Circular Perivascular Autofluorescence Pattern in Patients With Autoimmune Retinopathy.

Purpose: To report the characteristics and prevalence of a previously undescribed circular perivascular fundus autofluorescence (FAF) pattern in paraneoplastic and nonparaneoplastic autoimmune retinopathy. Methods: This retrospective case series used clinical and imaging data extracted from charts of patients with autoimmune retinopathy in whom FAF imaging was performed from the initial presentation to the last visit. Results: Six of 25 patients with autoimmune retinopathy and FAF imaging developed circular perivascular FAF changes. Three patients had paraneoplastic autoimmune retinopathy, and 3 had nonparaneoplastic autoimmune retinopathy. The lesions appeared a mean of 25 months after symptom onset; however, the timing varied from months to years and did not correlate with the overall disease course. The lesions were initially typically hyperautofluorescent and varied in progression, distribution, and quality. Optical coherence tomography showed hyperreflective subretinal deposits in the corresponding areas in most patients. Conclusions: To our knowledge, these are the first reported cases with this circular perivascular FAF pattern in nonparaneoplastic autoimmune retinopathy. This finding could also be a useful diagnostic imaging marker in some patients with autoimmune retinopathy.

Development of Portable Electronic Health Record Based Algorithms to Identify Individuals with Diabetic Retinopathy.

Objectives: To develop, validate and implement algorithms to identify diabetic retinopathy (DR) cases and controls from electronic health care records (EHR)s. Methods : We developed and validated EHR-based algorithms to identify DR cases and individuals with type I or II diabetes without DR (controls) in three independent EHR systems: Vanderbilt University Medical Center Synthetic Derivative (VUMC), the VA Northeast Ohio Healthcare System (VANEOHS), and Massachusetts General Brigham (MGB). Cases were required to meet one of three criteria: 1) two or more dates with any DR ICD-9/10 code documented in the EHR, or 2) at least one affirmative health-factor or EPIC code for DR along with an ICD9/10 code for DR on a different day, or 3) at least one ICD-9/10 code for any DR occurring within 24 hours of an ophthalmology exam. Criteria for controls included affirmative evidence for diabetes as well as an ophthalmology exam. Results: The algorithms, developed and evaluated in VUMC through manual chart review, resulted in a positive predictive value (PPV) of 0.93 for cases and negative predictive value (NPV) of 0.97 for controls. Implementation of algorithms yielded similar metrics in VANEOHS (PPV=0.94; NPV=0.86) and lower in MGB (PPV=0.84; NPV=0.76). In comparison, use of DR definition as implemented in Phenome-wide association study (PheWAS) in VUMC, yielded similar PPV (0.92) but substantially reduced NPV (0.48). Implementation of the algorithms to the Million Veteran Program identified over 62,000 DR cases with genetic data including 14,549 African Americans and 6,209 Hispanics with DR. Conclusions/Discussion: We demonstrate the robustness of the algorithms at three separate health-care centers, with a minimum PPV of 0.84 and substantially improved NPV than existing high-throughput methods. We strongly encourage independent validation and incorporation of features unique to each EHR to enhance algorithm performance for DR cases and controls.

Interleukin-6 and Macular Edema: A Review of Outcomes with Inhibition.

This paper describes the current literature on the molecular pathophysiology of interleukin-6 (IL-6) in the genesis of macular edema and on the outcomes with IL-6 inhibitors in the treatment of non-infectious macular edema. The role of IL-6 in the development of macular edema has been well elucidated. IL-6 is produced by multiple cells of the innate immune system and leads to a higher likelihood of developing autoimmune inflammatory diseases, such as non-infectious uveitis, through a variety of mechanisms. These include increasing the helper T-cell population over the regulatory T-cell population and leading to the increased expression of inflammatory cytokines, such as tumor necrosis factor-alpha. In addition to being key in the generation of uveitis and subsequent macular edema through these inflammatory pathways, IL-6 also can lead to the development of macular edema through other pathways. IL-6 induces the production of vascular endothelial growth factor (VEGF) and facilitates vascular leakage by downregulating tight junction proteins in retinal endothelial cells. Clinically, the use of IL-6 inhibitors has been found to be efficacious primarily in the context of treatment-resistant non-infectious uveitis and secondary macular edema. IL-6 is a key cytokine in retinal inflammation and macular edema. It is thus not surprising that the use of IL-6 inhibitors in treatment-resistant macular edema in the setting of non-infectious uveitis has been well documented as an effective treatment option. The use of IL-6 inhibitors in macular edema secondary to non-uveitic processes has only begun to be explored.

