From patients to partners: participant-centric initiatives in biomedical research.

Advances in computing technology and bioinformatics mean that medical research is increasingly characterized by large international consortia of researchers that are reliant on large data sets and biobanks. These trends raise a number of challenges for obtaining consent, protecting participant privacy concerns and maintaining public trust. Participant-centred initiatives (PCIs) use social media technologies to address these immediate concerns, but they also provide the basis for long-term interactive partnerships. Here, we give an overview of this rapidly moving field by providing an analysis of the different PCI approaches, as well as the benefits and challenges of implementing PCIs.

Patient Perspectives on Sharing Anonymized Personal Health Data Using a Digital System for Dynamic Consent and Research Feedback: A Qualitative Study.

BACKGROUND: Electronic health records are widely acknowledged to provide an important opportunity to anonymize patient-level health care data and collate across populations to support research. Nonetheless, in the wake of public and policy concerns about security and inappropriate use of data, conventional approaches toward data governance may no longer be sufficient to respect and protect individual privacy. One proposed solution to improve transparency and public trust is known as Dynamic Consent, which uses information technology to facilitate a more explicit and accessible opportunity to opt out. In this case, patients can tailor preferences about whom they share their data with and can change their preferences reliably at any time. Furthermore, electronic systems provide opportunities for informing patients about data recipients and the results of research to which their data have contributed. OBJECTIVE: To explore patient perspectives on the use of anonymized health care data for research purposes. To evaluate patient perceptions of a Dynamic Consent model and electronic system to enable and implement ongoing communication and collaboration between patients and researchers. METHODS: A total of 26 qualitative interviews and three focus groups were conducted that included a video presentation explaining the reuse of anonymized electronic patient records for research. Slides and tablet devices were used to introduce the Dynamic Consent system for discussion. A total of 35 patients with chronic rheumatic disease with varying levels of illness and social deprivation were recruited from a rheumatology outpatient clinic; 5 participants were recruited from a patient and public involvement health research network. RESULTS: Patients were supportive of sharing their anonymized electronic patient record for research, but noted a lack of transparency and awareness around the use of data, making it difficult to secure public trust. While there were general concerns about detrimental consequences of data falling into the wrong hands, such as insurance companies, 39 out of 40 (98%) participants generally considered that the altruistic benefits of sharing health care data outweighed the risks. Views were mostly positive about the use of an electronic interface to enable greater control over consent choices, although some patients were happy to share their data without further engagement. Participants were particularly enthusiastic about the system as a means of enabling feedback regarding data recipients and associated research results, noting that this would improve trust and public engagement in research. This underlines the importance of patient and public involvement and engagement throughout the research process, including the reuse of anonymized health care data for research. More than half of patients found the touch screen interface easy to use, although a significant minority, especially those with limited access to technology, expressed some trepidation and felt they may need support to use the system. CONCLUSIONS: Patients from a range of socioeconomic backgrounds viewed a digital system for Dynamic Consent positively, in particular, feedback about data recipients and research results. Implementation of a digital Dynamic Consent system would require careful interface design and would need to be located within a robust data infrastructure; it has the potential to improve trust and engagement in electronic medical record research.

Latent antibiotic resistance genes are abundant, diverse, and mobile in human, animal, and environmental microbiomes.

