Persistent pain, long-term opioids, and restoring trust in the patient-clinician relationship.

The erosion of trust in the patient-clinician relationship is an underappreciated, and vital, component of the prescription opioid crisis. Drawing from lived experience of patients and clinicians, and a narrative evidence review, this report discusses how opioid use for persistent pain can impact the patient-clinician relationship from the vantage points of the patient and the family physician. For patients, the stress of dealing with persistent pain, misalignment with clinicians regarding goals of care, experiences of disrespect and stigma, fear of abrupt tapers, and frustration with a fragmented health system, all combine to breed a lack of trust. Clinicians, for their part, experience challenges due to inadequate resources for pain management and opioid safety, pressure to deprescribe opioids rapidly, inconsistent prescribing practices of colleagues, 'policing' opioid prescriptions when concern arises for opioid use disorder and adversarial relationships with frustrated patients wary of clinician intentions. As a result, many clinicians struggle to maintain a therapeutic relationship with patients in great need of empathy and healing. To support implementation of evidence-based guidelines and achieve public health goals of safer prescribing and reducing harm from prescription opioids, we recommend steps health systems and clinicians can take to rebuild trust in the patient-clinician relationship, enable patient-centered pain care, and embed patient perspectives into opioid safety processes. PERSPECTIVE: Erosion of patient-clinician trust is a barrier to implementing evidence-based guidelines that aim to improve opioid safety. This paper explores lived patient and clinician experiences and recommends steps for health systems and clinicians to rebuild this trust as a strategy to actualize the benefits of adherence to these guidelines.

Virtual practice facilitation as an implementation strategy for launching opioid safety committees for quality improvement in primary care: feasibility, acceptability, and intervention fidelity.

BACKGROUND: Practice facilitation (PF) is an evidence-based multicomponent in-person implementation strategy. COVID-19-related lockdowns caused many implementation initiatives to rapidly shift to virtual settings, but there is limited evidence on PF deployed exclusively using virtual meeting platforms. Our objective was to assess the feasibility and acceptability of virtual PF used in a primary care setting to implement interdisciplinary opioid safety committees (OSCs) to improve care for patients using opioid medicines for persistent pain and reduce high-dose opioid prescribing. We also describe alignment of virtual PF with the core functions of PF and fidelity of participating clinics to the OSC intervention. METHODS: We applied qualitative and quantitative methods to evaluate virtual PF used to implement a quality improvement project at Kaiser Permanente Washington, an integrated health system in Washington State. We established interdisciplinary OSCs in primary care clinics using virtual PF. OSCs were tasked with promoting opioid safety and high-quality pain care through population management and chart reviews. We used administrative data to calculate feasibility measures including attendance and retention. Acceptability data came from interviews with OSC members conducted by evaluators. Measures of fidelity to the OSC intervention were abstracted from meeting notes and administrative data. We used qualitative methods to assess the adherence of virtual PF to the core functions of PF. RESULTS: Facilitators carried out a comprehensive PF approach virtually and demonstrated adherence to the core functions of PF. We established OSCs in eight clinics and conducted an average of 17.5 virtual PF meetings over eight months of PF for each clinic. Average attendance was 75% and we had 84% retention. OSC members were highly satisfied with virtual PF. Facilitators effectively supported teams through implementation and technical challenges and OSC members gained skills through virtual PF. We implemented OSCs with high fidelity, suggesting virtual PF is an effective implementation strategy. CONCLUSIONS: We found virtual PF is a feasible and acceptable implementation strategy for this intervention and identified strategies to support care teams through challenges. Our findings can help inform future implementation efforts, especially those hoping to engage geographically dispersed clinics or remote clinical staff. TRIAL REGISTRATION: Not applicable.

Cysteamine toxicity presenting with acute encephalopathy and spastic tetraparesis.

