Ca2+-dependent phosphodiesterase 1 regulates the plasticity of striatal spiny projection neuron glutamatergic synapses.

Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Our studies reveal that SPNs manifest a heterosynaptic, nitric oxide (NO)-dependent form of long-term postsynaptic depression of glutamatergic SPN synapses (NO-LTD) that is preferentially engaged at quiescent synapses. Plasticity is gated by Ca2+ entry through CaV1.3 Ca2+ channels and phosphodiesterase 1 (PDE1) activation, which blunts intracellular cyclic guanosine monophosphate (cGMP) and NO signaling. Both experimental and simulation studies suggest that this Ca2+-dependent regulation of PDE1 activity allows for local regulation of dendritic cGMP signaling. In a mouse model of Parkinson disease (PD), NO-LTD is absent because of impaired interneuronal NO release; re-balancing intrastriatal neuromodulatory signaling restores NO release and NO-LTD. Taken together, these studies provide important insights into the mechanisms governing NO-LTD in SPNs and its role in psychomotor disorders such as PD.

Correction: GABAergic regulation of striatal spiny projection neurons depends upon their activity state.

[This corrects the article DOI: 10.1371/journal.pbio.3002483.].

Rem2 interacts with CaMKII at synapses and restricts long-term potentiation in hippocampus.

Synaptic plasticity, the process whereby neuronal connections are either strengthened or weakened in response to stereotyped forms of stimulation, is widely believed to represent the molecular mechanism that underlies learning and memory. The holoenzyme calcium/calmodulin-dependent protein kinase II (CaMKII) plays a well-established and critical role in the induction of a variety of forms of synaptic plasticity such as long-term potentiation (LTP), long-term depression (LTD) and depotentiation. Previously, we identified the GTPase Rem2 as a potent, endogenous inhibitor of CaMKII. Here, we report that knock out of Rem2 enhances LTP at the Schaffer collateral to CA1 synapse in hippocampus, consistent with an inhibitory action of Rem2 on CaMKII in vivo. Further, re-expression of WT Rem2 rescues the enhanced LTP observed in slices obtained from Rem2 conditional knock out (cKO) mice, while expression of a mutant Rem2 construct that is unable to inhibit CaMKII in vitro fails to rescue increased LTP. In addition, we demonstrate that CaMKII and Rem2 interact in dendritic spines using a 2pFLIM-FRET approach. Taken together, our data lead us to propose that Rem2 serves as a brake on synaptic potentiation via inhibition of CaMKII activity. Further, the enhanced LTP phenotype we observe in Rem2 cKO slices reveals a previously unknown role for Rem2 in the negative regulation of CaMKII function.

Ca 2+ -dependent phosphodiesterase 1 regulates the plasticity of striatal spiny projection neuron glutamatergic synapses.

Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Although considerable attention has been paid to the mechanisms underlying synaptic strengthening and new learning, little scrutiny has been given to those involved in the attenuation of synaptic strength that attends suppression of a previously learned association. Our studies revealed a novel, non-Hebbian, long-term, postsynaptic depression of glutamatergic SPN synapses induced by interneuronal nitric oxide (NO) signaling (NO-LTD) that was preferentially engaged at quiescent synapses. This form of plasticity was gated by local Ca 2+ influx through CaV1.3 Ca 2+ channels and stimulation of phosphodiesterase 1 (PDE1), which degraded cyclic guanosine monophosphate (cGMP) and blunted NO signaling. Consistent with this model, mice harboring a gain-of-function mutation in the gene coding for the pore-forming subunit of CaV1.3 channels had elevated depolarization-induced dendritic Ca 2+ entry and impaired NO-LTD. Extracellular uncaging of glutamate and intracellular uncaging of cGMP suggested that this Ca 2+ -dependent regulation of PDE1 activity allowed for local regulation of dendritic NO signaling. This inference was supported by simulation of SPN dendritic integration, which revealed that dendritic spikes engaged PDE1 in a branch-specific manner. In a mouse model of Parkinson's disease (PD), NO-LTD was absent not because of a postsynaptic deficit in NO signaling machinery, but rather due to impaired interneuronal NO release. Re-balancing intrastriatal neuromodulatory signaling in the PD model restored NO release and NO-LTD. Taken together, these studies provide novel insights into the mechanisms governing NO-LTD in SPN and its role in psychomotor disorders, like PD.

Rem2 interacts with CaMKII at synapses and restricts long-term potentiation in hippocampus.