BACKGROUND: Bacterial communities in humans, animals, and the external environment maintain a large collection of antibiotic resistance genes (ARGs). However, few of these ARGs are well-characterized and thus established in existing resistance gene databases. In contrast, the remaining latent ARGs are typically unknown and overlooked in most sequencing-based studies. Our view of the resistome and its diversity is therefore incomplete, which hampers our ability to assess risk for promotion and spread of yet undiscovered resistance determinants. RESULTS: A reference database consisting of both established and latent ARGs (ARGs not present in current resistance gene repositories) was created. By analyzing more than 10,000 metagenomic samples, we showed that latent ARGs were more abundant and diverse than established ARGs in all studied environments, including the human- and animal-associated microbiomes. The pan-resistomes, i.e., all ARGs present in an environment, were heavily dominated by latent ARGs. In comparison, the core-resistome, i.e., ARGs that were commonly encountered, comprised both latent and established ARGs. We identified several latent ARGs shared between environments and/or present in human pathogens. Context analysis of these genes showed that they were located on mobile genetic elements, including conjugative elements. We, furthermore, identified that wastewater microbiomes had a surprisingly large pan- and core-resistome, which makes it a potentially high-risk environment for the mobilization and promotion of latent ARGs. CONCLUSIONS: Our results show that latent ARGs are ubiquitously present in all environments and constitute a diverse reservoir from which new resistance determinants can be recruited to pathogens. Several latent ARGs already had high mobile potential and were present in human pathogens, suggesting that they may constitute emerging threats to human health. We conclude that the full resistome-including both latent and established ARGs-needs to be considered to properly assess the risks associated with antibiotic selection pressures. Video Abstract.

Extensive screening reveals previously undiscovered aminoglycoside resistance genes in human pathogens.

Antibiotic resistance is a growing threat to human health, caused in part by pathogens accumulating antibiotic resistance genes (ARGs) through horizontal gene transfer. New ARGs are typically not recognized until they have become widely disseminated, which limits our ability to reduce their spread. In this study, we use large-scale computational screening of bacterial genomes to identify previously undiscovered mobile ARGs in pathogens. From ~1 million genomes, we predict 1,071,815 genes encoding 34,053 unique aminoglycoside-modifying enzymes (AMEs). These cluster into 7,612 families (<70% amino acid identity) of which 88 are previously described. Fifty new AME families are associated with mobile genetic elements and pathogenic hosts. From these, 24 of 28 experimentally tested AMEs confer resistance to aminoglycoside(s) in Escherichia coli, with 17 providing resistance above clinical breakpoints. This study greatly expands the range of clinically relevant aminoglycoside resistance determinants and demonstrates that computational methods enable early discovery of potentially emerging ARGs.

A global synthesis of high-resolution stable isotope data from benthic foraminifera of the last deglaciation.

We present the first version of the Ocean Circulation and Carbon Cycling (OC3) working group database, of oxygen and carbon stable isotope ratios from benthic foraminifera in deep ocean sediment cores from the Last Glacial Maximum (LGM, 23-19 ky) to the Holocene (<10 ky) with a particular focus on the early last deglaciation (19-15 ky BP). It includes 287 globally distributed coring sites, with metadata, isotopic and chronostratigraphic information, and age models. A quality check was performed for all data and age models, and sites with at least millennial resolution were preferred. Deep water mass structure as well as differences between the early deglaciation and LGM are captured by the data, even though its coverage is still sparse in many regions. We find high correlations among time series calculated with different age models at sites that allow such analysis. The database provides a useful dynamical approach to map physical and biogeochemical changes of the ocean throughout the last deglaciation.

Gulf Stream density structure and transport during the past millennium.

The Gulf Stream transports approximately 31 Sv (1 Sv = 10(6) m(3) s(-1)) of water and 1.3 x 10(15) W of heat into the North Atlantic ocean. The possibility of abrupt changes in Gulf Stream heat transport is one of the key uncertainties in predictions of climate change for the coming centuries. Given the limited length of the instrumental record, our knowledge of Gulf Stream behaviour on long timescales must rely heavily on information from geologic archives. Here we use foraminifera from a suite of high-resolution sediment cores in the Florida Straits to show that the cross-current density gradient and vertical current shear of the Gulf Stream were systematically lower during the Little Ice Age (ad approximately 1200 to 1850). We also estimate that Little Ice Age volume transport was ten per cent weaker than today's. The timing of reduced flow is consistent with temperature minima in several palaeoclimate records, implying that diminished oceanic heat transport may have contributed to Little Ice Age cooling in the North Atlantic. The interval of low flow also coincides with anomalously high Gulf Stream surface salinity, suggesting a tight linkage between the Atlantic Ocean circulation and hydrologic cycle during the past millennium.

