Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.

How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.

Transient and Sustained Ganglion Cell Light Responses Are Differentially Modulated by Intrinsically Produced Reactive Oxygen Species Acting upon Specific Voltage-Gated Na+ Channel Isoforms.

Increasing spike rates drive greater neuronal energy demand. In turn, mitochondrial ATP production leads to the generation of reactive oxygen species (ROS) that can modulate ion channel gating. Does ROS production autoregulate the excitability of a neuron? We investigated the links between retinal ganglion cell (RGC) excitability and spike activity-driven ROS production in male and female mice. Changes to the light-evoked and current-evoked spike patterns of functionally identified αRGC subtypes, along with their NaV channel-gating properties, were recorded during experimentally induced decreases and increases of intracellular ROS. During periods of highest spike rates (e.g., following light onset in ON sustained RGCs and light offset in OFF sustained RGCs), these αRGC subtypes responded to reductions of ROS (induced by catalase or glutathione monoethyl ester) with higher spike rates. Increases in ROS (induced by mercaptosuccinate, antimycin-A, or H2O2) lowered spike rates. In ON and OFF transient RGCs, there were no changes in spike rate during ROS decreases but increased ROS increased spiking. This suggests that endogenous ROS are intrinsic neuromodulators in RGCs having high metabolic demands but not in RGCs with lower energy needs. We identified ROS-induced shifts in the voltage-dependent gating of specific isoforms of NaV channels that account for the modulation of ON and OFF sustained RGC spike frequency by ROS-mediated feedback. ROS-induced changes to NaV channel gating, affecting activation and inactivation kinetics, are consistent with the differing spike pattern alterations observed in RGC subtypes. Cell-autonomous generation of ROS during spiking contributes to tuning the spike patterns of RGCs.SIGNIFICANCE STATEMENT Energy production within retinal ganglion cells (RGCs) is accompanied by metabolic by-products harmful to cellular function. How these by-products modulate the excitability of RGCs bears heavily on visual function and the etiology of optic neuropathies. A novel hypothesis of how RGC metabolism can produce automodulation of electrical signaling was tested by identifying the characteristics and biophysical origins of changes to the excitability of RGCs caused by oxidizing by-products in the retina. This impacts our understanding of the pathophysiology of RGC dysfunction, supporting an emerging model in which increases in oxidizing chemical species during energy production, but not necessarily bioenergetic failure, lead to preferential degeneration of specific subtypes of RGCs, yielding loss of different aspects of visual capacity.

A Reporting Tool for Adapted Guidelines in Health Care: The RIGHT-Ad@pt Checklist.

BACKGROUND: Adaptation of existing guidelines can be an efficient way to develop contextualized recommendations. Transparent reporting of the adaptation approach can support the transparency and usability of the adapted guidelines. OBJECTIVE: To develop an extension of the RIGHT (Reporting Items for practice Guidelines in HealThcare) statement for the reporting of adapted guidelines (including recommendations that have been adopted, adapted, or developed de novo), the RIGHT-Ad@pt checklist. DESIGN: A multistep process was followed to develop the checklist: establishing a working group, generating an initial checklist, optimizing the checklist (through an initial assessment of adapted guidelines, semistructured interviews, a Delphi consensus survey, an external review, and a final assessment of adapted guidelines), and approval of the final checklist by the working group. SETTING: International collaboration. PARTICIPANTS: A total of 119 professionals participated in the development process. MEASUREMENTS: Participants' consensus on items in the checklist. RESULTS: The RIGHT-Ad@pt checklist contains 34 items grouped in 7 sections: basic information (7 items); scope (6 items); rigor of development (10 items); recommendations (4 items); external review and quality assurance (2 items); funding, declaration, and management of interest (2 items); and other information (3 items). A user guide with explanations and real-world examples for each item was developed to provide a better user experience. LIMITATION: The RIGHT-Ad@pt checklist requires further validation in real-life use. CONCLUSION: The RIGHT-Ad@pt checklist has been developed to improve the reporting of adapted guidelines, focusing on the standardization, rigor, and transparency of the process and the clarity and explicitness of adapted recommendations. PRIMARY FUNDING SOURCE: None.

