Recent advances in treatment of spatial neglect: networks and neuropsychology.

INTRODUCTION: Spatial neglect remains an underdiagnosed and undertreated consequence of stroke that imposes significant disability. A growing appreciation of brain networks involved in spatial cognition is helping us to develop a mechanistic understanding of different therapies under development. AREAS COVERED: This review focuses on neuromodulation of brain networks for the treatment of spatial neglect after stroke, using evidence-based approaches including 1) Cognitive strategies that are more likely to impact frontal lobe executive function networks; 2) Visuomotor adaptation, which may depend on the integrity of parietal and parieto- and subcortical-frontal connections and the presence of a particular subtype of neglect labeled Aiming neglect; 3) Non-invasive brain stimulation that may modulate relative levels of activity of the two hemispheres and depend on corpus callosum connectivity; and 4) Pharmacological modulation that may exert its effect primarily via right-lateralized networks more closely involved in arousal. EXPERT OPINION: Despite promising results from individual studies, significant methodological heterogeneity between trials weakened conclusions drawn from meta-analyses. Improved classification of spatial neglect subtypes will benefit research and clinical care. Understanding the brain network mechanisms of different treatments and different types of spatial neglect will make possible a precision medicine treatment approach.

A report card approach to describe temporal and spatial trends in parameters for coastal seagrass habitats.

Report cards that are designed to monitor environmental trends have the potential to provide a powerful communication tool because they are easy to understand and accessible to the general public, scientists, managers and policy makers. Given this functionality, they are increasingly popular in marine ecosystem reporting. We describe a report card method for seagrass that incorporates spatial and temporal variability in three metrics-meadow area, species and biomass-developed using long-term (greater than 10 years) monitoring data. This framework summarises large amounts of spatially and temporally complex data to give a numeric score that provides reliable comparisons of seagrass condition in both persistent and naturally variable meadows. We provide an example of how this is applied to seagrass meadows in an industrial port in the Great Barrier Reef World Heritage Area of north-eastern Australia.

Development of a Screencast-Based Flipped Classroom to Enrich Learning and Reduce Faculty Time Requirements in an Animal Welfare Master's Degree.

A new distance learning Master of Science (MSc) degree in Animal Welfare Science, Ethics and Law was established in 2016 within the Centre for Animal Welfare at the University of Winchester, UK. Our program recruited students worldwide, with enrollments increasing dramatically since its inception in 2016. However, despite rapid growth, our MSc has had only one full-time equivalent faculty member. With further projected sharp increases in student numbers, significant programmatic change was required for the MSc to remain viable. After consultation with our students and program team, we decided to transition to a flipped classroom teaching model. Piloting a screencast-based flipped classroom in one course, our objectives were to provide a more enriched, engaging, and effective student learning experience and to increase student satisfaction while concurrently saving staff time in future years. We aimed to provide a series of enriched screencast videos of short (∼20-minute) durations, with contents clearly signposted. The new teaching model was well received. Within our 2021 program survey, 100% of respondents expressed a wish to see our screencast-based flipped classroom approach continued, and 71%-86% wished to see it implemented in various additional courses. This model has greatly enriched students' learning experiences, increasing student engagement and satisfaction while also freeing staff time to engage in discussion fora and additional live sessions. Learning and achievement outcomes also appear positive. We plan to steadily integrate this model across additional courses, although initial time investment will be significant. Hence, this new model will be implemented over several semesters.

Community-specific "desired" states for seagrasses through cycles of loss and recovery.

Seagrass habitats provide critical ecosystem services, yet there is ongoing concern over mounting pressures and continuing degradation. Defining a desired state for these habitats is a key step in implementing appropriate management but is often difficult given the challenges of available data and an evaluation of where to set benchmarks. We use more than 20 years of historical seagrass biomass data (1995-2018) for the diverse seagrass communities of Australia's Great Barrier Reef World Heritage Area (GBRWHA) to develop desired state benchmarks. Desired state for seagrass biomass was estimated for 25 of 36 previously defined seagrass communities with the remainder having insufficient data. Desired state varied by more than one order of magnitude between community types and was influenced by the mix of species in the communities and the range of environmental conditions. We identify a historical, decadal-scale cycle of decline with recovery to desired state in coastal intertidal communities. In contrast a number of the estuary and coastal subtidal communities have not recovered to desired state biomass. Understanding a historical context is critically important for setting benchmarks and making informed management decisions on the present state of seagrass in the GBRWHA. The approach we have developed is scalable for monitoring, management and assessment of pressures for other management areas and for other jurisdictions. Our results guide conservation planning through prioritization of the at-risk seagrass communities that are continuing to fall below their desired state.