Large-scale characterization of the macrolide resistome reveals high diversity and several new pathogen-associated genes.

Macrolides are broad-spectrum antibiotics used to treat a range of infections. Resistance to macrolides is often conferred by mobile resistance genes encoding Erm methyltransferases or Mph phosphotransferases. New erm and mph genes keep being discovered in clinical settings but their origins remain unknown, as is the type of macrolide resistance genes that will appear in the future. In this study, we used optimized hidden Markov models to characterize the macrolide resistome. Over 16 terabases of genomic and metagenomic data, representing a large taxonomic diversity (11 030 species) and diverse environments (1944 metagenomic samples), were searched for the presence of erm and mph genes. From this data, we predicted 28 340 macrolide resistance genes encoding 2892 unique protein sequences, which were clustered into 663 gene families (<70 % amino acid identity), of which 619 (94 %) were previously uncharacterized. This included six new resistance gene families, which were located on mobile genetic elements in pathogens. The function of ten predicted new resistance genes were experimentally validated in Escherichia coli using a growth assay. Among the ten tested genes, seven conferred increased resistance to erythromycin, with five genes additionally conferring increased resistance to azithromycin, showing that our models can be used to predict new functional resistance genes. Our analysis also showed that macrolide resistance genes have diverse origins and have transferred horizontally over large phylogenetic distances into human pathogens. This study expands the known macrolide resistome more than ten-fold, provides insights into its evolution, and demonstrates how computational screening can identify new resistance genes before they become a significant clinical problem.

Laser-induced corneal injury: validation of a computer model to predict thresholds.

The exposure and emission limits of ICNIRP, IEC 60825-1 and ANSI Z136.1 to protect the cornea are based on a limited number of in-vivo studies. To broaden the database, a computer model was developed to predict injury thresholds in the wavelength range from 1050 nm to 10.6 µm and was validated by comparison with all applicable experimental threshold data (ED50) with exposure duration between 1.7 ns and 100 s. The model predictions compare favorably with the in-vivo data with an average ratio of computer prediction to ED50 of 0.94 (standard deviation ± 30%) and a maximum deviation of less than 2. This computer model can be used to improve exposure limits or for a quantitative risk analysis of a given exposure of the cornea.

Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter.

Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT(-/-)) mice exhibit early postnatal lethality, CHT heterozygous (CHT(+/-)) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT(+/-) mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT(+/-) mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT(+/-) mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease.

Consistently dated Atlantic sediment cores over the last 40 thousand years.

Rapid changes in ocean circulation and climate have been observed in marine-sediment and ice cores over the last glacial period and deglaciation, highlighting the non-linear character of the climate system and underlining the possibility of rapid climate shifts in response to anthropogenic greenhouse gas forcing. To date, these rapid changes in climate and ocean circulation are still not fully explained. One obstacle hindering progress in our understanding of the interactions between past ocean circulation and climate changes is the difficulty of accurately dating marine cores. Here, we present a set of 92 marine sediment cores from the Atlantic Ocean for which we have established age-depth models that are consistent with the Greenland GICC05 ice core chronology, and computed the associated dating uncertainties, using a new deposition modeling technique. This is the first set of consistently dated marine sediment cores enabling paleoclimate scientists to evaluate leads/lags between circulation and climate changes over vast regions of the Atlantic Ocean. Moreover, this data set is of direct use in paleoclimate modeling studies.

Laser-induced retinal damage threshold measurements with wavefront correction.

An adaptive optics (AO) system was incorporated into a laser retinal exposure setup in order to correct for refractive error and higher-order aberrations of the nonhuman primate (NHP) eye during an in vivo retinal ED(50) measurement. Using this system, the ED(50) for a 100-ms, 532-nm small spot size exposure was measured to be 1.05 mJ total intraocular energy (TIE), a reduction of 22% from the value measured without aberration correction. The ED(50) for a 3.5-ns, 532-nm exposure was measured to be 0.51 microJ TIE, the lowest ED(50) reported for a ns-duration exposure. This is a reduction of 37% from the value measured without aberration correction and is a factor of only 2.6 higher than the maximum permissible exposure (MPE) for a 3.5-ns, visible wavelength small spot size exposure. The trend of in vitro measurements using retinal explants suggests that the in vivo ED(50) for small spot-size exposures could potentially be one order of magnitude smaller than the previously reported in vivo ED(50). Distortion of the incident laser beam by ocular aberrations cannot fully explain the discrepancy between the in vivo measurements with no aberration correction and the in vitro results.