Novel hybrid action of GABA mediates inhibitory feedback in the mammalian retina.

The stream of visual information sent from photoreceptors to second-order bipolar cells is intercepted by laterally interacting horizontal cells that generate feedback to optimize and improve the efficiency of signal transmission. The mechanisms underlying the regulation of graded photoreceptor synaptic output in this nonspiking network have remained elusive. Here, we analyze with patch clamp recording the novel mechanisms by which horizontal cells control pH in the synaptic cleft to modulate photoreceptor neurotransmitter release. First, we show that mammalian horizontal cells respond to their own GABA release and that the results of this autaptic action affect cone voltage-gated Ca2+ channel (CaV channel) gating through changes in pH. As a proof-of-principle, we demonstrate that chemogenetic manipulation of horizontal cells with exogenous anion channel expression mimics GABA-mediated cone CaV channel inhibition. Activation of these GABA receptor anion channels can depolarize horizontal cells and increase cleft acidity via Na+/H+ exchanger (NHE) proton extrusion, which results in inhibition of cone CaV channels. This action is effectively counteracted when horizontal cells are sufficiently hyperpolarized by increased GABA receptor (GABAR)-mediated HCO3- efflux, alkalinizing the cleft and disinhibiting cone CaV channels. This demonstrates how hybrid actions of GABA operate in parallel to effect voltage-dependent pH changes, a novel mechanism for regulating synaptic output.

Calcium-activated BKCa channels govern dynamic membrane depolarizations of horizontal cells in rodent retina.

KEY POINTS: Large conductance, Ca2+ -activated K+ (BKCa ) channels play important roles in mammalian retinal neurons, including photoreceptors, bipolar cells, amacrine cells and ganglion cells, but they have not been identified in horizontal cells. BKCa channel blockers paxilline and iberiotoxin, as well as Ca2+ free solutions and divalent cation Cav channel blockers, eliminate the outwardly rectifying current, while NS1619 enhances it. In symmetrical 150 mm K+ , single channels had a conductance close to 250 pS, within the range of all known BKCa channels. In current clamped horizontal cells, BKCa channels subdue depolarizing membrane potential excursions, reduce the average resting potential and decrease oscillations. The results show that BKCa channel activation puts a ceiling on horizontal cell depolarization and regulates the temporal responsivity of the cells. ABSTRACT: Large conductance, calcium-activated potassium (BKCa ) channels have numerous roles in neurons including the regulation of membrane excitability, intracellular [Ca2+ ] regulation, and neurotransmitter release. In the retina, they have been identified in photoreceptors, bipolar cells, amacrine cells and ganglion cells, but have not been conclusively identified in mammalian horizontal cells. We found that outward current recorded between -30 and +60 mV is carried primarily in BKCa channels in isolated horizontal cells of rats and mice. Whole-cell outward currents were maximal at +50 mV and declined at membrane potentials positive to this value. This current was eliminated by the selective BKCa channel blocker paxilline (100 nm), iberiotoxin (10 µm), Ca2+ free solutions and divalent cation Cav channel blockers. It was activated by the BKCa channel activator NS1619 (30 µm). Single channel recordings revealed the conductance of the channels to be 244 ± 11 pS (n = 17; symmetrical 150 mm K+ ) with open probability being both voltage- and Ca2+ -dependent. The channels showed fast activation kinetics in response to Ca2+ influx and inactivation gating that could be modified by intracellular protease treatment, which suggests ß subunit involvement. Under current clamp, block of BKCa current increased depolarizing membrane potential excursions, raising the average resting potential and producing oscillations. BKCa current activation with NS1619 inhibited oscillations and hyperpolarized the resting potential. These effects underscore the functional role of BKCa current in limiting depolarization of the horizontal cell membrane potential and suggest actions of these channels in regulating the temporal responsivity of the cells.

