across the eight original articles and three commentaries included in the special issue. By advancing the science of partnership-focused research we will be able to bridge the gap between child mental health prevention and services research and practice.

Developing effective research-practice partnerships for creating a culture of evidence-based decision making.

With growing evidence that treatment as usual may have limited effectiveness in mental health the pressure on service providers to be accountable and produce evidence as to the effectiveness of their services has increased. Measurement Feedback Systems, such as the Contextualized Feedback System (CFS), have the potential to be powerful tools for service providers in assessing their own effectiveness at multiple levels with an organization. These systems represent an amalgamation of the data driven world of science and the experience driven world of clinical practice. However, the synthesis of these two worlds is not without significant challenges as these two very different cultures can easily clash. The key for successful collaboration in developing and implementing Measurement Feedback Systems is a good university-practice partnership that has a strong foundation in common goals and the positive relationships among its members. In addition, the partnership needs to be flexible so that it can adapt to new challenges and continuously grow with each obstacle. These are some of several lessons learned the authors of this article will share as part of their experience with developing and implementing CFS in one of the largest behavioral health service providers in the U.S.

An impetus to move the field forward: a look at child and adolescent mental health services participants' views of the prospects for change.

In September 2009 key stakeholders convened for the invitation-only Child and Adolescent Mental Health Services (CAMHS): Issues and Solutions conference. This paper provides a brief synopsis of the key high points and issues in children's mental health (CMH) and describes the process by which participants collectively brainstormed the priorities and distilled the four key foci for the new action agenda, and summarizes the key outcomes. In addition, this paper offers participants' perspectives on the conference. Based on observation notes and post-conference qualitative interviews, this paper reports conference participants' feedback on the event, their views on the prospects for change generated by the conference and suggestions for follow-up.