Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation.

The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of Tregs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.

The therapeutically actionable long non-coding RNA 'T-RECS' is essential to cancer cells' survival in NRAS/MAPK-driven melanoma.

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Pulmonary embolism response teams. A description of the first 36-month Australian experience.

BACKGROUND: High/intermediate-risk pulmonary embolism (PE) confers increased risk of cardiovascular morbidity and mortality. International guidelines recommend the formation of a PE response team (PERT) for PE management because of the complexity of risk stratification and emerging treatment options. However, there are currently no available Australian data regarding outcomes of PE managed through a PERT. AIMS: To analyse the clinical and outcome data of patients from an Australian centre with high/intermediate-risk PE requiring PERT-guided management. METHODS: We performed a retrospective observational study of 75 consecutive patients with high/intermediate-risk PE who had PERT involvement, between August 2018 and July 2021. We recorded clinical and interventional data at the time of PERT and assessed patient outcomes up to 30 days from PERT initiation. We used unpaired t tests to compare right to left ventricular (RV/LV) ratios by computed tomography criteria or transthoracic echocardiogram (TTE) at baseline and after interventions. RESULTS: Data were available for 74 patients. Initial computed tomography pulmonary angiography RV/LV ratio was increased at 1.65 ± 0.5 and decreased to 1.30 ± 0.29 following PERT-guided interventions (P < 0.001). TTE RV/LV ratio also decreased following PERT-guided management (1.09 ± 0.19 vs 0.93 ± 0.17; P < 0.001). 20% of patients had any bleeding complication, but two-thirds were mild, not requiring intervention. All-cause mortality was 6.8%, and all occurred within the first 7 days of admission. CONCLUSION: The PERT model is feasible in a large Australian centre in managing complex and time-critical PE. Our data demonstrate outcomes comparable with existing published international PERT data. However, successful implementation at other Australian institutions may require adequate centre-specific resource availability and the presence of multispeciality input.

A Comparative Study of Large Language Models, Human Experts, and Expert-Edited Large Language Models to Neuro-Ophthalmology Questions.

BACKGROUND: While large language models (LLMs) are increasingly used in medicine, their effectiveness compared with human experts remains unclear. This study evaluates the quality and empathy of Expert + AI, human experts, and LLM responses in neuro-ophthalmology. METHODS: This randomized, masked, multicenter cross-sectional study was conducted from June to July 2023. We randomly assigned 21 neuro-ophthalmology questions to 13 experts. Each expert provided an answer and then edited a ChatGPT-4-generated response, timing both tasks. In addition, 5 LLMs (ChatGPT-3.5, ChatGPT-4, Claude 2, Bing, Bard) generated responses. Anonymized and randomized responses from Expert + AI, human experts, and LLMs were evaluated by the remaining 12 experts. The main outcome was the mean score for quality and empathy, rated on a 1-5 scale. RESULTS: Significant differences existed between response types for both quality and empathy (P < 0.0001, P < 0.0001). For quality, Expert + AI (4.16 ± 0.81) performed the best, followed by GPT-4 (4.04 ± 0.92), GPT-3.5 (3.99 ± 0.87), Claude (3.6 ± 1.09), Expert (3.56 ± 1.01), Bard (3.5 ± 1.15), and Bing (3.04 ± 1.12). For empathy, Expert + AI (3.63 ± 0.87) had the highest score, followed by GPT-4 (3.6 ± 0.88), Bard (3.54 ± 0.89), GPT-3.5 (3.5 ± 0.83), Bing (3.27 ± 1.03), Expert (3.26 ± 1.08), and Claude (3.11 ± 0.78). For quality (P < 0.0001) and empathy (P = 0.002), Expert + AI performed better than Expert. Time taken for expert-created and expert-edited LLM responses was similar (P = 0.75). CONCLUSIONS: Expert-edited LLM responses had the highest expert-determined ratings of quality and empathy warranting further exploration of their potential benefits in clinical settings.

Spiced RCT: Success and Pain Associated with Intravenous Cannulation in the Emergency Department Randomized Controlled Trial.