Parallel Inhibition of Dopamine Amacrine Cells and Intrinsically Photosensitive Retinal Ganglion Cells in a Non-Image-Forming Visual Circuit of the Mouse Retina.

An inner retinal microcircuit composed of dopamine (DA)-containing amacrine cells and melanopsin-containing, intrinsically photosensitive retinal ganglion cells (M1 ipRGCs) process information about the duration and intensity of light exposures, mediating light adaptation, circadian entrainment, pupillary reflexes, and other aspects of non-image-forming vision. The neural interaction is reciprocal: M1 ipRGCs excite DA amacrine cells, and these, in turn, feed inhibition back onto M1 ipRGCs. We found that the neuropeptide somatostatin [somatotropin release inhibiting factor (SRIF)] also inhibits the intrinsic light response of M1 ipRGCs and postulated that, to tune the bidirectional interaction of M1 ipRGCs and DA amacrine cells, SRIF amacrine cells would provide inhibitory modulation to both cell types. SRIF amacrine cells, DA amacrine cells, and M1 ipRGCs form numerous contacts. DA amacrine cells and M1 ipRGCs express the SRIF receptor subtypes sst(2A) and sst4 respectively. SRIF modulation of the microcircuit was investigated with targeted patch-clamp recordings of DA amacrine cells in TH-RFP mice and M1 ipRGCs in OPN4-EGFP mice. SRIF increases K(+) currents, decreases Ca(2+) currents, and inhibits spike activity in both cell types, actions reproduced by the selective sst(2A) agonist L-054,264 (N-[(1R)-2-[[[(1S*,3R*)-3-(aminomethyl)cyclohexyl]methyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]spiro[1H-indene-1,4'-piperidine]-1'-carboxamide) in DA amacrine cells and the selective sst4 agonist L-803,087 (N(2)-[4-(5,7-difluoro-2-phenyl-1H-indol-3-yl)-1-oxobutyl]-L-arginine methyl ester trifluoroacetate) in M1 ipRGCs. These parallel actions of SRIF may serve to counteract the disinhibition of M1 ipRGCs caused by SRIF inhibition of DA amacrine cells. This allows the actions of SRIF on DA amacrine cells to proceed with adjusting retinal DA levels without destabilizing light responses by M1 ipRGCs, which project to non-image-forming targets in the brain.

Dopamine D1 receptor modulation of calcium channel currents in horizontal cells of mouse retina.

Horizontal cells form the first laterally interacting network of inhibitory interneurons in the retina. Dopamine released onto horizontal cells under photic and circadian control modulates horizontal cell function. Using isolated, identified horizontal cells from a connexin-57-iCre × ROSA26-tdTomato transgenic mouse line, we investigated dopaminergic modulation of calcium channel currents (ICa) with whole cell patch-clamp techniques. Dopamine (10 µM) blocked 27% of steady-state ICa, an action blunted to 9% in the presence of the L-type Ca channel blocker verapamil (50 µM). The dopamine type 1 receptor (D1R) agonist SKF38393 (20 µM) inhibited ICa by 24%. The D1R antagonist SCH23390 (20 µM) reduced dopamine and SKF38393 inhibition. Dopamine slowed ICa activation, blocking ICa by 38% early in a voltage step. Enhanced early inhibition of ICa was eliminated by applying voltage prepulses to +120 mV for 100 ms, increasing ICa by 31% and 11% for early and steady-state currents, respectively. Voltage-dependent facilitation of ICa and block of dopamine inhibition after preincubation with a Gßγ-blocking peptide suggested involvement of Gßγ proteins in the D1R-mediated modulation. When the G protein activator guanosine 5'-O-(3-thiotriphosphate) (GTPγS) was added intracellularly, ICa was smaller and showed the same slowed kinetics seen during D1R activation. With GTPγS in the pipette, additional block of ICa by dopamine was only 6%. Strong depolarizing voltage prepulses restored the GTPγS-reduced early ICa amplitude by 36% and steady-state ICa amplitude by 3%. These results suggest that dopaminergic inhibition of ICa via D1Rs is primarily mediated through the action of Gßγ proteins in horizontal cells.