A novel form of docetaxel polymeric micelles demonstrates anti-tumor and ascites-inhibitory activities in animal models as monotherapy or in combination with anti-angiogenic agents.

Malignant ascites (MA) is caused by intraperitoneal spread of solid tumor cells and results in a poor quality of life. Chemotherapy is a common first-line treatment for patients with MA. Taxotere ® (DTX) is widely used in solid tumor therapies. However, the low water solubility and side effects caused by additives in the formulation restrict the clinical application of docetaxel. HT001 is a clinical stage docetaxel micelle developed to overcome the solubility issue with improved safety profiles. To support clinical development and expand clinical application of HT001, this study used in vitro and in vivo approaches to investigate the anti-tumor effects of HT001 when applied as monotherapy or in combination with anti-angiogenic agents. HT001 demonstrated comparable anti-proliferative activities as docetaxel in a broad range of cancer cell lines in vitro. Furthermore, HT001 suppressed tumor growth in a dose-dependent manner in A549, MCF-7, and SKOV-3 xenograft tumor mouse models in vivo. In a hepatocellular carcinoma H22 malignant ascites-bearing mouse model, HT001 presented a dose-dependent inhibition of ascites production, prolonged animal survival, and reduced VEGF levels. When dosed at 20 mg/kg, the HT001-treated group exhibited curative results, with no ascites formation in 80% of mice at the end of the study while all the mice in the vehicle control group succumbed. Similar results were obtained in HT001 treatment of mice bearing malignant ascites produced by human ovarian cancer ES-2 cells. Notably, the combination of HT001 with Endostar not only significantly reduced ascites production but also prolonged survival of H22 ascites-bearing mice. HT001 showed similar PK and tissue distribution profiles as DTX in non-rodent hosts. Collectively, these results demonstrate potent anti-tumor activity of HT001 in multiple solid tumor models or malignant ascites models, and reveal synergistic effects with anti-angiogenic agents, supporting the clinical development and clinical expansion plans for HT001.

Anti-infliximab antibodies and clinical response in noninfectious uveitis and scleritis patients treated with infliximab: A retrospective review.

Purpose: To investigate the clinical response to infliximab in ocular inflammation patients who develop anti-infliximab antibodies (AIA) vs. those patients who do not develop AIA. Observations: A retrospective review was performed of patients treated with infliximab for noninfectious uveitis (NIU) or scleritis. Clinical response was determined as a composite clinical endpoint and classified as complete, partial, or absent. Nine of 32 infliximab-treated patients (28%) were found to develop AIA. Among the AIA-positive patients, clinical response was complete in 7 patients (78%) and partial in 2 patients (22%). Among the AIA-negative patients, clinical response was complete in 15 patients (65%), partial in 6 patients (26%) and absent in 2 patients (9%). Serum infliximab levels tended to decrease with appearance of AIA but rarely became undetectable. Conclusions and Importance: In this pilot study, AIA-positive patients did not have diminished clinical response to infliximab when compared with AIA-negative patients. There was a high rate of complete clinical response to infliximab in this group of NIU and scleritis patients. Approximately a quarter of patients developed AIA. AIA-positive patients did not have diminished rates of clinical response when compared with AIA-negative patients. This suggests that routine AIA monitoring may not be clinically useful, although validation of this finding in larger cohorts is necessary.

Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome.

OBJECTIVES: To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease. METHODS: This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. RESULTS: The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. CONCLUSION: ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.

Patient and caregiver factors in ambulatory incident reports: a mixed-methods analysis.

OBJECTIVES: Patients and caregivers are the primary stakeholders in ambulatory safety, given they perform daily chronic disease self-management, medication administration and outpatient follow-up. However, little attention has been given to their role in adverse events. We identified themes related to patient and caregiver factors and challenges in ambulatory safety incident reports from a Patient Safety Organization. METHODS: We conducted a mixed-methods analysis of ambulatory incident reports submitted to the Collaborative Healthcare Patient Safety Organization, including 450 hospitals or clinic members in 13 US states. We included events that had patient and/or caregiver behavioural, socioeconomic and clinical factors that may have contributed to the event. Two members of the team independently coded patient/caregiver factors, with dual coding of 20% of events. We then conducted a 'frequent item set' analysis to identify which factors most frequently co-occurred. We applied inductive analysis to the most frequent sets to interpret themes. Our team included a diverse stakeholder advisory council of patients, caregivers and healthcare staff. RESULTS: We analysed 522 incident reports and excluded 73 for a final sample of 449 events. Our co-occurrence analysis found the following three themes: (1) clinical advice may conflict with patient priorities; (2) breakdowns in communication and patient education cause medication adverse events and (3) patients with disabilities are vulnerable to the external environment. CONCLUSIONS: Ambulatory safety reports capture both structural and behavioural factors contributing to adverse events. Actionable takeaways include the following: improving clinician counselling of patients to convey medical advice to elicit priorities, enhanced education regarding medication adverse events and expanding safety precautions for patients with disabilities at home. Ambulatory safety reporting must include patients in reporting and event review for better mitigation of future harm.