BACKGROUND: Peripheral venous cannulation is one of the most common procedures in medicine. A larger cannula allows higher rates of fluid to be provided if needed in a deteriorating patient; however, it is also perceived that larger-gauge cannula placement is associated with increased pain and procedural difficulty. OBJECTIVE: This study aimed to compare the pain and procedural difficulty experienced during insertion between 18-gauge (18G) and 20-gauge (20G) cannulas. METHODS: We conducted a single-blinded, randomized controlled trial on adult patients who required peripheral IV cannulation within a tertiary hospital emergency department between April and October 2018. Patients were randomized to either the 18G or 20G cannula group. The primary outcomes of the study-pain experienced by patients and procedural difficulties experienced by clinical staff-were recorded on two separate 10-cm visual analog scales. Other outcomes include first-attempt success rate, operator designation, complications, and the intent and actual use of the IV cannula were documented on preformatted questionnaires. RESULTS: Data from 178 patients were included in the analysis. Eighty-nine patients were allocated to each cannula group. There were no statistically or clinically significant differences between mean pain score (0.23; 95% CI 0.56-1.02; p = 0.5662) and mean procedural difficulty score (0.12; 95% CI 0.66-0.93; p = 0.7396). between the two groups. There was no difference in first-attempt success rate (73 of 89 vs. 75 of 89; p = 0.1288), complications (2 of 89 vs. 1 of 89) between the 20G group and 18G group, respectively. CONCLUSIONS: There was no significant difference between the 18G or 20G cannula for either pain experienced by patients or procedural difficulty experienced by clinicians.

Eugenol Suppresses Platelet Activation and Mitigates Pulmonary Thromboembolism in Humans and Murine Models.

Platelets assume a pivotal role in the pathogenesis of cardiovascular diseases (CVDs), emphasizing their significance in disease progression. Consequently, addressing CVDs necessitates a targeted approach focused on mitigating platelet activation. Eugenol, predominantly derived from clove oil, is recognized for its antibacterial, anticancer, and anti-inflammatory properties, rendering it a valuable medicinal agent. This investigation delves into the intricate mechanisms through which eugenol influences human platelets. At a low concentration of 2 µM, eugenol demonstrates inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Notably, thrombin and U46619 remain unaffected by eugenol. Its modulatory effects extend to ATP release, P-selectin expression, and intracellular calcium levels ([Ca2+]i). Eugenol significantly inhibits various signaling cascades, including phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3ß, mitogen-activated protein kinases, and cytosolic phospholipase A2 (cPLA2)/thromboxane A2 (TxA2) formation induced by collagen. Eugenol selectively inhibited cPLA2/TxA2 phosphorylation induced by AA, not affecting p38 MAPK. In ADP-treated mice, eugenol reduced occluded lung vessels by platelet thrombi without extending bleeding time. In conclusion, eugenol exerts a potent inhibitory effect on platelet activation, achieved through the inhibition of the PLCγ2-PKC and cPLA2-TxA2 cascade, consequently suppressing platelet aggregation. These findings underscore the potential therapeutic applications of eugenol in CVDs.

Assessment of the Quality, Accountability, and Readability of Online Patient Education Materials for Optic Neuritis.