Creativity and Bipolar Disorder: Igniting a Dialogue.

Bipolar disorder (BD) has been related to heightened creativity, yet core questions remain unaddressed about this association. We used qualitative methods to investigate how highly creative individuals with BD understand the role of symptoms and treatment in their creativity, and possible mechanisms underpinning this link. Twenty-two individuals self-identified as highly creative and living with BD took part in focus groups and completed quantitative measures of symptoms, quality of life (QoL), and creativity. Using thematic analysis, five themes emerged: the pros and cons of mania for creativity, benefits of altered thinking, the relationship between creativity and medication, creativity as central to one's identity, and creativity's importance in stigma reduction and treatment. Despite reliance on a small sample who self-identified as having BD, findings shed light on previously mixed results regarding the influence of mania and treatment and suggest new directions for the study of mechanisms driving the creative advantage in BD.

Modulation of voltage-gated Ca2+ channels in rat retinal ganglion cells by gabapentin.

The α2δ auxiliary subunits of voltage-gated Ca2+ channels (VGCCs) are important modulators of VGCC function. Gabapentin interacts with α2δ1 and α2δ2 subunits and is reported to reduce Ca2+ channel current amplitude (ICa). This study aimed to determine the effects of gabapentin on VGCCs in retinal ganglion cells (RGCs). Whole cell patch clamp was used to record ICa in isolated RGCs, and calcium imaging was used to measure Ca2+ transients from RGCs in situ. Immunohistochemistry was used to detect the presence of α2δ1-containing VGCCs in isolated RGCs in the absence and presence of gabapentin pretreatment. Acute administration of gabapentin reduced ICa and Ca2+ transients compared to control conditions. In isolated RGCs, pretreatment with gabapentin (4-18 h) reduced ICa, and cell surface α2δ1 staining was reduced compared to nonpretreated cells. Acute administration of gabapentin to isolated RGCs that had been pretreated further reduced ICa. These results show that gabapentin has both short-term and long-term mechanisms to reduce ICa in isolated RGCs. Some Ca2+ channel blockers have been shown to protect RGCs in retinal trauma suggesting that modulation of VGCCs by gabapentin may prevent the deleterious effects of elevated Ca2+ levels in RGCs in trauma and disease.

Calcium channels in rat horizontal cells regulate feedback inhibition of photoreceptors through an unconventional GABA- and pH-sensitive mechanism.

Horizontal cells send inhibitory feedback to photoreceptors, helping form antagonistic receptive fields in the retina, but the neurotransmitter and the mechanisms underlying this signalling are not known. Since the proteins responsible for conventional Ca(2+)-dependent release of GABAergic synaptic vesicles are present in mammalian horizontal cells, we investigated this conventional mechanism as the means by which horizontal cells inhibit photoreceptors. Using Ca(2+) imaging in rat retinal slices, we confirm that horizontal cell depolarization with kainate inhibits and horizontal cell hyperpolarization with NBQX disinhibits the Ca(2+) signals produced by pH-sensitive activation of voltage-gated calcium channels (Ca channels) in photoreceptors. We show that while 100 µm Co(2+) reduces photoreceptor Ca(2+) signals, it disinhibits them at 10 µm, an effect reminiscent of earlier studies where low [Co(2+)] eliminated feedback. The low [Co(2+)] disinhibition is pH sensitive. We localized L-, N- and P/Q-type Ca channels in rat horizontal cells, and showed that both the N-type Ca channel blocker -conotoxin GVIA and the P/Q-type Ca channel blocker -agatoxin IVA increased Ca(2+) signals in photoreceptors in a pH-sensitive manner. Pronounced actions of GABAergic agents on feedback signals to photoreceptors were observed, and are pH sensitive, but are inconsistent with direct inhibition by GABA of photoreceptor [Ca(2+)]. Patch-clamp studies revealed that GABA activates a conductance having high bicarbonate permeability in isolated horizontal cells, suggesting that the commonality of pH sensitivity throughout the results could arise from a GABA autofeedback action in horizontal cells. This could change cleft pH with concomitant inhibitory influences on photoreceptor Ca channels.