Cystinosis is a lysosomal storage disorder usually presenting with renal disease in infancy. As soon as the diagnosis is made, cysteamine (a cystine-depleting medication), is started, significantly improving life expectancy. We describe a young woman taking lifelong cysteamine for nephropathic cystinosis, who became acutely encephalopathic with a spastic tetraparesis secondary to cysteamine toxicity, which was potentially worsened by copper deficiency. On replacing copper and reducing the dose of cysteamine, she made a full neurological recovery. We discuss the case, and review cystinosis and what is known about cysteamine toxicity.

Sustaining connections: feasibility and impact of long-term virtual patient engagement.

BACKGROUND: Virtual patient engagement has become more common in recent years. Emerging research suggests virtual engagement can increase accessibility for patients managing long-term health conditions and those living in larger geographic areas, but it can also be challenging to establish relationships and maintain engagement over time. Little is known about virtual engagement lasting more than two years, nor about the specific contributions of patients to virtual engagement projects. Here we describe a project where virtual engagement was sustained over a long period of time (3.5 years), measure patients' contributions to the work, and describe the facilitators and challenges of the project using the Valuing All Voices (VAV) patient engagement framework. METHODS: Five researchers recruited four patient partners living with persistent pain to work together virtually on a project to improve care for others with long-term pain. Researchers documented engagement activities and patient partner contributions and categorized them using Carman et al.'s 3 types of engagement. They also collected data via semi-structured group interviews with patient partners about the facilitators and challenges of the project using the VAV framework. RESULTS: In 3.5 years, patient partners contributed 487 h to the project, averaging 3.0 h per month, and participated in 40 meetings. They contributed to 17 products for patients, health care teams, and researchers. Most products (12 of 17) were created using the more in-depth engagement approaches of involvement or partnership and shared leadership. The group identified facilitators of the project across the five VAV domains of relationship-building, trust, understanding & acceptance, education & communication, and self-awareness, as well as some specific challenges such as keeping track of products across virtual platforms and managing the high volume of project information. CONCLUSIONS: Long-term virtual patient engagement is feasible and can use more in-depth engagement approaches. Additionally, it can result in substantial contributions from patients in terms of time, effort, and products. These findings can inform future long-term virtual patient engagement efforts and provide insight into how researchers can structure their activities to encourage and maintain deep engagement over time.

BACKGROUND: Virtual patient engagement has become more common in recent years. Virtual engagement can make it easier for people with long-term health conditions and from larger geographic areas to be involved, but it can also be challenging to establish relationships and maintain engagement over time. There are not many examples of virtual engagement projects lasting more than two years, and many projects do not describe patients' specific contributions to the work. Here we describe a 3.5-year project where we measured patients' contributions and described the facilitators and challenges of the project using the Valuing All Voices (VAV) patient engagement framework. METHODS: Five researchers worked with four patient partners living with persistent pain to improve health care for others with long-term pain. We tracked how we worked together and how patient partners contributed to the project. We categorized the products we created together using three types of engagement that range from less to more in-depth. Researchers also interviewed patient partners about the facilitators and challenges of working together virtually. RESULTS: In 3.5 years, patient partners contributed 487 h to the project, averaging 3.0 h per month, and participated in 40 meetings. They contributed to 17 different products. Twelve of the products used more in-depth engagement approaches. The group identified facilitators of the project across the five VAV domains, as well as some specific challenges. CONCLUSIONS: We found that long-term virtual patient engagement is feasible, can use in-depth engagement strategies, and can result in important contributions from patients in terms of time, effort, and products.

Recurrent herpes simplex virus encephalitis with presumptive Human Herpesvirus 6 chromosomal integration.