Most cases of optic neuritis (ON) occur in women and in patients between the ages of 15 and 45 years, which represents a key demographic of individuals who seek health information using the internet. As clinical providers strive to ensure patients have accessible information to understand their condition, assessing the standard of online resources is essential. To assess the quality, content, accountability, and readability of online information for optic neuritis. This cross-sectional study analyzed 11 freely available medical sites with information on optic neuritis and used PubMed as a gold standard for comparison. Twelve questions were composed to include the information most relevant to patients, and each website was independently examined by four neuro-ophthalmologists. Readability was analyzed using an online readability tool. Journal of the American Medical Association (JAMA) benchmarks, four criteria designed to assess the quality of health information further were used to evaluate the accountability of each website. Freely available online information. On average, websites scored 27.98 (SD ± 9.93, 95% CI 24.96-31.00) of 48 potential points (58.3%) for the twelve questions. There were significant differences in the comprehensiveness and accuracy of content across websites (p < .001). The mean reading grade level of websites was 11.90 (SD ± 2.52, 95% CI 8.83-15.25). Zero websites achieved all four JAMA benchmarks. Interobserver reliability was robust between three of four neuro-ophthalmologist (NO) reviewers (ρ = 0.77 between NO3 and NO2, ρ = 0.91 between NO3 and NO1, ρ = 0.74 between NO2 and NO1; all p < .05). The quality of freely available online information detailing optic neuritis varies by source, with significant room for improvement. The material presented is difficult to interpret and exceeds the recommended reading level for health information. Most websites reviewed did not provide comprehensive information regarding non-therapeutic aspects of the disease. Ophthalmology organizations should be encouraged to create content that is more accessible to the general public.

Sleep deficiency, operational fatigue and the interplay of compromising factors: Analysis to aid in fatigue management.

The United States Navy is a high-reliability organization that must maintain optimum performance under challenging conditions. One key challenge for sailors is obtaining sufficient sleep, which can lead to fatigue and other outcomes that compromise operational readiness. Identifying sleep issues and their causes is critical for military leaders to care for their personnel, and to make informed, risk-based operational decisions. Though previous studies in shipboard environments have implicated factors responsible for insufficient sleep (e.g. poor sleep environment and work demands), there has been less research into characterizing the complex interplay among such factors in relation to sleep and work-related fatigue outcomes. This study seeks to address this gap. Data were drawn from the Afloat Safety Climate Assessment Survey of 7617 sailors from 73 ships. The survey included demographic characteristics and measures of crew endurance (e.g. sleep, occupational impairment due to fatigue). Descriptive analyses characterized the presence and severity of sleep issues across subpopulations and operational settings (e.g. the type of ship); structural equation modelling techniques characterized and quantified the statistical associations among factors. The results indicate that sleep deficits are widespread, holding across subpopulations and operational settings. Though sleep deficits varied across subpopulations, no group obtained an average of more than 7 hr of sleep per night. Fatigue-induced occupational functional impairment was directly related to sleep deficiency, and sleep environment and job-related factors were contributors to sleep deficiency. Moreover, job-related factors emerged as potentially more consequential. Lastly, factors may exist aboard a ship that could help promote better sleep.

Can Tele-Neuro-Ophthalmology Be Useful Beyond the Pandemic?

PURPOSE OF THE REVIEW: Neuro-ophthalmologists rapidly adopted telehealth during the COVID-19 pandemic to minimize disruption to patient care. This article reviews recent research on tele-neuro-ophthalmology adoption, current limitations, and potential use beyond the pandemic. The review considers how digital transformation, including machine learning and augmented reality, may be applied to future iterations of tele-neuro-ophthalmology. RECENT FINDINGS: Telehealth utilization has been sustained among neuro-ophthalmologists throughout the pandemic. Adoption of tele-neuro-ophthalmology may provide solutions to subspecialty workforce shortage, patient access, physician wellness, and trainee educational needs within the field of neuro-ophthalmology. Digital transformation technologies have the potential to augment tele-neuro-ophthalmology care delivery by providing automated workflow solutions, home-based visual testing and therapies, and trainee education via simulators. Tele-neuro-ophthalmology use has and will continue beyond the COVID-19 pandemic. Digital transformation technologies, when applied to telehealth, will drive and revolutionize the next phase of tele-neuro-ophthalmology adoption and use in the years to come.

Tele-Neuro-Ophthalmology Utilization, Availability, and Attitudes: Update 1 Year Into the COVID-19 Public Health Emergency.