Engaging diverse patients in a diverse world: the development and preliminary evaluation of educational modules to support diversity in patient engagement research.

BACKGROUND: Current practices for engaging patients in patient-oriented research (POR) result in a narrow pool of patient perspectives being reflected in POR. This project aims to address gaps in methodological knowledge to foster diversity in POR, through the co-design and evaluation of a series of educational modules for health researchers in British Columbia, Canada. METHODS: Modules were co-created by a team of academic researchers and patient partners from hardly-reached communities. The modules are presented using the Tapestry Tool, an interactive, online educational platform. Our evaluation framework focused on engagement, content quality, and predicted behavior change. The User Engagement Scale short form (UES-SF) measured participants' level of engagement with the modules. Survey evaluation items assessed the content within the modules and participants' perceptions of how the modules will impact their behavior. Evaluation items modeled on the theory of planned behavior, administered before and after viewing the modules, assessed the impact of the modules on participants' perceptions of diversity in POR. RESULTS: Seventy-four health researchers evaluated the modules. Researchers' engagement and ratings of module content were high. Subjective behavioral control over fostering diversity in POR increased significantly after viewing the modules. CONCLUSIONS: Our results suggest the modules may be an engaging way to provide health researchers with tools and knowledge to increase diversity in health research. Future studies are needed to investigate best practices for engaging with communities not represented in this pilot project, such as children and youth, Indigenous Peoples, and Black communities. While educational interventions represent one route to increasing diversity in POR, individual efforts must occur in tandem with high-level changes that address systemic barriers to engagement.

Patient-Oriented research (POR) recognizes patients as partners in the research process, contributing valuable knowledge and lived experience to improve health outcomes and research translation. Unfortunately, POR presently does not represent all patients: patient partners involved in research tend to be white, middle-class women. Limited diversity in POR may limit research impact, in part because health research is not fully inclusive of the people requiring healthcare services and support. Although they recognize the need for diversity, many health researchers do not understand how to foster this. To empower health researchers with tools and knowledge to foster diversity in POR, we coordinated teams that co-created a set of educational modules. These teams included academic researchers and patient partners from seldom-heard communities in health research. The modules were built using the Tapestry Tool, an interactive, educational platform. We evaluated the modules using online surveys of 74 health researchers for three things: quality of module content, how engaging they were, and how they impacted health researchers' views on diversity in POR. Our results show that the modules' content was high quality and engaging. After viewing the modules, health researchers were more likely to feel like they had a role in engaging with more diverse people in their research, and felt that they had the tools, knowledge, and ability to do so. Education and knowledge for health researchers are a first step to increasing diversity in POR settings, but systemic barriers to inclusion also need attention.

Intrinsic oscillatory activity arising within the electrically coupled AII amacrine-ON cone bipolar cell network is driven by voltage-gated Na+ channels.