A spatial analysis of seagrass habitat and community diversity in the Great Barrier Reef World Heritage Area.

The Great Barrier Reef World Heritage Area (GBRWHA) in north eastern Australia spans 2500 km of coastline and covers an area of ~ 350,000 km2. It includes one of the world's largest seagrass resources. To provide a foundation to monitor, establish trends and manage the protection of seagrass meadows in the GBRWHA we quantified potential seagrass community extent using six random forest models that include environmental data and seagrass sampling history. We identified 88,331 km2 of potential seagrass habitat in intertidal and subtidal areas: 1111 km2 in estuaries, 16,276 km2 in coastal areas, and 70,934 km2 in reef areas. Thirty-six seagrass community types were defined by species assemblages within these habitat types using multivariate regression tree models. We show that the structure, location and distribution of the seagrass communities is the result of complex environmental interactions. These environmental conditions include depth, tidal exposure, latitude, current speed, benthic light, proportion of mud in the sediment, water type, water temperature, salinity, and wind speed. Our analysis will underpin spatial planning, can be used in the design of monitoring programs to represent the diversity of seagrass communities and will facilitate our understanding of environmental risk to these habitats.

Connecting targets for catchment sediment loads to ecological outcomes for seagrass using multiple lines of evidence.

Catchment impacts on downstream ecosystems are difficult to quantify, but important for setting management targets. Here we compared 12 years of monitoring data of seagrass area and biomass in Cleveland Bay, northeast Australia, with discharge and associated sediment loads from nearby rivers. Seagrass biomass and area exhibited different trajectories in response to river inputs. River discharge was a slightly better predictor of seagrass indicators than total suspended solid (TSS) loads, indicating that catchment effects on seagrass are not restricted to sediment. Linear relationships between Burdekin River TSS loads delivered over 1-4 years and seagrass condition in Cleveland Bay generated Ecologically Relevant Targets (ERT) for catchment sediment inputs. Our predicted ERTs were comparable to those previously estimated using mechanistic models. This study highlights the challenges of linking catchment inputs to condition of downstream ecosystems, and the importance of integrating a variety of metrics and approaches to increase confidence in ERTs.

Evaluating the impact of image guidance in the surgical setting: a systematic review.

BACKGROUND: Image guidance has been clinically available for over a period of 20 years. Although research increasingly has a translational emphasis, overall the clinical uptake of image guidance systems in surgery remains low. The objective of this review was to establish the metrics used to report on the impact of surgical image guidance systems used in a clinical setting. METHODS: A systematic review of the literature was carried out on all relevant publications between January 2000 and April 2016. Ovid MEDLINE and Embase databases were searched using a title strategy. Reported outcome metrics were grouped into clinically relevant domains and subsequent sub-categories for analysis. RESULTS: In total, 232 publications were eligible for inclusion. Analysis showed that clinical outcomes and system interaction were consistently reported. However, metrics focusing on surgeon, patient and economic impact were reported less often. No increase in the quality of reporting was observed during the study time period, associated with study design, or when the clinical setting involved a surgical specialty that had been using image guidance for longer. CONCLUSIONS: Publications reporting on the clinical use of image guidance systems are evaluating traditional surgical outcomes and neglecting important human and economic factors, which are pertinent to the uptake, diffusion and sustainability of image-guided surgery. A framework is proposed to assist researchers in providing comprehensive evaluation metrics, which should also be considered in the design phase. Use of these would help demonstrate the impact in the clinical setting leading to increased clinical integration of image guidance systems.

Clinical and Physiologic Predictors and Postoperative Outcomes of Near Dehiscence Syndrome.