BACKGROUND: Telehealth was rapidly adopted early in the COVID-19 pandemic as a way to provide medical care while reducing risk of SARS-CoV2 transmission. Since then, telehealth utilization has evolved differentially according to subspecialty. This study assessed changes in neuro-ophthalmology during the first year of the COVID-19 pandemic. METHODS: Telehealth utilization and opinions pre-COVID-19, early pandemic (spring 2020), and 1 year later (spring 2021) were surveyed among practicing neuro-ophthalmologists in and outside the United States using an online platform. Demographics, self-reported utilization, perceived benefits, barriers, and examination suitability were collected over a 2-week period in May 2021. RESULTS: A total of 135 practicing neuro-ophthalmologists (81.5% United States, 47.4% females, median age 45-54 years) completed the survey. The proportion of participants using video visits remained elevated during COVID + 1 year (50.8%) compared with pre-COVID (6%, P < 0.0005, McNemar), although decreased compared with early COVID (67%, P < 0.0005). Video visits were the most commonly used methodology. The proportion of participants using remote testing (42.2% vs 46.2%), virtual second opinions (14.5% vs 11.9%, P = 0.45), and eConsults (13.5% vs 16.2%, P = 0.38) remained similar between early and COVID + 1 year ( P = 0.25). The majority selected increased access to care, better continuity of care, and enhanced patient appointment efficiency as benefits, whereas reimbursement, liability, disruption of in-person clinic flow, limitations of video examinations, and patient technology use were barriers. Many participants deemed many neuro-ophthalmic examination elements unsuitable when collected during a live video session, although participants believed some examination components could be evaluated adequately through a review of ancillary testing or outside records. CONCLUSIONS: One year into the COVID-19 pandemic, neuro-ophthalmologists maintained telemedicine utilization at rates higher than prepandemic levels. Tele-neuro-ophthalmology remains a valuable tool in augmenting patient care.

Interprofessional Electronic Consultations for the Diagnosis and Management of Neuro-Ophthalmic Conditions.

BACKGROUND: Interprofessional electronic consultation (eConsult) is a telemedicine modality in which consulting providers review outside records and provide recommendations without in-person consultation. The purpose of this study was to describe the utilization of eConsults in the management of neuro-ophthalmic conditions. METHODS: Retrospective cohort study of all patients who received an eConsult for a neuro-ophthalmic condition at a single quaternary referral center from 2018 to 2020. Main outcome measures included proportion of eConsults in which sufficient data were provided to the neuro-ophthalmologist to generate a definitive management decision, proportion of patients for whom an in-person neuro-ophthalmology evaluation was recommended, and the eConsult's impact on patient care. RESULTS: Eighty eConsults were conducted on 78 patients during the 3-year study period. Forty-eight (60.0%) subjects were female, mean age was 54 years, and 65 (81.3%) were White. The median time from eConsult request to completion was 4 days (range: 0-34 days). The most frequent eConsult questions were vision/visual field disturbances in 28 (35.0%) cases, optic neuropathies in 22 (27.5%), and optic disc edema in 17 (21.3%). At the time of eConsult, sufficient prior information was provided in 35 (43.8%) cases for the neuro-ophthalmologist to provide a definitive management decision. In 45 (56.3%) eConsults, further diagnostic testing was recommended. In-person neuro-ophthalmology consultation was recommended in 24 (30.0%) cases. Sixty-one (76.3%) eConsults provided diagnostic and/or treatment direction, and 12 (15.0%) provided reassurance. CONCLUSION: eConsults increase access to timely neuro-ophthalmic care and provide diagnostic and treatment direction to non-neuro-ophthalmology providers when sufficient information is provided at the time of eConsult.

Social Media in Neuro-Ophthalmology: Paradigms, Opportunities, and Strategies.