Synaptic plasticity, the process whereby neuronal connections are either strengthened or weakened in response to stereotyped forms of stimulation, is widely believed to represent the molecular mechanism that underlies learning and memory. The holoenzyme CaMKII plays a well-established and critical role in the induction of a variety of forms of synaptic plasticity such as long-term potentiation (LTP), long-term depression (LTD) and depotentiation. Previously, we identified the GTPase Rem2 as a potent, endogenous inhibitor of CaMKII. Here, we report that knock out of Rem2 enhances LTP at the Schaffer collateral to CA1 synapse in hippocampus, consistent with an inhibitory action of Rem2 on CaMKII in vivo. Further, re-expression of WT Rem2 rescues the enhanced LTP observed in slices obtained from Rem2 conditional knock out (cKO) mice, while expression of a mutant Rem2 construct that is unable to inhibit CaMKII in vitro fails to rescue increased LTP. In addition, we demonstrate that CaMKII and Rem2 interact in dendritic spines using a 2pFLIM-FRET approach. Taken together, our data lead us to propose that Rem2 serves as a brake on runaway synaptic potentiation via inhibition of CaMKII activity. Further, the enhanced LTP phenotype we observe in Rem2 cKO slices reveals a previously unknown role for Rem2 in the negative regulation of CaMKII function.

A Phenomenological Study of Postgraduate Medical Trainees' Incidental Learning Experiences and Psychological Well-Being During the COVID-19 Pandemic.

BACKGROUND:  During the COVID-19 pandemic, postgraduate medical trainees contributed significantly to the healthcare workforce, as multiple vulnerabilities in the healthcare system and medical training were expounded. The burden of training, learning, and working at this time introduced unique psychological and emotional stressors within a context of generalized volatility and radically different ways to work and learn. This study explored postgraduate trainees' experiences with coping, managing, and learning during the COVID-19 pandemic. METHODOLOGY:  Using a phenomenological approach, semistructured interviews were conducted with an intradisciplinary sample (n = 8) of postgraduate trainees in Newfoundland and Labrador, Canada, between May and October 2022. Five researchers performed inductive and deductive thematic analysis to develop a coding structure and identify common themes. RESULTS:  The COVID-19 pandemic prompted the use of restrictive public health measures and an unprecedented shift from in-person to virtual learning. This affected trainees' exposure to normalized learning experiences, training rotations, and opportunities to learn from peers and staff. Certainly, trainees reported that virtual learning improved their educational experiences in unique ways, increased engagement and attendance, and enabled regular meetings and learning when in-person options were unavailable. Trainees also reported enhanced self-directed learning skills, greater ownership of and leadership in their education, and increased confidence and experience with virtual care. Some also reported a perceived increase in elements of emotional intelligence (e.g., self-awareness, empathy, and compassion). CONCLUSIONS:  Trainees reported a variety of incidental learning experiences from working and training during COVID-19. Although some experiences were challenging, there was a perception that such experiences led to new learnings that were beneficial to one's professional development and future career, as well as implications for future training provided to trainees. While there was a reported shift in the culture surrounding postgraduate trainees' health and safety, respondents also described the need for additional support for postgraduate trainees' well-being during a pandemic.

GABAergic regulation of striatal spiny projection neurons depends upon their activity state.

Synaptic transmission mediated by GABAA receptors (GABAARs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at subthreshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical, and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration. In perforated patch recordings, activation of GABAARs, either by uncaging of GABA or by optogenetic stimulation of GABAergic synapses, evoked currents with a reversal potential near -60 mV in both juvenile and adult SPNs. Transcriptomic analysis and pharmacological work suggested that this relatively positive GABAAR reversal potential was not attributable to NKCC1 expression, but rather to HCO3- permeability. Regardless, from down-state potentials, optogenetic activation of dendritic GABAergic synapses depolarized SPNs. This GABAAR-mediated depolarization summed with trailing ionotropic glutamate receptor (iGluR) stimulation, promoting dendritic spikes and increasing somatic depolarization. Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to dendritic iGluR signaling and promoted dendritic spikes. Taken together, our results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation for the role of intrastriatal GABAergic circuits.

Semaphorin 4D induced inhibitory synaptogenesis decreases epileptiform activity and alters progression to Status Epilepticus in mice.

