The dementia care study (D-CARE): Recruitment strategies and demographic characteristics of participants in a pragmatic randomized trial of dementia care.

INTRODUCTION: Pragmatic research studies that include diverse dyads of persons living with dementia (PLWD) and their family caregivers are rare. METHODS: Community-dwelling dyads were recruited for a pragmatic clinical trial evaluating three approaches to dementia care. Four clinical trial sites used shared and site-specific recruitment strategies to enroll health system patients. RESULTS: Electronic health record (EHR) queries of patients with a diagnosis of dementia and engagement of their clinicians were the main recruitment strategies. A total of 2176 dyads were enrolled, with 80% recruited after the onset of the pandemic. PLWD had a mean age of 80.6 years (SD 8.5), 58.4% were women, and 8.8% were Hispanic/Latino, and 11.9% were Black/African American. Caregivers were mostly children of the PLWD (46.5%) or spouses/partners (45.2%), 75.8% were women, 9.4% were Hispanic/Latino, and 11.6% were Black/African American. DISCUSSION: Health systems can successfully enroll diverse dyads in a pragmatic clinical trial.

Polysorbate 80-Induced Anaphylactoid Reaction and the Effects on Cardiovascular Function: Dose Threshold and Species Comparison.

Polysorbate 80 (PS80) is commonly used in pre-clinical formulations. The dose threshold for cardiovascular (CV) changes and hypersensitivity reaction in the dog was assessed and compared to other species. PS80 was administered by intravenous (IV) bolus (.5, 1 mg/kg), IV infusion (.3, .5, 1, 3 mg/kg), subcutaneous (SC) injection (5, 10, 15 mg/kg) and oral gavage (10 mg/kg) to dogs with CV monitoring. Monkeys and minipigs received PS80 by IV infusion at 3 mg/kg. Plasma histamine concentration was measured following PS80 IV infusion and with diphenhydramine pre-treatment in dogs only. In dogs, PS80 was not associated with CV changes at doses up to 15 mg/kg SC and 10 mg/kg oral, but decreased blood pressure and increased heart rate with IV bolus at ≥ .5 mg/kg and IV infusion at ≥ 1.0 mg/kg and decreased body temperature with IV infusion at 3 mg/kg was observed. Transient edema and erythema were noted with all administration routes, in all three species including doses that were devoid of CV effects. In monkeys and minipigs, PS80 did not induce CV, cutaneous or histamine concentration changes. These results suggest that mild, transient skin changes occur following PS80 administration at doses that are not associated with CV effects in the dogs. In dogs, the cardiovascular effect threshold was <.5 mg/kg for IV bolus, .3 mg/kg for IV infusion, 15 mg/kg for SC injection, and 10 mg/kg for oral administration. Monkey and minipig were refractory to PS80-induced histamine release at 3 mg/kg by IV infusion over 15 minutes.

Foreign Body Reaction, Retinal Degeneration, and Epiretinal Membranes Associated With Intravitreal Administration of PLGA Rods.

Long-acting delivery platforms for intravitreal therapies are an active area of research in ophthalmic drug development. The aim of these platforms is to decrease the burden of intravitreal therapies for patients, by increasing the period between intravitreal injections. This brief communication describes the in-life, histologic and immunohistochemical findings associated with repeat-dose intravitreal administration of poly D, L sustained lactide-co-glycolide polymeric rods, an intravitreal depot, in the cynomolgus monkey (Macaca fascicularis). These nonclinical investigations illustrate a pattern of foreign body reaction around intravitreal depots at the temporal pars plana and demonstrated the histopathologic and immunohistologic features of retinal degeneration and epiretinal membrane formation in the inferior retina.

Nonclinical Toxicology and Biocompatibility Program Supporting Clinical Development and Registration of the Port Delivery System With Ranibizumab for Neovascular Age-Related Macular Degeneration.

The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed to provide continuous intravitreal release of ranibizumab for extended durations. The PDS consists of a permanent, surgically placed, refillable intraocular implant; a customized formulation of ranibizumab; and ancillary devices to support surgery and refill procedures. A toxicology program was conducted to evaluate the ocular toxicology and biocompatibility of the PDS to support its clinical development program and product registrational activities. PDS safety studies included a 6-month chronic toxicology evaluation in minipigs as well as evaluation of nonfunctional surrogate implants (comprised of the same implant materials but without ranibizumab) in rabbits. Biocompatibility of the implant and ancillary devices was evaluated in both in vitro and in vivo studies. Implants and extracts from implants and ancillary devices were nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. Ocular findings were comparable between implanted and sham-operated eyes, and no systemic toxicity was observed. The results of this nonclinical toxicology program demonstrated that the PDS was biocompatible and that intravitreal delivery of ranibizumab via the PDS did not introduce any new toxicology-related safety concerns relative to intravitreal injections, supporting ongoing PDS clinical development and product registrational evaluation.

Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung.

Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed. Mucociliary clearance in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long-lived, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.

Transient blockade of delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation.

Rejection remains a major clinical challenge limiting allograft survival after solid organ transplantation. Both cellular and humoral immunity contribute to this complication, with increased recognition of Ab-mediated damage during acute and chronic rejection. Using a mouse model of MHC-mismatched heart transplantation, we report markedly protective effects of Notch inhibition, dampening both T cell and Ab-driven rejection. T cell-specific pan-Notch blockade prolonged heart allograft survival and decreased IFN-γ and IL-4 production by alloreactive T cells, especially when combined with depletion of recipient CD8(+) T cells. These effects were associated with decreased infiltration by conventional T cells and an increased proportion of regulatory T cells in the graft. Transient administration of neutralizing Abs specific for delta-like (Dll)1/4 Notch ligands in the peritransplant period led to prolonged acceptance of allogeneic hearts, with superior outcome over Notch inhibition only in T cells. Systemic Dll1/4 inhibition decreased T cell cytokines and graft infiltration, germinal center B cell and plasmablast numbers, as well as production of donor-specific alloantibodies and complement deposition in the transplanted hearts. Dll1 or Dll4 inhibition alone provided partial protection. Thus, pathogenic signals delivered by Dll1/4 Notch ligands early after transplantation promote organ rejection through several complementary mechanisms. Transient interruption of these signals represents an attractive new therapeutic strategy to enhance long-term allograft survival.

Therapeutic antibody targeting of individual Notch receptors.

The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to differentiation and disease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.

General Intelligence (g): Overview of a Complex Construct and Its Implications for Genetics Research.

Current technology has dramatically increased the prevalence of studies to establish the genetic correlates of a wide variety of human characteristics, including not only the physical attributes that determine what we look like and the risk of physiological disease but also the psychological and cognitive characteristics that often define who we are as individuals. Perhaps one of the most deeply personal and often controversial characteristics is the concept of general intelligence, known in the psychological literature as "g." As with the genetic study of any complex trait, the first step in studying the genetics of g is to carefully define the characteristic of interest. For g, this entails establishing what intelligence means and providing a clear operational definition for how it will be measured. In this paper, we provide a brief historical and theoretical overview of the construct of general intelligence, describe its relationship to the contemporary measurement of intelligence, and discuss these concepts in light of the challenges associated with defining g as a characteristic in the study of genetics.

Obligations and Concerns of an Organization Like the Center for Talented Youth.

There is another set of entities that needs to be brought into the conversation about the ethical, legal, and social implications of scientific conduct. This widely varied group includes not-for-profit educational, academic, public-service, and philanthropic organizations other than the type mentioned above as well as for-profit businesses. Despite their major differences, these organizations may all be in a position to make decisions, directly or indirectly, about the conduct of scientific research. And those decisions may have a significant impact on the parties normally involved in thinking and talking about obligations and concerns-the researchers, the subjects, and the general public. Yet there are few if any conceptual frameworks to help organizations address the ethical, legal, and social issues related to conducting scientific research. There are also few resources to help organizations find and develop the expertise required to make responsible decisions or communicate those decisions in ways that could support and advance the ethical conduct of research. In what follows, we try to identify and explore the duties, rights, and interests of one such organization, the Center for Talented Youth at Johns Hopkins University, when asked to play a supporting role in research on the genetics of intelligence. As central agents in this case, we hope to demonstrate why organizations like CTY cannot be neglected in the broader effort to ensure trustworthy research into the genetics of intelligence.

Persistent and stable biases in spatial learning mechanisms predict navigational style.

A wealth of evidence in rodents and humans supports the central roles of two learning systems--hippocampal place learning and striatal response learning--in the formation of spatial representations to support navigation. Individual differences in the ways that these mechanisms are engaged during initial encoding and subsequent navigation may provide a powerful framework for explaining the wide range of variability found in the strategies and solutions that make up human navigational styles. Previous work has revealed that activation in the hippocampal and striatal networks during learning could predict navigational style. Here, we used functional magnetic resonance imaging to investigate the relative activations in these systems during both initial encoding and the act of dynamic navigation in a learned environment. Participants learned a virtual environment and were tested on subsequent navigation to targets within the environment. We observed that a given individual had a consistent balance of memory system engagement across both initial encoding and subsequent navigation, a balance that successfully predicted the participants' tendencies to use novel shortcuts versus familiar paths during dynamic navigation. This was further supported by the observation that the activation during subsequent retrieval was not dependent on the type of solution used on a given trial. Taken together, our results suggest a model in which the place- and response-learning systems are present in parallel to support a variety of navigational behaviors, but stable biases in the engagement of these systems influence what solutions might be available for any given individual.

Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy.

Introduction: Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities. Methods: We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This "PD1/IL15" selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials. Results: The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0-4.1 days) compared to wild-type IL-15 (half-life ∼1.1 h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003 mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data. Conclusion: This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

Cognitive mappers to creatures of habit: differential engagement of place and response learning mechanisms predicts human navigational behavior.

Learning to navigate plays an integral role in the survival of humans and other animals. Research on human navigation has largely focused on how we deliberately map out our world. However, many of us also have experiences of navigating on "autopilot" or out of habit. Animal models have identified this cognitive mapping versus habit learning as two dissociable systems for learning a space--a hippocampal place-learning system and a striatal response-learning system. Here, we use this dichotomy in humans to understand variability in navigational style by demonstrating that brain activation during spatial encoding can predict where a person's behavior falls on a continuum from a more flexible cognitive map-like strategy to a more rigid creature-of-habit approach. These findings bridge the wealth of knowledge gained from animal models and the study of human behavior, opening the door to a more comprehensive understanding of variability in human spatial learning and navigation.

Characterizing the Details of Spatial Construction: Cognitive Constraints and Variability.

Spatial construction-the activity of creating novel spatial arrangements or copying existing ones-is a hallmark of human spatial cognition. Spatial construction abilities predict math and other academic outcomes and are regularly used in IQ testing, but we know little about the cognitive processes that underlie them. In part, this lack of understanding is due to both the complex nature of construction tasks and the tendency to limit measurement to the overall accuracy of the end goal. Using an automated recording and coding system, we examined in detail adults' performance on a block copying task, specifying their step-by-step actions, culminating in all steps in the full construction of the build-path. The results revealed the consistent use of a structured plan that unfolded in an organized way, layer by layer (bottom to top). We also observed that complete layers served as convergence points, where the most agreement among participants occurred, whereas the specific steps taken to achieve each of those layers diverged, or varied, both across and even within individuals. This pattern of convergence and divergence suggests that the layers themselves were serving as the common subgoals across both inter and intraindividual builds of the same model, reflecting cognitive "chunking." This structured use of layers as subgoals was functionally related to better performance among builders. Our findings offer a foundation for further exploration that may yield insights into the development and training of block-construction as well as other complex cognitive-motor skills. In addition, this work offers proof-of-concept for systematic investigation into a wide range of complex action-based cognitive tasks.

Spatial memory in the real world: long-term representations of everyday environments.

When people learn an environment, they appear to establish a principle orientation just as they would determine the "top" of a novel object. Evidence for reference orientations has largely come from observations of orientation dependence in pointing judgments: Participants are most accurate when asked to recall the space from a particular orientation. However, these investigations have used highly constrained encoding in both time-scale and navigational goals, leaving open the possibility that larger spaces experienced during navigational learning depend on a different organizational scheme. To test this possibility, we asked undergraduates to perform judgments of relative direction on familiar landmarks around their well-learned campus. Participants showed clear evidence for a single reference orientation, generally aligned along salient axes defined by the buildings and paths. This result argues that representing space involves the establishment of a reference orientation, a requirement that endures over repeated exposures and extensive experience.

Changes in neuronal activation patterns in response to androgen deprivation therapy: a pilot study.

BACKGROUND: A common treatment option for men with prostate cancer is androgen deprivation therapy (ADT). However, men undergoing ADT may experience physical side effects, changes in quality of life and sometimes psychiatric and cognitive side effects. METHODS: In this study, hormone naïve patients without evidence of metastases with a rising PSA were treated with nine months of ADT. Functional magnetic resonance imaging (fMRI) of the brain during three visuospatial tasks was performed at baseline prior to treatment and after nine months of ADT in five subjects. Seven healthy control patients, underwent neuroimaging at the same time intervals. RESULTS: ADT patients showed reduced, task-related BOLD-fMRI activation during treatment that was not observed in control subjects. Reduction in activation in right parietal-occipital regions from baseline was observed during recall of the spatial location of objects and mental rotation. CONCLUSIONS: Findings, while preliminary, suggest that ADT reduces task-related neural activation in brain regions that are involved in mental rotation and accurate recall of spatial information.