OBJECTIVE: To identify predictors of near dehiscence (ND) or thin rather than dehiscent bone overlying the superior semicircular canal in patients with signs and symptoms suggestive of superior semicircular canal dehiscence syndrome (SCDS), as well as postoperative outcomes. STUDY DESIGN: Retrospective case-control study. SETTING: Tertiary referral center. PATIENTS: All 288 patients who underwent middle cranial fossa approach for repair of SCDS (1998-2018) were reviewed for cases of ND. Demographics, symptoms, and clinical signs including nystagmus, ocular vestibular-evoked myogenic potential (oVEMP) amplitude, cervical vestibular-evoked myogenic potential (cVEMP) thresholds, and low-frequency air-bone gap were compared before and after surgery. MAIN OUTCOME MEASURE: Presence of preoperative ND and postoperative symptoms and physiologic measures. RESULTS: Seventeen cases of ND (16 patients, 17 ears) and 34 cases (34 ears) of frank SCDS were identified. ND cases differed from frank dehiscence cases in that they were less likely to have nystagmus in response to ear canal pressure or loud sounds, OR = 0.05 (95% CI 0.01-0.25) and Valsalva, OR = 0.08 (0.01-0.67), smaller peak-to-peak oVEMP amplitudes, OR = 0.84 (0.75-0.95), and higher cVEMP thresholds, OR = 1.21 (1.07-1.37). Patients with ND had similar symptoms to those with frank SCDS before surgery, and after surgery had outcomes similar to patients with frank SCDS. CONCLUSIONS: In patients with symptoms consistent with SCDS, predictors of ND include absence of nystagmus in response to pressure/loud sounds, greater cVEMP thresholds, and smaller oVEMP amplitudes. We propose ND is on a spectrum of dehiscence that partially accounts for the diversity of clinical presentations of patients with SCDS.

A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma.

Multiple myeloma (MM) is an incurable hematologic malignancy of plasma cells, with an estimated 30,000 new cases diagnosed each year in the United States, signifying the need for new therapeutic approaches. We hypothesized that targeting MM using a bispecific antibody (biAb) to simultaneously engage both innate and adaptive cytolytic immune cells could present potent antitumor activity. We engineered a biAb by fusing an anti-CS1 single-chain variable fragment (scFv) and an anti-NKG2D scFv (CS1-NKG2D biAb). Although NKG2D is a potent activation receptor ubiquitously expressed on mostly cytolytic immune cells including NK cells, CD8+ T cells, γδ T cells, and NKT cells, the CS1 tumor-associated antigen on MM represents a promising target. CS1-NKG2D biAb engaged human MM cell lines and NKG2D+ immune cells, forming immune synapses. In effector cells, CS1-NKG2D biAb triggered the phosphorylation of AKT, a downstream protein kinase of the activated NKG2D-DAP10 complex. The EC50 values of CS1-NKG2D biAb for CS1high and for CS1low MM cell lines with effector PBMCs were 10-12 and 10-9 mol/L, respectively. CS1-NKG2D biAb acted through multiple types of immune cells, and this induced cytotoxicity was both CS1- and NKG2D-specific. In vivo, survival was significantly prolonged using CS1-NKG2D biAb in a xenograft NOD-SCIDIL2γc-/- (NSG) mouse model engrafted with both human PBMCs and MM cell lines. Collectively, we demonstrated that the CS1-NKG2D biAb facilitated an enhanced immune synapse between CS1+ MM cells and NKG2D+ cytolytic innate and antigen-specific effector cells, which, in turn, activated these immune cells for improved clearance of MM. Cancer Immunol Res; 6(7); 776-87. ©2018 AACR.

Differential white matter involvement associated with distinct visuospatial deficits after right hemisphere stroke.

Visuospatial attention depends on the integration of multiple processes, and people with right hemisphere lesions after a stroke may exhibit severe or no visuospatial deficits. The anatomy of core components of visuospatial attention is an area of intense interest. Here we examine the relationship between the disruption of core components of attention and lesion distribution in a heterogeneous group (N = 70) of patients with right hemisphere strokes regardless of the presence of clinical neglect. Deficits of lateralized spatial orienting, measured as the difference in reaction times for responding to visual targets in the contralesional or ipsilesional visual field, and deficits in re-orienting attention, as measured by the difference in reaction times for invalidly versus validly cued targets, were measured using a computerized spatial orienting task. Both measures were related through logistic regression and a novel ridge regression method to anatomical damage measured with magnetic resonance imaging. While many regions were common to both deficit maps, a deficit in lateralized spatial orienting was more associated with lesions in the white matter underlying the posterior parietal cortex, and middle and inferior frontal gyri. A deficit in re-orienting of attention toward unattended locations was associated with lesions in the white matter of the posterior parietal cortex, insular cortex and less so with white matter involvement of the anterior frontal lobe. An hodological analysis also supports this partial dissociation between the white matter tracts that are damaged in lateralized spatial biases versus impaired re-orienting. Our results underscore that the integrity of fronto-parietal white matter tracts is crucial for visuospatial attention and that different attention components are mediated by partially distinct neuronal substrates.