Previously we demonstrated that intra-hippocampal infusion of purified, Semaphorin 4D (Sema4D) extracellular domain (ECD) into the mouse hippocampus rapidly promotes formation of GABAergic synapses and decreases seizure susceptibility in mice. Given the relatively fast action of Sema4D treatment revealed by these studies, we sought to determine the time course of Sema4D treatment on hippocampal network activity using an acute hippocampal slice preparation. We performed long-term extracellular recordings from area CA1 encompassing a 2-hour application of Sema4D and found that hippocampal excitation is suppressed for hours following treatment. We also asked if Sema4D treatment could ameliorate seizures in an acute seizure model: the kainic acid (KA) mouse model. We demonstrate that Sema4D treatment delays and suppresses ictal activity, delays the transition to Status Epilepticus (SE), and lessens the severity of SE. Lastly, we sought to explore alternative methods of Sema4D delivery to hippocampus and thus created an Adeno Associated Virus expressing the ECD of Sema4D. Our data reveal that virally delivered, chronically overexpressed Sema4D-ECD promotes GABAergic synapse formation and suppresses ictal activity and progression to SE. These results provide proof of concept that viral delivery of Sema4D is an efficacious and promising delivery method to abate epileptiform activity and progression to SE.

Patient Experiences With Virtual Care During the COVID-19 Pandemic: Phenomenological Focus Group Study.

BACKGROUND: Virtual care has expanded during the COVID-19 pandemic and enabled greater access and continuity of care for many patients. From a patient-oriented research perspective, understanding the patient experience with virtual care appointments is an important first step in identifying ways to better support patient use and satisfaction. OBJECTIVE: The purpose of this qualitative study was (1) to explore patients' experiences and perspectives with the adoption and use of virtual care during COVID-19 in Newfoundland and Labrador, Canada, and (2) identify the education and informational needs of patients to inform future strategies for supporting patient use of virtual care. METHODS: Using a phenomenological approach, we conducted a focus group interview with a purposive sample of patient representatives representing a cross-section of the population of the province of Newfoundland and Labrador. Five patient representatives were recruited from the Newfoundland and Labrador Support Patient Advisory Council and participated in the focus group. The focus group was conducted in February 2022 via videoconferencing technology. Using thematic analysis, we identified several recurrent themes that described respondents' experiences with the use of virtual care during COVID-19, as well as their perceptions of education and informational needs to support more effective patient use of virtual care. RESULTS: Respondents felt that virtual care is a beneficial addition to the health care system, enabling greater convenience and access to health care services. Key barriers and challenges in adopting and using virtual care appear to primarily arise from patients' lack of knowledge, understanding, and familiarity with respect to virtual care. Cost, technological access, connectivity, and low digital literacy were challenges for some patients, particularly in rural communities and among older patient population. Patient education and support were critical and needed to be inclusive, easy to understand, and include information regarding privacy, security, consent, and the technology itself. The types of patient education experiences regarded as most helpful included peer support and knowledge sharing among patients themselves. CONCLUSIONS: Beyond the COVID-19 pandemic, virtual care will have a continuing role in enhancing the continuity of care for patients through more convenient access. The education and informational needs of patients are important considerations in promoting the adoption and use of virtual care. Key education and informational needs and strategies were identified to enable and empower patients with the knowledge, digital literacy skills, and support to effectively use virtual care.

State-dependent GABAergic regulation of striatal spiny projection neuron excitability.

Synaptic transmission mediated by GABA A receptors (GABA A Rs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at sub-threshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration. Activation of GABA A Rs, either by uncaging of GABA or by optogenetic stimulation of GABAergic synapses, evoked currents with a reversal potential near -60 mV in perforated patch recordings from both juvenile and adult SPNs. Molecular profiling of SPNs suggested that this relatively positive reversal potential was not attributable to NKCC1 expression, but rather to a dynamic equilibrium between KCC2 and Cl-/HCO3-cotransporters. Regardless, from down-state potentials, optogenetic activation of dendritic GABAergic synapses depolarized SPNs. This GABAAR-mediated depolarization summed with trailing ionotropic glutamate receptor (iGluR) stimulation, promoting dendritic spikes and increasing somatic depolarization. Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to coincident glutamatergic input. Taken together, our results demonstrate that GABA A Rs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation of the role intrastriatal GABAergic circuits.

Prenatal diagnosis of vascular anomalies.