In the rd1 mouse model for retinal degeneration, the loss of photoreceptors results in oscillatory activity (∼10­20 Hz) within the remnant electrically coupled network of retinal ON cone bipolar and AII amacrine cells. We tested the role of hyperpolarization-activated currents (I(h)), voltage-gated Na(+) channels and gap junctions in mediating such oscillatory activity. Blocking I(h) (1 mm Cs(+)) hyperpolarized the network and augmented activity, while antagonizing voltage-dependent Na(+) channels (1 µm TTX) abolished oscillatory activity in the AII amacrine-ON cone bipolar cell network. Voltage-gated Na(+) channels were only observed in AII amacrine cells, implicating these cells as major drivers of activity. Pharmacologically uncoupling the network (200 µm meclofenamic acid (MFA)) blocked oscillations in all cells indicating that Na(+) channels exert their influence over multiple cell types within the network. In wt retina, occluding photoreceptor inputs to bipolar cells (10 µm NBQX and 50 µm l-AP4) resulted in a mild (∼10 mV) hyperpolarization and the induction of oscillatory activity within the AII amacrine-ON cone bipolar cell network. These oscillations had similar properties to those observed in rd1 retina, suggesting that no major degeneration-induced network rewiring is required to trigger spontaneous oscillations. Finally, we constructed a simplified computational model that exhibited Na(+) channel-dependent network oscillations. In this model, mild heterogeneities in channel densities between individual neurons reproduced our experimental findings. These results indicate that TTX-sensitive Na(+) channels in AII amacrine cells trigger degeneration-induced network oscillations, which provide a persistent synaptic drive to downstream remnant neurons, thus appearing to replace photoreceptors as the principal drivers of retinal activity.

Updating clinical practice recommendations: is it worthwhile and when?

BACKGROUND: Keeping clinical practice recommendations up-to-date with a continually evolving evidence base presents challenges. Resources required to update recommendations compete with those needed to evaluate newer treatments. METHODS: We describe an approach developed by the UK National Institute for Health and Clinical Excellence (NICE) for updating clinical practice recommendations for new interventional procedures and we evaluate relevant initial experience of using this system. Depending on whether evidence for a procedure is judged adequate or inadequate for safety and efficacy, use in clinical practice is usually recommended with either "normal" or "special" arrangements for patient consent, data collection and institutional oversight, respectively. We examined whether differences in the state of the evidence at the initial and the updated appraisal of procedures were associated with changed recommendations. RESULTS: Since 2008, updating of recommendations focuses on procedures with initially inadequate evidence. "Special arrangements" recommendations about eleven procedures were updated after 3.3-6.5 years (median, 5.3 years), and recommendations for six were changed to "normal arrangements." Overall, procedures with changed ("special-to-normal") recommendations had a greater increase in the number of patients included in observational studies published since the initial guidance. CONCLUSIONS: Procedures with changed ("special-to-normal") recommendations generally had greater increases in their evidence base. Although uncertainties about optimal methods for keeping evidence-based recommendations up-to-date remain, this experience should be useful to policy makers in developing processes for prioritizing scarce resources for updating clinical practice recommendations. Further studies are needed about the value placed on "updated" recommendations by clinicians, policy-makers, and patients.

Visual processing: When two synaptic strata are better than one.

Two pillars of retinal function, horizontal cell feedback to photoreceptors and center-surround antagonistic receptive fields, are linked in a cause-and-effect relationship. New findings extend the horizontal cell signaling repertoire, prompting insight into the circuits necessary for outer retinal visual processing.

Enhanced supported living for people with severe and persistent mental health problems: A qualitative investigation.

Supported living has been shown to improve functioning and social inclusion in people with severe and persistent mental health problems, reduce hospitalisation and provide secure accommodation in a population where housing needs are often unmet. Conversely, living in supported accommodation has been depicted by some as depersonalising, marginalising and an ordeal to survive. Discussions regarding housing and support often lack a thorough consideration of individual experiences, with a reliance on quantitative surveys. The question remains how to assure that supported accommodations actually are supportive of the residents' ongoing recovery process. The present study sought to shed light on the experiences of residents in an enhanced supported living service in the United Kingdom. Semi-structured interviews were conducted with nine residents of the service between July 2020 and February 2021. Transcripts were analysed using thematic analysis and indicated three superordinate themes of experiences considered valuable to residents: (1) support from care staff which was readily available; (2), a sense of community and daily activity offered by the residence and on-site activities; and (3) the experience of supported living as a stepping-stone in an ongoing recovery process. Findings indicate the power of comprehensive care with supportive staff, peer-relations, autonomy and fostering hope in empowering individuals in their ongoing recovery.

Supporting Self-management and Quality of Life in Bipolar Disorder With the PolarUs App (Alpha): Protocol for a Mixed Methods Study.