Optimizing Retention in a Pragmatic Trial of Community-Living Older Persons: The STRIDE Study.

OBJECTIVES: The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study is testing the effectiveness of a multifactorial intervention to prevent serious fall injuries. Our aim was to describe procedures that were implemented to optimize participant retention; report retention yields by age, sex, clinical site, and follow-up time; provide reasons for study withdrawals; and highlight the successes and lessons learned from the STRIDE retention efforts. DESIGN: Pragmatic cluster randomized trial. SETTING: A total of 86 primary care practices within 10 US healthcare systems. PARTICIPANTS: A total of 5451 community-living persons, 70 years of age or older, at high risk for serious fall injuries. MEASUREMENTS: Study outcomes were collected every 4 months by a central call center. Reconsent was required to extend follow-up beyond the originally planned 36 months. RESULTS: Over a median follow-up of 3.2 years (interquartile range = 2.8-3.7 y), 439 (8.1%) participants died and 600 (11.0%) withdrew their consent or did not reconsent to extend follow-up beyond 36 months, yielding rates (per 100 person-years) of deaths and withdrawals of 2.6 and 3.6, respectively. The withdrawal rate increased with advancing age, was comparable for men and women, and did not differ much by clinical site. The most common reasons for withdrawal were illness and unable to contact for reconsent at 36 months. Completion of the follow-up interviews was greater than 93% at each time point. Most participants completed all (71.8%) or all but one (9.2%) of the follow-up interviews. The most common reason for not completing a follow-up interview was unable to contact, with rates ranging from 2.8% at 40 months to 4.6% at 20 months. CONCLUSION: Completion of the thrice-yearly follow-up interviews in STRIDE was high, and retention of participants over 44 months exceeded the original projections. The procedures used in STRIDE, together with lessons learned, should assist other investigators who are planning or conducting large pragmatic trials of vulnerable older persons. J Am Geriatr Soc 68:1242-1249, 2020.

Framework for advancing rigorous research.

There is a pressing need to increase the rigor of research in the life and biomedical sciences. To address this issue, we propose that communities of 'rigor champions' be established to campaign for reforms of the research culture that has led to shortcomings in rigor. These communities of rigor champions would also assist in the development and adoption of a comprehensive educational platform that would teach the principles of rigorous science to researchers at all career stages.

Orientation dependence of spatial memory acquired from auditory experience.

The present study investigated whether memory for a room-sized spatial layout learned through auditory localization of sounds exhibits orientation dependence similar to that observed for spatial memory acquired from stationary viewing of the environment. Participants learned spatial layouts by viewing objects or localizing sounds and then performed judgments of relative direction among remembered locations. The results showed that direction judgments following auditory learning were performed most accurately at a particular orientation in the same way as were those following visual learning, indicating that auditorily encoded spatial memory is orientation dependent. In combination with previous findings that spatial memories derived from haptic and proprioceptive experiences are also orientation dependent, the present finding suggests that orientation dependence is a general functional property of human spatial memory independent of learning modality.

Cognitive and neural development of individuated self-representation in children.

Processing the self-relevance of information facilitates recall. Similarly, processing close-other-related information facilitates recall to a lesser degree than processing self-relevant information. This memory advantage may be viewed as an index of the degree to which the representation of self is differentiated from representations of close others. To test developmental hypotheses concerning the self, this study examined the relation of memory for self- and mother-referentially processed information in participants age 7-13 years (Experiment 1: N = 37; Experiment 2: N = 14). Memory for words encoded with reference to oneself increases with age, relative to memory for words encoded with reference to one's mother. When used as an individual difference measure, the difference in self versus mother memory correlates with regions of the rostral anterior cingulate associated with affective salience.

The effects of arts-integrated instruction on memory for science content.

Strong correlational evidence suggests that involvement in the arts improves students' academic outcomes and memory of learning events [1-3]. It is unclear whether the improved outcomes are the result of general exposure to the arts, the integration of arts into content instruction, the use of effective instructional practices, or a combination of these factors. Moreover, as a growing number of studies suggest that arts-integrated pedagogy enhances learning, few empirical studies have explicitly examined the direct effect of an arts-integrated curriculum on learning and specifically on students' memory for non-arts academic content. Thus, this study sought to determine the effects of arts-integrated lessons on long-term memory for science content. We hypothesized that embedding arts-based activities into conventionally taught lessons would produce learning outcomes as good as or better than traditional instruction. This paper describes the results of a randomized control trial that measured retention of science content using arts-integrated science units and matched units employing convention science instruction. The study was conducted in 16 fifth-grade classrooms in an urban mid-Atlantic school district.