Vascular anomalies are rare disorders that encompass a group of lesions characterized by abnormal development of the lymphovascular system. Majority of these anomalies are present at birth and could potentially be detected during the prenatal period on imaging. This allows for early intervention and prompt management to improve outcomes. However, they can be difficult to diagnose, given the rarity and overlapping findings. In this review article, we provide a comprehensive overview of congenital vascular anomalies with a liberal use of images of recent cases at our center emphasizing prenatal imaging findings and the natural history of these conditions.

Use of Extended Reality in Medical Education: An Integrative Review.

Extended reality (XR) has emerged as an innovative simulation-based learning modality. An integrative review was undertaken to explore the nature of evidence, usage, and effectiveness of XR modalities in medical education. One hundred and thirty-three (N = 133) studies and articles were reviewed. XR technologies are commonly reported in surgical and anatomical education, and the evidence suggests XR may be as effective as traditional medical education teaching methods and, potentially, a more cost-effective means of curriculum delivery. Further research to compare different variations of XR technologies and best applications in medical education and training are required to advance the field. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01698-4.

Systemic racial disparities in funding rates at the National Science Foundation.

Concerns about systemic racism at academic and research institutions have increased over the past decade. Here, we investigate data from the National Science Foundation (NSF), a major funder of research in the United States, and find evidence for pervasive racial disparities. In particular, white principal investigators (PIs) are consistently funded at higher rates than most non-white PIs. Funding rates for white PIs have also been increasing relative to annual overall rates with time. Moreover, disparities occur across all disciplinary directorates within the NSF and are greater for research proposals. The distributions of average external review scores also exhibit systematic offsets based on PI race. Similar patterns have been described in other research funding bodies, suggesting that racial disparities are widespread. The prevalence and persistence of these racial disparities in funding have cascading impacts that perpetuate a cumulative advantage to white PIs across all of science, technology, engineering, and mathematics.

Virtual care and COVID-19: A survey study of adoption, satisfaction and continuing education preferences of healthcare providers in Newfoundland and Labrador, Canada.

Introduction: Virtual care has expanded during COVID-19 and enabled continued access to healthcare services. For many healthcare providers, the adoption of virtual care has been a new experience in the provision of healthcare services. The purpose of this survey study was to explore healthcare providers' experiences with virtual care during COVID-19. Methods: A web-based survey-questionnaire was developed by applying Rogers' theory of diffusion of innovation and distributed to healthcare providers (physicians, nurses and allied health professionals) in Newfoundland and Labrador, Canada to explore virtual care experiences, satisfaction and continuing professional development (CPD) needs. Analyses included descriptive statistics and thematic analysis of survey responses. Results: Fifty-one percent of respondents (n = 432) indicated they were currently offering virtual care and a majority (68.9%) reported it has improved their work experience. Telephone appointments were preferred over videoconferencing by respondents, with key challenges including the inability to conduct a physical exam, patients' cell phone services being unreliable and patients knowing how to use videoconferencing. Majority of respondents (57.5%) reported quality of care by telephone was lower than in-person, whereas quality of care by videoconferencing was equivalent to in-person. Main benefits of virtual care included increased patient access, ability to work from home, and reduction in no-show appointments. Key supports for adopting virtual care included in-house organizational supports (e.g., technical support staff), local colleague support, and technology training. Important topics for virtual care CPD included complying with regulatory standards/rules, understanding privacy or ethical boundaries, and developing competency and digital professionalism while engaging in virtual care. Discussion: Beyond the COVID-19 pandemic, virtual care will have a continuing role in enhancing continuity of care through access that is more convenient. Survey findings reveal a number of opportunities for supporting healthcare providers in use of virtual care, including CPD, guidelines and resources to support adaptation to virtual care provision (e.g., virtual examinations/assessments), as well as patient educational support.

Using mobile technology in assessment of entrustable professional activities in undergraduate medical education.