BACKGROUND: Quality of life (QoL) is increasingly being recognized as a key outcome of interventions for bipolar disorder (BD). Mobile phone apps can increase access to evidence-based self-management strategies and provide real-time support. However, although individuals with lived experiences desire support with monitoring and improving broader health domains, existing BD apps largely target mood symptoms only. Further, evidence from the broader mobile health (mHealth) literature has shown that the desires and goals of end users are not adequately considered during app development, and as a result, engagement with mental health apps is suboptimal. To capitalize on the potential of apps to optimize wellness in BD, there is a need for interventions developed in consultation with real-world users designed to support QoL self-monitoring and self-management. OBJECTIVE: This mixed methods pilot study was designed to evaluate the alpha version of the newly developed PolarUs app, developed to support QoL self-monitoring and self-management in people with BD. Co-designed using a community-based participatory research framework, the PolarUs app builds on the web-based adaptation of a BD-specific QoL self-assessment measure and integrates material from a web-based portal providing information on evidence-informed self-management strategies in BD. The primary objectives of this project were to evaluate PolarUs app feasibility (via behavioral use metrics), the impact of PolarUs (via the Brief Quality of Life in Bipolar Disorder scale, our primary outcome measure), and explore engagement with the PolarUs app (via quantitative and qualitative methods). METHODS: Participants will be residents of North America (N=150), aged >18 years, with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of BD type 1, BD type 2, or BD not otherwise specified as assessed by structured diagnostic interview. An embedded mixed methods research design will be adopted; qualitative interviews with a purposefully selected subsample (approximately, n=30) of participants will be conducted to explore in more depth feasibility, impact, and engagement with the PolarUs app over the 12-week study period. RESULTS: At the time of publication of this protocol, the development of the alpha version of the PolarUs app was complete. Participant enrollment has begun in June 2022. Data collection is expected to be completed by December 2022. CONCLUSIONS: Beyond contributing knowledge on the feasibility and impact of a novel app to support QoL and self-management in BD, this study will also provide new insights related to engagement with mHealth apps. Furthermore, it will function as a case study of successful co-design between people with BD, health care providers, and BD researchers, providing a template for the future use of community-based participatory research frameworks in mHealth intervention development. The results will be used to further refine the PolarUs app and inform the design of a larger clinical trial. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/36213.

Evaluating the quality, safety, and functionality of commonly used smartphone apps for bipolar disorder mood and sleep self-management.

BACKGROUND: Individuals with bipolar disorder (BD) are increasingly turning to smartphone applications (apps) for health information and self-management support. While reviews have raised concerns regarding the effectiveness and safety of publicly available apps for BD, apps surveyed may not reflect what individuals with BD are using. The present study had two aims: first, to characterize the use of health apps to support mood and sleep amongst people with BD, and second, to evaluate the quality, safety and functionality of the most commonly used self-management apps. METHODS: A web-based survey was conducted to explore which apps people with BD reported using to support self-management of mood and sleep. The characteristics of the most commonly nominated apps were described using a standardized framework, including their privacy policy, clinical foundations, and functionality. RESULTS: Respondents (n = 919) were 77.9% female with a mean age of 36.9 years. 41.6% of participants (n = 382) reported using a self-management app to support mood or sleep. 110 unique apps were nominated in relation to mood, and 104 unique apps nominated in relation to sleep; however, most apps were only mentioned once. The nine most frequently nominated apps related to mood and sleep were subject to further evaluation. All reviewed apps offered a privacy policy, however user control over data was limited and the complexity of privacy policies was high. Only one app was developed for BD populations. Half of reviewed apps had published peer-reviewed evidence to support their claims of efficacy, but little research was specific to BD. CONCLUSION: Findings illustrate the potential of smartphone apps to increase the reach of psychosocial interventions amongst people with BD. Apps were largely created by commercial developers and designed for the general population, highlighting a gap in the development and dissemination of evidence-informed apps for BD. There may be risks in using generic health apps for BD self-management; clinicians should enquire about patients' app use to foster conversations about their particular benefits and limitations.