Identifying knowledge gaps in seagrass research and management: An Australian perspective.

Seagrass species form important marine and estuarine habitats providing valuable ecosystem services and functions. Coastal zones that are increasingly impacted by anthropogenic development have experienced substantial declines in seagrass abundance around the world. Australia, which has some of the world's largest seagrass meadows and is home to over half of the known species, is not immune to these losses. In 1999 a review of seagrass ecosystems knowledge was conducted in Australia and strategic research priorities were developed to provide research direction for future studies and management. Subsequent rapid evolution of seagrass research and scientific methods has led to more than 70% of peer reviewed seagrass literature being produced since that time. A workshop was held as part of the Australian Marine Sciences Association conference in July 2015 in Geelong, Victoria, to update and redefine strategic priorities in seagrass research. Participants identified 40 research questions from 10 research fields (taxonomy and systematics, physiology, population biology, sediment biogeochemistry and microbiology, ecosystem function, faunal habitats, threats, rehabilitation and restoration, mapping and monitoring, management tools) as priorities for future research on Australian seagrasses. Progress in research will rely on advances in areas such as remote sensing, genomic tools, microsensors, computer modeling, and statistical analyses. A more interdisciplinary approach will be needed to facilitate greater understanding of the complex interactions among seagrasses and their environment.

Dynamics of a deep-water seagrass population on the Great Barrier Reef: annual occurrence and response to a major dredging program.

Global seagrass research efforts have focused on shallow coastal and estuarine seagrass populations where alarming declines have been recorded. Comparatively little is known about the dynamics of deep-water seagrasses despite evidence that they form extensive meadows in some parts of the world. Deep-water seagrasses are subject to similar anthropogenic threats as shallow meadows, particularly along the Great Barrier Reef lagoon where they occur close to major population centres. We examine the dynamics of a deep-water seagrass population in the GBR over an 8 year period during which time a major capital dredging project occurred. Seasonal and inter-annual changes in seagrasses were assessed as well as the impact of dredging. The seagrass population was found to occur annually, generally present between July and December each year. Extensive and persistent turbid plumes from a large dredging program over an 8 month period resulted in a failure of the seagrasses to establish in 2006, however recruitment occurred the following year and the regular annual cycle was re-established. Results show that despite considerable inter annual variability, deep-water seagrasses had a regular annual pattern of occurrence, low resistance to reduced water quality but a capacity for rapid recolonisation on the cessation of impacts.

High-Intensity, Unilateral Resistance Training of a Non-Paretic Muscle Group Increases Active Range of Motion in a Severely Paretic Upper Extremity Muscle Group after Stroke.

Limited rehabilitation strategies are available for movement restoration when paresis is too severe following stroke. Previous research has shown that high-intensity resistance training of one muscle group enhances strength of the homologous, contralateral muscle group in neurologically intact adults. How this "cross education" phenomenon might be exploited to moderate severe weakness in an upper extremity muscle group after stroke is not well understood. The primary aim of this study was to examine adaptations in force-generating capacity of severely paretic wrist extensors resulting from high intensity, dynamic contractions of the non-paretic wrist extensors. A secondary, exploratory aim was to probe neural adaptations in a subset of participants from each sample using a single-pulse, transcranial magnetic stimulation (TMS) protocol. Separate samples of neurologically intact controls (n = 7) and individuals ≥4 months post stroke (n = 6) underwent 16 sessions of training. Following training, one-repetition maximum of the untrained wrist extensors in the control group and active range of motion of the untrained, paretic wrist extensors in the stroke group were significantly increased. No changes in corticospinal excitability, intracortical inhibition, or interhemispheric inhibition were observed in control participants. Both stroke participants who underwent TMS testing, however, exhibited increased voluntary muscle activation following the intervention. In addition, motor-evoked potentials that were unobtainable prior to the intervention were readily elicited afterwards in a stroke participant. Results of this study demonstrate that high-intensity resistance training of a non-paretic upper extremity muscle group can enhance voluntary muscle activation and force-generating capacity of a severely paretic muscle group after stroke. There is also preliminary evidence that corticospinal adaptations may accompany these gains.