Viral encephalitis can lead to encephalopathy, epileptic activity, focal neurological deficits, and death. Prompt recognition and a high index of clinical suspicion can lead to early initiation of appropriate management. We describe an interesting case of a 61-year-old presenting with fever and altered mental status, diagnosed with numerous episodes of viral encephalitis caused by divergent and recurrent viruses. On his initial presentation, lumbar puncture revealed lymphocytic pleocytosis and positivity for Human Herpesvirus 6 (HHV-6), and he was treated with ganciclovir. On subsequent admissions, he was diagnosed with recurrent HHV-6 encephalitis as well as Herpes Simplex Virus 1 encephalitis and treated with ganciclovir, foscarnet and acyclovir. Despite prolonged courses of treatment and resolution of symptoms, he continued to have persistently high plasma viral loads of HHV-6, consistent with probable chromosomal integration. In this report, we emphasize the clinical pearl of chromosomally integrated HHV-6 that can present in a patient with persistently high plasma viral loads of HHV-6, that are non-responsive to treatment. Individuals with chromosomally integrated HHV-6 may be more susceptible to other viral infections.

Longitudinal MRI brain studies in live adult zebrafish.

Zebrafish (Danio rerio) has been successfully used for decades in developmental studies and disease modelling. The remarkable uptake of zebrafish as a model system is partly due to its transparency during the early weeks of its development, allowing in vivo imaging of cellular and molecular processes. However, this key advantage wears off when tissues become opaque as the animal reaches juvenile and adult stages, rendering access to tissues for live imaging and longitudinal studies difficult. Here we provide a novel approach to image and assess tissue integrity of adult zebrafish using MRI on live zebrafish suitable for longitudinal studies. We built a 3D-printed life support chamber and designed a protocol-directed sedation regime to recover adult zebrafish after scanning in a 9.4 T MRI scanner. Our life support chamber is cheap and easy to create using 3D printing, allowing other groups to copy our template for quick setup. Additionally, we optimized the delivery of contrast agent to enhance brain signals in order to refine current delivery, usually delivered intravenously in rodents. We show here that immersion in gadolinium was a viable alternative to intraperitoneal injection to reduce T1 relaxation times. This resulted in protocol refinement as per the 3Rs guidelines and improved image contrast in adult zebrafish disease models. In conclusion, we provide here a detailed methodology to allow longitudinal studies of brain tissue integrity of adult zebrafish, combining safe and efficient delivery of contrast agent and live MRI. This technique can be used to bridge the gap between in vivo studies and longitudinal brain analysis in adult zebrafish, and can be applied to the ever-growing number of adult zebrafish models of ageing and neurodegenerative diseases.

Building Team-based Primary Care: Lessons From an Academic-Community Network Partnership.

BACKGROUND: Team-based care is fundamental to providing high-quality health care for patients. However, moving from a traditional, hierarchical way of providing care to team-based care is challenging and involves systematic and sustained process changes. OBJECTIVES: To describe the implementation and evaluation of a partnership between academics, clinic, and community to improve team-based care in primary care practices serving vulnerable populations utilizing a structured change package and implementation support. METHODS: The partners 1) created a six-strategy structured change package, 2) designed implementation support, and 3) evaluated implementation using an assessment scale at baseline and every 6 months. RESULTS: Practices improved in all care-team functions from May 2015 to August 2018, with the most improvement seen in population management, planned care and empanelment. CONCLUSIONS: Academic-community partnerships can use evidence-based practice supports to measurably improve team-based care in primary care practices serving vulnerable populations.

Ancient marine sediment DNA reveals diatom transition in Antarctica.

Antarctica is one of the most vulnerable regions to climate change on Earth and studying the past and present responses of this polar marine ecosystem to environmental change is a matter of urgency. Sedimentary ancient DNA (sedaDNA) analysis can provide such insights into past ecosystem-wide changes. Here we present authenticated (through extensive contamination control and sedaDNA damage analysis) metagenomic marine eukaryote sedaDNA from the Scotia Sea region acquired during IODP Expedition 382. We also provide a marine eukaryote sedaDNA record of ~1 Mio. years and diatom and chlorophyte sedaDNA dating back to ~540 ka (using taxonomic marker genes SSU, LSU, psbO). We find evidence of warm phases being associated with high relative diatom abundance, and a marked transition from diatoms comprising <10% of all eukaryotes prior to ~14.5 ka, to ~50% after this time, i.e., following Meltwater Pulse 1A, alongside a composition change from sea-ice to open-ocean species. Our study demonstrates that sedaDNA tools can be expanded to hundreds of thousands of years, opening the pathway to the study of ecosystem-wide marine shifts and paleo-productivity phases throughout multiple glacial-interglacial cycles.