Thermal lensing in ocular media exposed to continuous-wave near-infrared radiation: the 1150-1350-nm region.

Ocular damage threshold data remain sparse in the continuous wave (CW), near-infrared (NIR) radiation region save for the 1300-nm area that has been investigated in the past several decades. The 1300-nm ocular damage data have yielded unusual characteristics where CW retinal damage was observed in rabbit models, but never in nonhuman primate models. This paper reviews the existing 1300-nm ocular damage threshold data in terms of the fundamental criteria of an action spectrum to assist in explaining laser-tissue effects from near-infrared radiation in the eye. Reviewing the action spectrum criteria and existing NIR retinal lesion data lend evidence toward the significant presence of thermal lensing in ocular media affecting damage, a relatively unexplored mechanism of laser-tissue interaction.

Ex vivo and computer model study on retinal thermal laser-induced damage in the visible wavelength range.

Excised bovine eyes are used as models for threshold determination of 532-nm laser-induced thermal damage of the retina in the pulse duration regime of 100 micros to 2 s for varying laser spot size diameters. The thresholds as determined by fluorescence viability staining compare well with the prediction of an extended Thompson-Gerstman computer model. Both models compare well with published Rhesus monkey threshold data. A previously unknown variation of the spot size dependence is seen for different pulse durations, which allows for a more complete understanding of the retinal thermal damage. Current International Commission on Nonionized Radiation Protection (ICNIRP), American National Standards Institute (ANS), and International Electromechanical Commission (IEC) laser and incoherent optical radiation exposure limits can be increased for extended sources for pulsed exposures. We conclude that the damage mechanism at threshold detected at 24 and 1 h for the nonhuman primate model is retinal pigment epithelium (RPE) cell damage and not thermal coagulation of the sensory retina. This work validates the bovine ex vivo and computer models for prediction of thresholds of thermally induced damage in the time domain of 10 micros to 2 s, which provides the basis for safety analysis of more complicated retinal exposure scenarios such as repetitive pulses, nonconstant retinal irradiance profiles, and scanned exposure.

Steroidal and nonsteroidal antiinflammatory medications can improve photoreceptor survival after laser retinal photocoagulation.

OBJECTIVE: To determine whether methylprednisolone or indomethacin can enhance photoreceptor survival after laser retinal injury in an animal model. DESIGN: Experimental study. PARTICIPANTS: Twenty rhesus monkeys. METHODS: Twenty rhesus monkeys (Macaca mulatta) received a grid of argon green (514.5 nm, 10 ms) laser lesions in the macula of the right eye and a grid of neodymium:yttrium-aluminum-garnet (Nd:YAG; 1064 nm, 10 ns) lesions in the macula of the left eye, followed by randomization to 2 weeks of treatment in 1 of 4 treatment groups: high-dose methylprednisolone, moderate-dose methylprednisolone, indomethacin, or control. The lesions were assessed at day 1, day 14, 2 months, and 4 months. The authors were masked to the treatment group. This report discusses the histologic results of ocular tissue harvested at 4 months. MAIN OUTCOME MEASURE: The number of surviving photoreceptor cell nuclei within each lesion was compared with the number of photoreceptor nuclei in surrounding unaffected retina. The proportion of surviving photoreceptor nuclei was compared between each treatment group. RESULTS: Argon retinal lesions in the high-dose steroid treatment group and the indomethacin treatment group demonstrated improved photoreceptor survival compared with the control group (P = 0.004). Hemorrhagic Nd:YAG lesions demonstrated improved survivability with indomethacin treatment compared with controls (P = 0.003). In nonhemorrhagic Nd:YAG laser retinal lesions, the lesions treated with moderate-dose steroids demonstrated improved photoreceptor survival compared with the control group (P = 0.004). CONCLUSIONS: Based on histologic samples of retinal laser lesions 4 months after injury, treatment with indomethacin resulted in improved photoreceptor survival in argon laser lesions and hemorrhagic Nd:YAG laser lesions. Treatment with systemic methylprednisolone demonstrated improved photoreceptor survival in argon retinal lesions and in nonhemorrhagic Nd:YAG lesions.