Common behavioral clusters and subcortical anatomy in stroke.

A long-held view is that stroke causes many distinct neurological syndromes due to damage of specialized cortical and subcortical centers. However, it is unknown if a syndrome-based description is helpful in characterizing behavioral deficits across a large number of patients. We studied a large prospective sample of first-time stroke patients with heterogeneous lesions at 1-2 weeks post-stroke. We measured behavior over multiple domains and lesion anatomy with structural MRI and a probabilistic atlas of white matter pathways. Multivariate methods estimated the percentage of behavioral variance explained by structural damage. A few clusters of behavioral deficits spanning multiple functions explained neurological impairment. Stroke topography was predominantly subcortical, and disconnection of white matter tracts critically contributed to behavioral deficits and their correlation. The locus of damage explained more variance for motor and language than memory or attention deficits. Our findings highlight the need for better models of white matter damage on cognition.

Large-scale changes in network interactions as a physiological signature of spatial neglect.

The relationship between spontaneous brain activity and behaviour following focal injury is not well understood. Here, we report a large-scale study of resting state functional connectivity MRI and spatial neglect following stroke in a large (n=84) heterogeneous sample of first-ever stroke patients (within 1-2 weeks). Spatial neglect, which is typically more severe after right than left hemisphere injury, includes deficits of spatial attention and motor actions contralateral to the lesion, and low general attention due to impaired vigilance/arousal. Patients underwent structural and resting state functional MRI scans, and spatial neglect was measured using the Posner spatial cueing task, and Mesulam and Behavioural Inattention Test cancellation tests. A principal component analysis of the behavioural tests revealed a main factor accounting for 34% of variance that captured three correlated behavioural deficits: visual neglect of the contralesional visual field, visuomotor neglect of the contralesional field, and low overall performance. In an independent sample (21 healthy subjects), we defined 10 resting state networks consisting of 169 brain regions: visual-fovea and visual-periphery, sensory-motor, auditory, dorsal attention, ventral attention, language, fronto-parietal control, cingulo-opercular control, and default mode. We correlated the neglect factor score with the strength of resting state functional connectivity within and across the 10 resting state networks. All damaged brain voxels were removed from the functional connectivity:behaviour correlational analysis. We found that the correlated behavioural deficits summarized by the factor score were associated with correlated multi-network patterns of abnormal functional connectivity involving large swaths of cortex. Specifically, dorsal attention and sensory-motor networks showed: (i) reduced interhemispheric functional connectivity; (ii) reduced anti-correlation with fronto-parietal and default mode networks in the right hemisphere; and (iii) increased intrahemispheric connectivity with the basal ganglia. These patterns of functional connectivity:behaviour correlations were stronger in patients with right- as compared to left-hemisphere damage and were independent of lesion volume. Our findings identify large-scale changes in resting state network interactions that are a physiological signature of spatial neglect and may relate to its right hemisphere lateralization.

Resting-state functional connectivity and its association with multiple domains of upper-extremity function in chronic stroke.

BACKGROUND: Recent work has shown that resting-state functional connectivity (rsFC) between homotopic, motor-related brain regions is associated with upper-extremity control early after stroke. OBJECTIVES: This study examined various patterns of rsFC in chronic stroke, a time at which extensive neural reorganization has occurred. Associations between homotopic somatomotor connectivity and clinical measures, representing separate domains of upper-extremity function, were determined. METHODS: A total of 19 persons ≥6 months poststroke participated. Four connectivity patterns within a somatomotor network were quantified using functional magnetic resonance imaging. Upper-extremity gross muscle activation, control, and real-world use were evaluated with the Motricity Index, Action Research Arm Test, and accelerometry, respectively. RESULTS: Connectivity between homotopic regions was stronger than that in the contralesional and ipsilesional hemispheres. No differences in connectivity strength were noted between homotopic pairs, indicating that a specific brain structure was not driving somatomotor network connectivity. Homotopic connectivity was significantly associated with both upper-extremity control (r = 0.53; P= .02) and real-world use (r = 0.54; P= .02); however, there was no association with gross muscle activation (r = 0.23; P=.34). The combination of clinical measures accounted for 40% of the variance in rsFC (= .05). CONCLUSIONS: The results reported here expand on previous findings, indicating that homotopic rsFC persists in chronic stroke and discriminates between varying levels of upper-extremity control and real-world use. Further work is needed to evaluate its adequacy as a biomarker of motor recovery following stroke.