BACKGROUND: The adoption of competency-based medical education requires objective assessments of a learner's capability to carry out clinical tasks within workplace-based learning settings. This study involved an evaluation of the use of mobile technology to record entrustable professional activity assessments in an undergraduate clerkship curriculum. APPROACH: A paper-based form was adapted to a mobile platform called eClinic Card. Students documented workplace-based assessments throughout core clerkship and preceptors confirmed accuracy via mobile phones. Assessment scores for the 2017-2018 academic year were collated and analyzed for all core rotations, and preceptors and students were surveyed regarding the mobile assessment experience. EVALUATION: The mobile system enabled 80 students and 624 preceptors to document 6850 assessment submissions across 47 clinical sites over a 48-week core clerkship curriculum. Students' scores demonstrated progressive improvement across all entrustable professional activities with stage-appropriate levels of independence reported by end of core clerkship. Preceptors and students were satisfied with ease of use and dependability of the mobile assessment platform; however, students felt quality of formative coaching feedback could be improved. REFLECTION: Our preliminary evaluation suggests the use of mobile technology to assess entrustable professional activity achievement across a core clerkship curriculum is a feasible and acceptable modality for workplace-based assessment. The use of mobile technology supported a programmatic assessment approach. However, meaningful coaching feedback, as well as faculty development and support, emerged as key factors influencing successful adoption and usage of entrustable professional activities within an undergraduate medical curriculum.

Peer assessment of professionalism in undergraduate medical education.

BACKGROUND: Fostering professional behaviour has become increasingly important in medical education and non-traditional approaches to assessment of professionalism may offer a more holistic representation of students' professional behaviour development. Emerging evidence suggests peer assessment may offer potential as an alternative method of professionalism assessment. We introduced peer assessment of professionalism in pre-clerkship phases of undergraduate medical education curriculum at our institution and evaluated suitability of adopting a professional behaviour scale for longitudinal tracking of student development, and student comfort and acceptance of peer assessment. METHODS: Peer assessment was introduced using a validated professional behaviours scale. Students conducted repeated, longitudinal assessments of their peers from small-group, clinical skills learning activities. An electronic assessment system was used to collect peer assessments, collate and provide reports to students. Student opinions of peer assessment were initially surveyed before introducing the process, confirmatory analyses were conducted of the adopted scale, and students were surveyed to explore satisfaction with the peer assessment process. RESULTS: Students across all phases of the curriculum were initially supportive of anonymous peer assessment using small-group learning sessions. Peer scores showed improvement over time, however the magnitude of increase was limited by ceiling effects attributed to the adopted scale. Students agreed that the professional behaviours scale was easy to use and understand, however a majority disagreed that peer assessment improved their understanding of professionalism or was a useful learning experience. CONCLUSIONS: Peer assessment of professional behaviours does expose students to the process of assessing one's peers, however the value of such processes at early stages of medical education may not be fully recognized nor appreciated by students. Electronic means for administering peer assessment is feasible for collecting and reporting peer feedback. Improvement in peer assessed scores was observed over time, however student opinions of the educational value were mixed and indeterminate.

Person Ability Scores as an Alternative to Norm-Referenced Scores as Outcome Measures in Studies of Neurodevelopmental Disorders.

Although norm-referenced scores are essential to the identification of disability, they possess several features which affect their sensitivity to change. Norm-referenced scores often decrease over time among people with neurodevelopmental disorders who exhibit slower-than-average increases in ability. Further, the reliability of norm-referenced scores is lower at the tails of the distribution, resulting in floor effects and increased measurement error for people with neurodevelopmental disorders. In contrast, the person ability scores generated during the process of constructing a standardized test with item response theory are designed to assess change. We illustrate these limitations of norm-referenced scores, and relative advantages of ability scores, using data from studies of autism spectrum disorder and creatine transporter deficiency.

Examination of the ocean as a source for atmospheric microplastics.

Global plastic litter pollution has been increasing alongside demand since plastic products gained commercial popularity in the 1930's. Current plastic pollutant research has generally assumed that once plastics enter the ocean they are there to stay, retained permanently within the ocean currents, biota or sediment until eventual deposition on the sea floor or become washed up onto the beach. In contrast to this, we suggest it appears that some plastic particles could be leaving the sea and entering the atmosphere along with sea salt, bacteria, virus' and algae. This occurs via the process of bubble burst ejection and wave action, for example from strong wind or sea state turbulence. In this manuscript we review evidence from the existing literature which is relevant to this theory and follow this with a pilot study which analyses microplastics (MP) in sea spray. Here we show first evidence of MP particles, analysed by µRaman, in marine boundary layer air samples on the French Atlantic coast during both onshore (average of 2.9MP/m3) and offshore (average of 9.6MP/m3) winds. Notably, during sampling, the convergence of sea breeze meant our samples were dominated by sea spray, increasing our capacity to sample MPs if they were released from the sea. Our results indicate a potential for MPs to be released from the marine environment into the atmosphere by sea-spray giving a globally extrapolated figure of 136000 ton/yr blowing on shore.

Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study.

Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.

Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative.

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.