BACKGROUND: Social media (SoMe) is an integral part of life in the 21st century. Its potential for rapid dissemination and amplification of information offers opportunities for neuro-ophthalmologists to have an outsized voice to share expert-level knowledge with the public, other medical professionals, policymakers, and trainees. However, there are also potential pitfalls, because SoMe may spread incorrect or misleading information. Understanding and using SoMe enables neuro-ophthalmologists to influence and educate that would otherwise be limited by workforce shortages. EVIDENCE ACQUISITION: A PubMed search for the terms "social media" AND "neuro-ophthalmology," "social media" AND "ophthalmology," and "social media" AND "neurology" was performed. RESULTS: Seventy-two neurology articles, 70 ophthalmology articles, and 3 neuro-ophthalmology articles were analyzed. A large proportion of the articles were published in the last 3 years (2020, 2021, 2022). Most articles were analyses of SoMe content; other domains included engagement analysis such as Altmetric analysis, utilization survey, advisory opinion/commentary, literature review, and other. SoMe has been used in medicine to share and recruit for scientific research, medical education, advocacy, mentorship and medical professional networking, and branding, marketing, practice building, and influencing. The American Academy of Neurology, American Academy of Ophthalmology, and North American Neuro-Ophthalmology Society have developed guidelines on the use of SoMe. CONCLUSIONS: Neuro-ophthalmologists may benefit greatly from harnessing SoMe for the purposes of academics, advocacy, networking, and marketing. Regularly creating appropriate professional SoMe content can enable the neuro-ophthalmologist to make a global impact.

Toll-like Receptor 2 Mediates VEGF Overexpression and Mesothelial Hyperpermeability in Tuberculous Pleural Effusion.

Toll-like receptor (TLR) is essential for the immune response to Mycobacterium tuberculosis (MTB) infection. However, the mechanism whereby TLR mediates the MTB-induced pleural mesothelial hyperpermeability in tuberculous pleural effusion (TBPE) remains unclear. Pleural effusion size and pleural fluid levels of vascular endothelial growth factor (VEGF) and soluble TLR2 (sTLR2) in patients with TBPE (n = 36) or transudative pleural effusion (TPE, n = 16) were measured. The effects of MTB H37Ra (MTBRa) on pleural mesothelial permeability and the expression of VEGF and zonula occludens (ZO)-1 in human pleural mesothelial cells (PMCs) were assessed. Levels of VEGF and sTLR2 were significantly elevated in TBPE compared to TPE. Moreover, effusion VEGF levels correlated positively, while sTLR2 values correlated negatively, with pleural effusion size in TBPE. In human PMCs, MTBRa substantially activated JNK/AP-1 signaling and upregulated VEGF expression, whereas knockdown of TLR2 remarkably inhibited MTBRa-induced JNK phosphorylation and VEGF overexpression. Additionally, both MTBRa and VEGF markedly reduced ZO-1 expression and induced pleural mesothelial permeability, while TLR2 silencing or pretreatment with anti-VEGF antibody significantly attenuated the MTBRa-triggered effects. Collectively, TLR2 mediates VEGF overproduction and downregulates ZO-1 expression in human PMCs, leading to mesothelial hyperpermeability in TBPE. Targeting TLR2/VEGF pathway may confer a potential treatment strategy for TBPE.

Thromboembolic Presentations among Patients Hospitalized to the Intensive Care Unit for Coronavirus Disease 2019 (COVID-19) - A Northern Taiwan Single Center Experience.

Coronavirus Disease 2019 (COVID-19) has been associated with a high thromboembolic risk among patients in intensive care units. Asian populations may share a similar thromboembolic risk, but with a higher prevalence of arterial thromboembolism than venous thromboembolism. To clarify this risk in Taiwan, this single-center retrospective study collected 27 consecutive intensive care unit patients with COVID-19 confirmed by polymerase chain reaction, with a median age of 67.6 years (male 81.5%). Twenty-three patients received prophylactic anticoagulation (85.2%), and there were four bleeding events (14.8%). Nine patients had thromboembolism (33.3%), including three with deep vein thrombosis, two with peripheral artery thromboembolism, and four with ischemic stroke. There were no significant clinical differences between the patients with or without thromboembolism. Initial serum ferritin [adjusted odds ratio (OR): 13.19, 95% confidence interval (CI): 1.01-172.07] and peak serum procalcitonin (adjusted OR: 18.93, 95% CI: 1.08-330.91) were associated with a higher risk of thromboembolism. Furthermore, prophylactic anticoagulation (adjusted OR: 0.01, 95% CI: < 0.001-0.55) was associated with a lower risk of thromboembolism. All cases of deep vein thrombosis and one peripheral artery thromboembolism occurred at intravascular catheter locations. No association between thromboembolism and survival was found (age-adjusted hazard ratio: 0.55, 95% CI: 0.10-2.95). In conclusion, the prevalence of COVID-19 thromboembolism among Taiwanese patients in intensive care units was high, even with prophylactic anticoagulation. Serum ferritin and procalcitonin may identify high-risk populations. Prophylactic anticoagulation may reduce the risk of thromboembolism with a manageable bleeding risk. Larger prospective studies are needed to clarify the risk of COVID-19 thromboembolism and its risk factors in the post-Omicron era.