Correction: Recommendations From the Twitter Hashtag #DoctorsAreDickheads: Qualitative Analysis.

[This corrects the article DOI: 10.2196/17595.].

Recommendations From the Twitter Hashtag #DoctorsAreDickheads: Qualitative Analysis.

BACKGROUND: The social media site Twitter has 145 million daily active users worldwide and has become a popular forum for users to communicate their health care concerns and experiences as patients. In the fall of 2018, a hashtag titled #DoctorsAreDickheads emerged, with almost 40,000 posts calling attention to health care experiences. OBJECTIVE: This study aims to identify common health care conditions and conceptual themes represented within the phenomenon of this viral Twitter hashtag. METHODS: We analyzed a random sample of 5.67% (500/8818) available tweets for qualitative analysis between October 15 and December 31, 2018, when the hashtag was the most active. Team coders reviewed the same 20.0% (100/500) tweets and the remainder individually. We abstracted the user's health care role and clinical conditions from the tweet and user profile, and used phenomenological content analysis to identify prevalent conceptual themes through sequential open coding, memoing, and discussion of concepts until an agreement was reached. RESULTS: Our final sample comprised 491 tweets and unique Twitter users. Of this sample, 50.5% (248/491) were from patients or patient advocates, 9.6% (47/491) from health care professionals, 4.3% (21/491) from caregivers, 3.7% (18/491) from academics or researchers, 1.0% (5/491) from journalists or media, and 31.6% (155/491) from non-health care individuals or other. The most commonly mentioned clinical conditions were chronic pain, mental health, and musculoskeletal conditions (mainly Ehlers-Danlos syndrome). We identified 3 major themes: disbelief in patients' experience and knowledge that contributes to medical errors and harm, the power inequity between patients and providers, and metacommentary on the meaning and impact of the #DoctorsAreDickheads hashtag. CONCLUSIONS: People publicly disclose personal and often troubling health care experiences on Twitter. This adds new accountability for the patient-provider interaction, highlights how harmful communication affects diagnostic safety, and shapes the public's viewpoint of how clinicians behave. Hashtags such as this offer valuable opportunities to learn from patient experiences. Recommendations include developing best practices for providers to improve communication, supporting patients through challenging diagnoses, and promoting patient engagement.

What Safety Events Are Reported For Ambulatory Care? Analysis of Incident Reports from a Patient Safety Organization.

INTRODUCTION: Health care staff document patient safety events using incident reporting systems, which are compiled within Patient Safety Organization databases. Researchers sought to describe the patterns and characteristics of incident reporting behaviors for ambulatory care from in-situ reporting systems from the United States. METHODS: The team analyzed safety reports in ambulatory settings collected from a Patient Safety Organization comprising 400 hospital members in 10 states, from May 2012 to October 2018. All events involving moderate harm, severe harm, and death were included, as well as subsamples of events with missing harm, no harm, and mild harm. The team deductively coded incident types and if patient or caregiver challenges were involved. A multivariate logistic regression was conducted to identify predictors of higher harm (severe harm and death) among safety events reported. RESULTS: Of 2,701 events, there were 51 deaths, 159 severe harm events, 1,180 moderate harm, 926 mild harm, 384 no harm, and 1 unknown. Most were from outpatient subspecialty care, while 5.2% were from home/community, and 2.1% were from primary care. Medication-related events were most common (45.3%). In multivariate analysis, diagnostic errors (adjusted odds ratio [aOR] 11.5), patient/caregiver challenges (aOR 2.2), and events in the home/community (aOR 2.0) and in psychiatric settings (aOR 5.0) were associated with higher harm. CONCLUSION: Outpatient reporting systems are limited for primary care and home/community settings, but ambulatory care systems report more harmful events related to diagnosis and patient and caregiver challenges. Improved standardization of reporting, focus on diagnosis, and novel approaches of safety reporting that engage patients will be necessary to improve capture of preventable events affecting patients and to develop system-level solutions.