N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux.

Amphetamine (AMPH) elicits its behavioral effects by acting on the dopamine (DA) transporter (DAT) to induce DA efflux into the synaptic cleft. We previously demonstrated that a human DAT construct in which the first 22 amino acids were truncated was not phosphorylated by activation of protein kinase C, in contrast to wild-type (WT) DAT, which was phosphorylated. Nonetheless, in all functions tested to date, which include uptake, inhibitor binding, oligomerization, and redistribution away from the cell surface in response to protein kinase C activation, the truncated DAT was indistinguishable from the full-length WT DAT. Here, however, we show that in HEK-293 cells stably expressing an N-terminal-truncated DAT (del-22 DAT), AMPH-induced DA efflux is reduced by approximately 80%, whether measured by superfusion of a population of cells or by amperometry combined with the patch-clamp technique in the whole cell configuration. We further demonstrate in a full-length DAT construct that simultaneous mutation of the five N-terminal serine residues to alanine (S/A) produces the same phenotype as del-22-normal uptake but dramatically impaired efflux. In contrast, simultaneous mutation of these same five serines to aspartate (S/D) to simulate phosphorylation results in normal AMPH-induced DA efflux and uptake. In the S/A background, the single mutation to Asp of residue 7 or residue 12 restored a significant fraction of WT efflux, whereas mutation to Asp of residues 2, 4, or 13 was without significant effect on efflux. We propose that phosphorylation of one or more serines in the N-terminus of human DAT, most likely Ser7 or Ser12, is essential for AMPH-induced DAT-mediated DA efflux. Quite surprisingly, N-terminal phosphorylation shifts DAT from a "reluctant" state to a "willing" state for AMPH-induced DA efflux, without affecting inward transport. These data raise the therapeutic possibility of interfering selectively with AMPH-induced DA efflux without altering physiological DA uptake.

Variation of laser-induced retinal injury thresholds with retinal irradiated area: 0.1-s duration, 514-nm exposures.

The retinal injury threshold dose for laser exposure varies as a function of the irradiated area on the retina. Zuclich reported thresholds for laser-induced retinal injury from 532 nm, nanosecond-duration laser exposures that varied as the square of the diameter of the irradiated area on the retina. We report data for 0.1-s-duration retinal exposures to 514-nm, argon laser irradiation. Thresholds for macular injury at 24 h are 1.05, 1.40, 1.77, 3.58, 8.60, and 18.6 mJ for retinal exposures at irradiance diameters of 20, 69, 136, 281, 562, and 1081 microm, respectively. These thresholds vary as the diameter of the irradiated retinal area. The relationship between the retinal injury threshold and retinal irradiance diameter is a function of the exposure duration. The 0.1-s-duration data of this experiment and the nanosecond-duration data of Zuclich show that the ED(50) (50% effective dose) for exposure to a highly collimated beam does not decrease relative to the value obtained for a retinal irradiance diameter of 100 microm. These results can form the basis to improve current laser safety guidelines in the nanosecond-duration regime. These results are relevant for ophthalmic devices incorporating both wavefront correction and retinal exposure to a collimated laser.

Wavelength dependence of ocular damage thresholds in the near-ir to far-ir transition region: proposed revisions to MPES.