Characterization and Utility of Remote Interpretation of Visual Field Diagnostic Testing in an Academic Center.

BACKGROUND: The use of remote interpretation of data has risen in neuro-ophthalmology to increase efficiency and maintain social distancing due to the coronavirus disease-19 pandemic. The purpose of this study is to characterize the use and efficiency of remote interpretation of visual fields (VFs) in an academic center and to determine how often the VF interpretation was consistent with the patient's clinical history and imaging at the time of the consult. METHODS: This is a retrospective study at a single academic center that enrolled all patients receiving a remote interpretation of VF from January 1, 2012, through December 31, 2012. Data were collected regarding the referring department, indication for the VF, interpretation of the VF and comparison with any prior VFs, any associated interventions with the VF, and available follow-up VFs. The main outcome measures included 1) characterizing the use of remote VF interpretations and 2) how many remote VF interpretation results were consistent with the referring diagnosis based on the patient's clinical history and imaging. RESULTS: One hundred eighty patients received remote interpretation of VFs. The most frequent referring departments were endocrinology (79; 44%), neurology (51; 28%), and neurosurgery (43; 24%). The VF indications included parasellar lesion (107; 59%), seizure disorder (26; 14%), meningioma (19; 11%), vascular lesion (11; 6%), and others (17; 9%). There were 78 patients (43%) that had an intervention before the VF, whereas 49 (27%) were preoperative VFs. Eighty-seven (48%) of the VFs were interpreted as abnormal. Of all the 180 remote interpretation of VFs, 156 (87%) had VF interpretations that were consistent with the clinical question posed by the referring provider based on clinical history and imaging. Among the other 24 remote VF interpretations (13% of total remote VF interpretations), there was no clear interpretation because of either additional unexpected VF defects (n = 5, 21%), VF defect mismatch (n = 6, 25%), or unreliable VFs (n = 13, 54%). The median wait time for patients receiving remote VF interpretations was 1 day. CONCLUSIONS: Remote interpretation of VFs was most often requested by endocrinology, neurology, and neurosurgery and could be performed very quickly. The most common indications were parasellar lesions, and just less than half of patients receiving remote VF interpretations had a prior intervention. A majority of remote VF interpretations were able to answer the clinical question, given the patient's clinical history and imaging. Remote interpretation of VFs may thus offer referring departments a more efficient method of obtaining VF interpretations than in-office neuro-ophthalmology examinations.

The Impact of COVID-19 on Neuro-Ophthalmology Office Visits and Adoption of Telemedicine Services.

BACKGROUND: The COVID-19 public health emergency (PHE) has significantly changed medical practice in the United States, including an increase in the utilization of telemedicine. Here, we characterize change in neuro-ophthalmic care delivery during the early COVID-19 PHE, including a comparison of care delivered via telemedicine and in office. METHODS: Neuro-ophthalmology outpatient encounters from 3 practices in the United States (4 providers) were studied during the early COVID-19 PHE (March 15, 2020-June 15, 2020) and during the same dates 1 year prior. For unique patient visits, patient demographics, visit types, visit format, and diagnosis were compared between years and between synchronous telehealth and in-office formats for 2020. RESULTS: There were 1,276 encounters for 1,167 patients. There were 30% fewer unique patient visits in 2020 vs 2019 (477 vs 670) and 55% fewer in-office visits (299 vs 670). Compared with 2019, encounters in 2020 were more likely to be established, to occur via telemedicine and to relate to an efferent diagnosis. In 2020, synchronous telehealth visits were more likely to be established compared with in-office encounters. CONCLUSIONS: In the practices studied, a lower volume of neuro-ophthalmic care was delivered during the early COVID-19 public health emergency than in the same period in 2019. The type of care shifted toward established patients with efferent diagnoses and the modality of care shifted toward telemedicine.