Migration of silicone oil for retinal detachment.

Here we describe two, separate, and unique radiological findings in two distinct patients, sequelae from prior silicone oil injection for management of retinal detachment. In both cases we present bilateral, frontal horn hyperdense "masses" without appreciable enhancement or surrounding vasogenic edema. Both cases serve as important reminders of the potential for silicone oil migration and its unique radiological presentation, which has the potential to be a radiologic mimic of intracerebral hemorrhage and significantly change medical management of individuals presenting with transient ischemic attack or cerebrovascular accident.

Serine-arginine-rich protein kinase-1 inhibition for the treatment of diabetic retinopathy.

Angiogenic VEGF isoforms are upregulated in diabetic retinopathy (DR), driving pathological growth and fluid leakage. Serine-arginine-rich protein kinase-1 (SRPK1) regulates VEGF splicing, and its inhibition blocks angiogenesis. We tested the hypothesis that SRPK1 is activated in diabetes, and an SRPK1 inhibitor (SPHINX31) switches VEGF splicing in DR and prevents increased vascular permeability into the retina. SRPK1 was activated by high glucose (HG), in a PKC-dependent manner, and was blocked by SPHINX31. HG induced release of SRSF1 from the nuclear speckles, which was also SRPK1 dependent, and increased retinal pigment epithelial (RPE) monolayer admittance, which was reversed by SRPK1 inhibition (P < 0.05). Diabetes increased retinal permeability and thickness after 14 days which was blocked by treatment with SPHINX31 eye drops (P < 0.0001). These results show that SRPK1 inhibition, administered as an eye drop, protected the retinal barrier from hyperglycemia-associated loss of integrity in RPE cells in vitro and in diabetic rats in vivo. A clinical trial of another SRPK1 inhibitor has now been initiated in patients with diabetic macular edema.NEW & NOTEWORTHY VEGF-A165b splicing is induced by hyperglycemia through PKC-mediated activation of SRPK1 in RPE cells, increasing their permeability and angiogenic capability. SRPK1 inhibitors can be given as eye drops to reduce retinal permeability and edema in diabetic retinopathy.

Dorsal arachnoid web: A rare clinical entity.

A dorsal arachnoid web is a rare entity involving abnormal formation of arachnoid mater into a dense web which may result in ventral herniation of the spinal cord and significant neurologic symptoms. Back pain or a compressive myelopathy are two of the most common presenting symptoms. CT myelogram or MRI can aid in the diagnosis of arachnoid web, and management of includes surgical and conservative approaches. Herein, we describe two interesting cases of arachnoid webs highlighting the diagnostic approach and differences in the approach to management of each case.

Preventing persistent postsurgical pain: A systematic review and component network meta-analysis.