This report summarizes the results of a series of infrared (IR) laser-induced ocular damage studies conducted over the past decade. The studies examined retinal, lens, and corneal effects of laser exposures in the near-IR to far-IR transition region (wavelengths from 1.3-1.4 mum with exposure durations ranging from Q-switched to continuous wave). The corneal and retinal damage thresholds are tabulated for all pulsewidth regimes, and the wavelength dependence of the IR thresholds is discussed and contrasted to laser safety standard maximum permissible exposure limits. The analysis suggests that the current maximum permissible exposure limits could be beneficially revised to (1) relax the IR limits over wavelength ranges where unusually high safety margins may unintentionally hinder applications of recently developed military and telecommunications laser systems; (2) replace step-function discontinuities in the IR limits by continuously varying analytical functions of wavelength and pulsewidth which more closely follow the trends of the experimental retinal (for point-source laser exposures) and corneal ED50 threshold data; and (3) result in an overall simplification of the permissible exposure limits over the wavelength range from 1.2-2.6 mum. A specific proposal for amending the IR maximum permissible exposure limits over this wavelength range is presented.

Retinal injury thresholds for blue wavelength lasers.

The interaction mechanism leading to laser-induced retinal alteration can be thermal or non-thermal, depending upon the wavelength of the laser radiation and the duration of the exposure. To investigate the effect of exposure duration on the interaction mechanism, retinal injury thresholds in the rhesus monkey were experimentally measured for exposure to laser radiation at wavelengths of 441.6, 457.9, 476.5, and 496.5 nm. Exposure durations were 0.1, 1, 5, 16, and 100 s; and 1/e retinal irradiance diameters were 50, 125, and 327 microm. Tissue response was observed via ophthalmoscope 1 h and 48 h post exposure. Thermal and non-thermal damage thresholds were obtained depending upon the exposure duration. These threshold data are in agreement with data previously reported in the literature for 100-s duration exposures, but differences were noted for shorter exposures. The current study yielded an estimated injury threshold for 1-s duration, 327-microm retinal irradiance diameter exposures at 441.6 nm, which is an order of magnitude higher than that previously reported. This study provides evidence that laser-induced retinal damage is primarily induced via thermal mechanisms for exposures shorter than 5 s in duration. Arguments are presented that support an amendment of the thermal hazard function, R(lambda).

Dynamic consent: a possible solution to improve patient confidence and trust in how electronic patient records are used in medical research.

With one million people treated every 36 hours, routinely collected UK National Health Service (NHS) health data has huge potential for medical research. Advances in data acquisition from electronic patient records (EPRs) means such data are increasingly digital and can be anonymised for research purposes. NHS England's care.data initiative recently sought to increase the amount and availability of such data. However, controversy and uncertainty following the care.data public awareness campaign led to a delay in rollout, indicating that the success of EPR data for medical research may be threatened by a loss of patient and public trust. The sharing of sensitive health care data can only be done through maintaining such trust in a constantly evolving ethicolegal and political landscape. We propose that a dynamic consent model, whereby patients can electronically control consent through time and receive information about the uses of their data, provides a transparent, flexible, and user-friendly means to maintain public trust. This could leverage the huge potential of the EPR for medical research and, ultimately, patient and societal benefit.

Dynamic consent: a patient interface for twenty-first century research networks.

Biomedical research is being transformed through the application of information technologies that allow ever greater amounts of data to be shared on an unprecedented scale. However, the methods for involving participants have not kept pace with changes in research capability. In an era when information is shared digitally at the global level, mechanisms of informed consent remain static, paper-based and organised around national boundaries and legal frameworks. Dynamic consent (DC) is both a specific project and a wider concept that offers a new approach to consent; one designed to meet the needs of the twenty-first century research landscape. At the heart of DC is a personalised, digital communication interface that connects researchers and participants, placing participants at the heart of decision making. The interface facilitates two-way communication to stimulate a more engaged, informed and scientifically literate participant population where individuals can tailor and manage their own consent preferences. The technical architecture of DC includes components that can securely encrypt sensitive data and allow participant consent preferences to travel with their data and samples when they are shared with third parties. In addition to improving transparency and public trust, this system benefits researchers by streamlining recruitment and enabling more efficient participant recontact. DC has mainly been developed in biobanking contexts, but it also has potential application in other domains for a variety of purposes.