Stable mossy fiber long-term potentiation requires calcium influx at the granule cell soma, protein synthesis, and microtubule-dependent axonal transport.

The synapses formed by the mossy fiber (MF) axons of hippocampal dentate gyrus granule neurons onto CA3 pyramidal neurons exhibit an intriguing form of experience-dependent synaptic plasticity that is induced and expressed presynaptically. In contrast to most other CNS synapses, long-term potentiation (LTP) at the MF-CA3 synapse is readily induced even during blockade of postsynaptic glutamate receptors. Furthermore, blocking voltage-gated Ca(2+) channels prevents MF-LTP, supporting an involvement of presynaptic Ca(2+) signaling via voltage-gated Ca(2+) channels in MF-LTP induction. We examined the contribution of activity in both dentate granule cell somata and MF terminals to MF-LTP. We found that the induction of stable MF-LTP requires tetanization-induced action potentials not only at MF boutons, but also at dentate granule cell somata. Similarly, blocking Ca(2+) influx via voltage-gated Ca(2+) channels only at the granule cell soma was sufficient to disrupt MF-LTP. Finally, blocking protein synthesis or blocking fast axonal transport mechanisms via disruption of axonal tubulin filaments resulted in decremental MF-LTP. Collectively, these data suggest that-in addition to Ca(2+) influx at the MF terminals-induction of MF synaptic plasticity requires action potential-dependent Ca(2+) signaling at granule cell somata, protein synthesis, and fast axonal transport along MFs. A parsimonious interpretation of these results is that somatic activity triggers protein synthesis at the soma; newly synthesized proteins are then transported to MF terminals, where they contribute to the stabilization of MF-LTP. Finally, the present data imply that synaptic plasticity at the MF-CA3 synapse can be affected by local modulation of somatic and presynaptic Ca(2+) channel activity.

Established non-union of an operatively managed trans-scaphoid perilunate fracture dislocation progressing to spontaneous union.

Perilunate dislocations and fracture dislocations represent uncommon and unusual injuries that are often missed at initial presentation and diagnosed late in up to 25% of cases. Prompt open reduction, carpal stabilisation and ligamentous repair is required to reduce the risk of complications. We report a case of an established scaphoid non-union in an operatively managed perilunate fracture dislocation that spontaneously united almost 2 years after the initial injury, just before a planned revision scaphoid fixation with bone grafting. This case highlights the importance of initial clinical assessment together with appropriate radiographs and follow-up of these injuries post-operatively, especially when complications such as non-union arise.

Digital Health Literacy in Bipolar Disorder: International Web-Based Survey.

BACKGROUND: Web-based resources can support people with bipolar disorder (BD) to improve their knowledge and self-management. However, publicly available resources are heterogeneous in terms of their quality and ease of use. Characterizing digital health literacy (the skillset that enable people to navigate and make use of health information in a web-based context) in BD will support the development of educational resources. OBJECTIVE: The aim of this study was to develop understanding of digital health literacy and its predictors in people with BD. METHODS: A web-based survey was used to explore self-reported digital health literacy (as measured by the e-Health Literacy Scale [eHEALS]) in people with BD. Multiple regression analysis was used to evaluate potential predictors, including demographic/clinical characteristics and technology use. RESULTS: A total of 919 respondents (77.9% female; mean age 36.9 years) completed the survey. Older age (ß=0.09; P=.01), postgraduate education (ß=0.11; P=.01), and current use of self-management apps related to BD (ß=0.13; P<.001) were associated with higher eHEALS ratings. CONCLUSIONS: Levels of self-reported digital health literacy were comparable or higher than other studies in the general population and specific physical/mental health conditions. However, individuals with BD who are younger, have completed less education, or are less familiar with mental health apps may require extra support to safely and productively navigate web-based health resources. Relevant educational initiatives are discussed. Future studies should evaluate skill development interventions for less digitally literate groups.