BACKGROUND AND OBJECTIVES: Evidence for perioperative methods to prevent persistent postsurgical pain (PPP) is uncertain, in part because few treatments have been directly compared. Here we have used component network meta-analysis (cNMA) to incorporate both direct and indirect evidence in the evaluation of the efficacy and tolerability of pharmacological and neural block treatments. DATABASES AND DATA TREATMENT: We searched the Cochrane Central Registry of Controlled Trials, Embase, MEDLINE, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry up to January 2021 for randomized, double-masked, controlled trials that reported the prevalence of PPP. We assessed trial quality with the Cochrane risk of bias tool (RoB 2.0). We analysed the results with frequentist cNMA models. The primary outcome was the relative risk (RR) of PPP. We assessed efficacy in relation to a clinically important effect size of RR = 0.9, which is a 10% improvement with treatment. RESULTS: The analysis included 107 trials (13,553 participants) of 13 treatments. The effects of complex interventions were the multiplicative effects of their components. Compared with placebo, serotonin-norepinephrine reuptake inhibitors (SNRIs), neural block alone, or in combination with NMDA receptor blockers or gabapentanoids were effective. Treatments with benefit in the immediate post-operative period predicted a reduced risk of PPP. CONCLUSIONS: Several treatments and treatment combinations effectively reduce PPP prevalence. Pain outcomes in the immediate postoperative period are an important mediator of PPP. Multimodal interventions can be analysed using cNMA. SIGNIFICANCE: Systematic reviews of PPP prevention usually focus on the efficacy of specific treatments in comparison with control interventions. In this study we used component network meta-analysis to compare interventions to each other, including both pharmacological and neural block techniques, and multimodal interventions. Interventions that are not effective alone may improve the efficacy of multimodal interventions that include neural block techniques. Immediate postoperative benefit was an important mediator for reduction of PPP. STUDY REGISTRATION: PROSPERO: CRD42018085570 https://www.crd.york.ac.uk/prospero/.

Transmission Electron Microscopy of Endothelium.

Transmission electron microscopy using resin sections still remains an exceptionally useful tool in evaluating cellular ultrastucture within tissue. For the endothelium the best method for maintaining such structure is perfusion fixation: fixing the tissue under physiological pressure. Here the focus is on a method of maintaining the vascular wall structure including the endothelial glycocalyx and extending this with tilt series tomography. Shown are typical histological sections from multiple capillary beds including brain, heart and retina using a lanthanide staining technique (LaDy GAGa) to highlight that the differences in normo-physiology are substantial.It is hoped that users will find the notes useful in deciding which specific staining and imaging method would suit their needs so this technically challenging, and low throughput methodology, is used to its best effect.

Noninvasive Measurement of Retinal Microvascular Permeability During Loss of Endothelial Quiescence.

In the retina EC dysfunction and angiogenesis are driven by an altered microenvironment e.g., diabetes, leading to hypoxia and inflammation in the retinal layers, resulting in excessive vascular leakage and growth. The gold standard for measuring blood-retinal barrier permeability in response to disease and or therapy has been the gold standard Evans blue (EB) assay. However, this technique has limitations in vivo, including nonspecific tissue binding and toxicity. Here we describe a novel imaging methodology combining sodium fluorescein fundus angiography (FFA) with mathematical quantification allowing retinal permeability to be noninvasively and accurately measured at multiple time points in the same animal, minimizing animal use in line with the 3Rs framework. In addition, this technique is a nontoxic, high throughput, sensitive, and cost-effective alternative technique to the Evans blue assay. Moreover, this technique can be translated to other species.

Quantification of Angiogenesis in Laser Choroidal Neovascularization.

Murine laser-induced laser choroidal neovascularization is a widely used and robust model of wet (exudative) age-related macular degeneration (wAMD). wAMD is one of the leading causes of blindness in the Western world. In brief, a focused laser beam is used to penetrate Bruch's membrane, which separates the choriocapillaris (well-vascularized choroid layer) from the pigmented layers of the retina. Damage to the integrity of this membrane during diabetes leads to fluid accumulation and vascular invasion into the subretinal layers resulting in a progressive worsening of vision. Here we describe a 14-day model using untreated C57/Bl6 mice, but it is equally applicable to incorporation into transgenic studies and therapeutic agent development (such as eye drops), injection of therapeutic agents (including antibodies), and for longer time course studies. In vivo functional analysis or lesioned choroids can be studied with further immunohistochemical staining for further analyses.

Recurrent Episodes of Transient Global Amnesia: A Rare Clinical Entity.