Why use a connectivity-based approach to study stroke and recovery of function?

The brain is organized into a set of widely distributed networks. Therefore, although structural damage from stroke is focal, remote dysfunction can occur in regions connected to the area of lesion. Historically, neuroscience has focused on local processing due in part to the absence of tools to study the function of distributed networks. In this article we discuss how a more comprehensive understanding of the effects of stroke can be attained using resting state functional connectivity BOLD magnetic resonance imaging (resting state fcMRI). Resting state fcMRI has a number of advantages over task-evoked fMRI for studying brain network reorganization in response to stroke, including the ability to image subjects with a broad range of impairments and the ability to study multiple networks simultaneously. We describe our rationale for using resting state connectivity as a tool for investigating the neural substrates of stroke recovery in a heterogeneous population of stroke patients and discuss the main questions we hope to answer, in particular whether resting state fcMRI measures in the acute phase of stroke can predict subsequent recovery. Early results suggest that disruption of inter-hemispheric connectivity in the somatomotor network and the dorsal attention network is more strongly associated with behavioral impairment in those domains than is intra-hemispheric connectivity within either the lesioned or unaffected hemisphere. We also observe in the somatomotor network an interesting interaction between corticospinal tract damage and decreased inter-hemispheric connectivity that suggests that both processes combine to contribute to neuromotor impairment after stroke. A connectivity-based approach will provide greater insight into network reorganization in the acute and chronic phases after stroke and will contribute to improving prognostic ability and the development of therapeutic interventions.

Upstream dysfunction of somatomotor functional connectivity after corticospinal damage in stroke.

BACKGROUND: Recent studies have shown that focal injuries can have remote effects on network function that affect behavior, but these network-wide repercussions are poorly understood. OBJECTIVE: This study tested the hypothesis that lesions specifically to the outflow tract of a distributed network can result in upstream dysfunction in structurally intact portions of the network. In the somatomotor system, this upstream dysfunction hypothesis predicted that lesions of the corticospinal tract might be associated with functional disruption within the system. Motor impairment might then reflect the dual contribution of corticospinal damage and altered network functional connectivity. METHODS: A total of 23 subacute stroke patients and 13 healthy controls participated in the study. Corticospinal tract damage was quantified using a template of the tract generated from diffusion tensor imaging in healthy controls. Somatomotor network functional integrity was determined by resting state functional connectivity magnetic resonance imaging. RESULTS: The extent of corticospinal damage was negatively correlated with interhemispheric resting functional connectivity, in particular with connectivity between the left and right central sulcus. Although corticospinal damage accounted for much of the variance in motor performance, the behavioral impact of resting connectivity was greater in subjects with mild or moderate corticospinal damage and less in those with severe corticospinal damage. CONCLUSIONS: Our results demonstrated that dysfunction of cortical functional connectivity can occur after interruption of corticospinal outflow tracts and can contribute to impaired motor performance. Recognition of these secondary effects from a focal lesion is essential for understanding brain-behavior relationships after injury, and they may have important implications for neurorehabilitation.

Rehabilitation after stroke: current state of the science.

Stroke rehabilitation is evolving into a clinical field based on the neuroscience of recovery and restoration. There has been substantial growth in the number and quality of clinical trials performed. Much effort now is directed toward motor restoration and is being led by trials of constraint-induced movement therapy. Although the results do not necessarily support that constraint-induced movement therapy is superior to other training methods, this treatment has become an important vehicle for developing clinical trial methods and studying the physiology underlying activity-based rehabilitation strategies. Other promising interventions include robotic therapy delivery, magnetic and electrical cortical stimulation, visualization, and constraint-driven aphasia therapies. Amphetamine has not been demonstrated to be effective, and studies of other pharmacologic agents are still preliminary. Future studies will incorporate refinements in clinical trial methods and improved activity- and technology-based interventions.