Survey of Telehealth Adoption by Neuro-ophthalmologists During the COVID-19 Pandemic: Benefits, Barriers, and Utility.

BACKGROUND: During the COVID-19 pandemic, telehealth modalities have come to prominence as a strategy for providing patient care when in-person care provision opportunities are limited. The degree of adoption by neuro-ophthalmologists has not been quantified. METHODS: Telehealth utilization pre-COVID-19 and peri-COVID-19 was surveyed among practicing neuro-ophthalmologists in and outside the United States using an online platform. Demographics, perceived benefits, barriers, and utility for different neuro-ophthalmic conditions were collected. Data collection occurred over a 2-week period in May 2020. RESULTS: Two hundred eight practicing neuro-ophthalmologists (81.3% United States, 50.2% females, age range <35 to >65, mode 35-44 years) participated in the survey. Utilization of all telehealth modalities increased from pre-COVID to peri-COVID (video visit 3.9%-68.3%, P < 0.0005, remote interpretation of testing 26.7%-32.2%, P = 0.09, online second opinion 7.9%-15.3%, P = 0.001, and interprofessional e-consult 4.4%-18.7%, P < 0.0005, McNemar). The majority selected access, continuity, and patient efficiency of care as benefits and data quality as a barrier. Telehealth was felt to be most helpful for conditions relying on history, external examination, and previously collected ancillary testing and not helpful for conditions requiring funduscopic examination. CONCLUSIONS: Telehealth modality usage by neuro-ophthalmologists increased during the COVID-19 pandemic. Identified benefits have relevance both during and beyond COVID-19. Further work is needed to address barriers in their current and future states to maintain these modalities as viable care delivery options.

Osteogenic circulating endothelial progenitor cells are linked to electrocardiographic conduction abnormalities in rheumatic patients.

BACKGROUND: Osteogenic circulating endothelial progenitor cells (EPC) play a pathogenic role in cardiovascular system degeneration through promulgating vasculature calcification, but its role in conduction disorders as part of the cardiovascular degenerative continuum remained unknown. AIM: To investigate the role of osteocalcin (OCN)-expressing circulating EPCs in cardiac conduction disorders in the unique clinical sample of rheumatoid arthritis (RA) susceptible to both abnormal bone metabolism and cardiac conduction disorders. METHODS: We performed flow cytometry studies in 134 consecutive asymptomatic patients with rheumatoid arthritis to derive osteogenic circulating OCN-positive (OCN+) CD34+KDR+ vs. CD34+CD133+KDR+ conventional EPC. Study endpoint was the prespecified combined endpoint of electrocardiographic conduction abnormalities. RESULTS: Total prevalence of cardiac conduction abnormality was 9% (n = 12). All patients except one had normal sinus rhythm. One patient had atrial fibrillation. No patient had advanced atrioventricular (AV) block. Prevalence of first-degree heart block (>200 ms), widened QRS duration (>120 ms) and right bundle branch block were 6.7%, 2.1%, and 2.2% respectively. Circulating osteogenic OCN+ CD34+ KDR+ EPCs were significantly higher among patients with cardiac conduction abnormalities (p = 0.039). Elevated OCN+ CD34+ KDR+ EPCs> 75th percentile was associated with higher prevalence of cardiac conduction abnormalities (58.3% vs. 20.02%, p = 0.003). Adjusted for potential confounders, elevated OCN+ CD34+ KDR+ EPCs> 75th percentile remained independently associated with increased risk of cardiac conduction abnormalities (OR = 4.4 [95%CI 1.2-16.4], p = 0.028). No significant relation was found between conventional EPCs CD34+CD133+KDR+ and conduction abnormalities (p = 0.36). CONCLUSIONS: Elevated osteogenic OCN+ CD34+ KDR+ EPCs are independently associated with the presence of electrocardiographic conduction abnormalities in patients with rheumatoid arthritis, unveiling a potential novel pathophysiological mechanism.