Transient global amnesia (TGA) is a syndrome characterized by anterograde amnesia with otherwise intact cognitive function, resolving within 24 h of onset, occurring in the absence of neurological changes. Recurrent episodes remain rare. We report an interesting case of recurrent episodes of TGA in a 63-year-old woman presenting with altered mental status. She had no memory of antecedent events and demonstrated repetitive questioning but retained awareness of self. Physical examination and laboratory diagnostics were unremarkable. Brain magnetic resonance imaging revealed scattered foci of increased FLAIR signal within the bilateral periventricular and subcortical white matter. She was notably diagnosed with TGA a few months prior when she had presented with similar symptoms. During the current hospitalization, she remained alert and fully oriented, with resolution of perseveration. This case emphasizes the recognition of TGA as an important neurological diagnosis, uniquely describes not only the recurrence, but the short interval between recurrent episodes.

A roadmap to operationalize and evaluate impact in a learning health system.

BACKGROUND: Many health systems invest in initiatives to accelerate translation of knowledge into practice. However, organizations lack guidance on how to develop and operationalize such Learning Health System (LHS) programs and evaluate their impact. Kaiser Permanente Washington (KPWA) launched our LHS program in June 2017 and developed a logic model as a foundation to evaluate the program's impact. OBJECTIVE: To develop a roadmap for organizations that want to establish an LHS program, understand how LHS core components relate to one another when operationalized in practice, and evaluate and improve their progress. METHODS: We conducted a narrative review on LHS models, key model components, and measurement approaches. RESULTS: The KPWA LHS Logic Model provides a broad set of constructs relevant to LHS programs, depicts their relationship to LHS operations, harmonizes terms across models, and offers measurable operationalizations of each construct to guide other health systems. The model identifies essential LHS inputs, provides transparency into LHS activities, and defines key outcomes to evaluate LHS processes and impact. We provide reflections on the most helpful components of the model and identify areas that need further improvement using illustrative examples from deployment of the LHS model during the COVID-19 pandemic. CONCLUSION: The KPWA LHS Logic Model is a starting point for future LHS implementation research and a practical guide for healthcare organizations that are building, operationalizing, and evaluating LHS initiatives.

Hydrogen Sulfide Is a Novel Protector of the Retinal Glycocalyx and Endothelial Permeability Barrier.

Significantly reduced levels of the anti-inflammatory gaseous transmitter hydrogen sulfide (H2S) are observed in diabetic patients and correlate with microvascular dysfunction. H2S may protect the microvasculature by preventing loss of the endothelial glycocalyx. We tested the hypothesis that H2S could prevent or treat retinal microvascular endothelial dysfunction in diabetes. Bovine retinal endothelial cells (BRECs) were exposed to normal (NG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) ± the slow-release H2S donor NaGYY4137 in vitro. Glycocalyx coverage (stained with WGA-FITC) and calcein-labeled monocyte adherence were measured. In vivo, fundus fluorescein angiography (FFA) was performed in normal and streptozotocin-induced (STZ) diabetic rats. Animals received intraocular injection of NaGYY4137 (1 µM) or the mitochondrial-targeted H2S donor AP39 (100 nM) simultaneously with STZ (prevention) or on day 6 after STZ (treatment), and the ratio of interstitial to vascular fluorescence was used to estimate apparent permeability. NaGYY4137 prevented HG-induced loss of BREC glycocalyx, increased monocyte binding to BRECs (p ≤ 0.001), and increased overall glycocalyx coverage (p ≤ 0.001). In rats, the STZ-induced increase in apparent retinal vascular permeability (p ≤ 0.01) was significantly prevented by pre-treatment with NaGYY4137 and AP39 (p < 0.05) and stabilized by their post-STZ administration. NaGYY4137 also reduced the number of acellular capillaries (collagen IV + /IB4-) in the diabetic retina in both groups (p ≤ 0.05). We conclude that NaGYY4137 and AP39 protected the retinal glycocalyx and endothelial permeability barrier from diabetes-associated loss of integrity and reduced the progression of diabetic retinopathy (DR). Hydrogen sulfide donors that target the glycocalyx may therefore be a therapeutic candidate for DR.