Unique, dual-indexed sequencing adapters with UMIs effectively eliminate index cross-talk and significantly improve sensitivity of massively parallel sequencing.

BACKGROUND: Sample index cross-talk can result in false positive calls when massively parallel sequencing (MPS) is used for sensitive applications such as low-frequency somatic variant discovery, ancient DNA investigations, microbial detection in human samples, or circulating cell-free tumor DNA (ctDNA) variant detection. Therefore, the limit-of-detection of an MPS assay is directly related to the degree of index cross-talk. RESULTS: Cross-talk rates up to 0.29% were observed when using standard, combinatorial adapters, resulting in 110,180 (0.1% cross-talk rate) or 1,121,074 (0.29% cross-talk rate) misassigned reads per lane in non-patterned and patterned Illumina flow cells, respectively. Here, we demonstrate that using unique, dual-matched indexed adapters dramatically reduces index cross-talk to ≤1 misassigned reads per flow cell lane. While the current study was performed using dual-matched indices, using unique, dual-unrelated indices would also be an effective alternative. CONCLUSIONS: For sensitive downstream analyses, the use of combinatorial indices for multiplexed hybrid capture and sequencing is inappropriate, as it results in an unacceptable number of misassigned reads. Cross-talk can be virtually eliminated using dual-matched indexed adapters. These results suggest that use of such adapters is critical to reduce false positive rates in assays that aim to identify low allele frequency events, and strongly indicate that dual-matched adapters be implemented for all sensitive MPS applications.

Lipoteichoic acid upregulates plasminogen activator inhibitor-1 expression in parapneumonic effusions.

BACKGROUND AND OBJECTIVE: Parapneumonic effusion (PPE) is commonly caused by Gram-positive bacteria (GPB) and often presents with pleural loculation, which is characterized by overproduction of plasminogen activator inhibitor (PAI)-1. Lipoteichoic acid (LTA), a surface adhesion molecule of GPB, binds to the pleural mesothelium and triggers inflammation. However, the effects of LTA on PAI-1 expression in PPE and underlying mechanisms remain unclear. METHODS: Thirty consecutive patients with PPE were enrolled, including uncomplicated culture negative (CN, n = 11), Gram-negative bacteria (GNB, n = 7) and GPB (n = 12) groups stratified by pleural fluid characteristics and bacteriology, and the effusion PAI-1 levels were measured. In addition, human pleural mesothelial cells (PMC) were treated with LTA and the expression of PAI-1 and activation of signalling pathways were assayed. RESULTS: The median levels of PAI-1 were significantly higher in GPB (160.5 ng/mL) and GNB (117.0 ng/mL) groups than in the uncomplicated CN (58.0 ng/mL) group. In human PMC, LTA markedly upregulated PAI-1 mRNA and protein expression and enhanced elaboration of Toll-like receptor 2 (TLR2). Furthermore, LTA increased c-Jun N-terminal kinase (JNK) phosphorylation, induced activating transcription factor 2 (ATF2)/c-Jun nuclear translocation and activated PAI-1 promoter activity. Pretreatment with TLR2 siRNA significantly inhibited LTA-induced JNK phosphorylation and PAI-1 protein expression. CONCLUSION: Culture-positive PPE, especially that caused by GPB, has a significantly higher level of PAI-1 than uncomplicated CN PPE. LTA upregulates PAI-1 expression through activation of TLR2/JNK/activator protein 1 (AP-1) pathway in human PMC. Better understanding of the modulation of PAI-1 synthesis by LTA in PPE may provide potential therapies for infected pleural effusions.