Netrin-1 promotes glioblastoma cell invasiveness and angiogenesis by multiple pathways including activation of RhoA, cathepsin B, and cAMP-response element-binding protein.

Glioblastomas are very difficult tumors to treat because they are highly invasive and disseminate within the normal brain, resulting in newly growing tumors. We have identified netrin-1 as a molecule that promotes glioblastoma invasiveness. As evidence, netrin-1 stimulates glioblastoma cell invasion directly through Matrigel-coated transwells, promotes tumor cell sprouting and enhances metastasis to lymph nodes in vivo. Furthermore, netrin-1 regulates angiogenesis as shown in specific angiogenesis assays such as enhanced capillary endothelial cells (EC) sprouting and by increased EC infiltration into Matrigel plugs in vivo, as does VEGF-A. This netrin-1 signaling pathway in glioblastoma cells includes activation of RhoA and cyclic AMP response element-binding protein (CREB). A novel finding is that netrin-1-induced glioblastoma invasiveness and angiogenesis are mediated by activated cathepsin B (CatB), a cysteine protease that translocates to the cell surface as an active enzyme and co-localizes with cell surface annexin A2 (ANXA2). The specific CatB inhibitor CA-074Me inhibits netrin-1-induced cell invasion, sprouting, and Matrigel plug angiogenesis. Silencing of CREB suppresses netrin-1-induced glioblastoma cell invasion, sprouting, and CatB expression. It is concluded that netrin-1 plays an important dual role in glioblastoma progression by promoting both glioblastoma cell invasiveness and angiogenesis in a RhoA-, CREB-, and CatB-dependent manner. Targeting netrin-1 pathways may be a promising strategy for brain cancer therapy.

Survey on the management of orbital and intraocular tumors among oculofacial surgeons in the Asia-Pacific region.

A web-based anonymous survey was performed to assess the common practices of oculofacial surgeons in the management of orbital and intraocular tumors in the Asia-Pacific region. The questionnaire comprised a series of questions covering controversial topics sent via email to 131 oculofacial surgeons across 14 countries in the Asia-Pacific region. A total response rate of 61.7 % was achieved from May to December 2012. The most common benign orbital tumor was cavernous hemangioma (39.6 %) and the most common malignant orbital tumor was lymphoma (85.7 %). 40 % of surgeons recommended orbital radiation, for which the most common indications were thyroid eye disease (70.0 %) and malignancy (30.0 %). The most common orbitotomy approach was lateral (79.2 %). Most surgeons (87.1 %) offered enucleation for retinoblastoma, but there was also a significant proportion that offered chemoreduction with transpupillary thermotherapy or cryotherapy (58.1 %). Fewer surgeons offered brachytherapy (16.1 %) and intra-arterial chemotherapy (6.5 %). When performing enucleation for retinoblastoma, 81.8 % of surgeons performed a primary orbital implant placement. The most preferred type of implant was silicone/acrylic (90.2, 90.2 and 87.8 % for elderly, adults and children, respectively). The majority of surgeons used donor sclera (57.5 %) or no wrapping material at all (32.5 %). Almost all surgeons (95.1 %) did not drill and peg the implant for motility. We report the results of the first survey of oculofacial surgeons in the Asia-Pacific region on the management of intraocular and orbital tumors. In comparison with previous surveys performed in the USA and the UK, we found the practice patterns of the Asia-Pacific surgeons to be comparable.

Reframing Value-Based Care Management: Beyond Cost Reduction and Toward Patient Centeredness.

Importance: Care management programs are increasingly being utilized by health systems as a new foundational strategy to advance value-based care. These programs offer the promise of improving patient outcomes while decreasing health care utilization and costs. However, as these programs proliferate in number and specialization, the field of care management is increasingly at risk of fragmentation, inefficiency, and failure to meet the core needs of the patient. Observations: This review of the current state of care management identifies several key challenges for the field, including an unclear value proposition, a focus on system- vs patient-centered outcomes, increased specialization by private and public entrants that produces care fragmentation, and lack of coordination among health and social service entities. A framework is proposed for reorienting care management to truly address the needs of patients through acknowledging the dynamic nature of patient care needs, providing a continuum of need-targeted programming, coordinating care among all involved entities and staff, and performing regular evaluations of outcomes that include patient-centered and health equity measures. Guidance on how this framework can be implemented within a health system and an outline of recommendations is provided for how policymakers may incentivize the development of high value and more equitable care management programs. Conclusions and Relevance: With increased focus on care management as a cornerstone of value-based care, value-based health leaders and policymakers can improve the effectiveness and value of care management programs, reduce patient financial burden for care management services, and promote stakeholder coordination.

Is the Gap Closing? Comparison of Sociodemographic Disparities in COVID-19 Hospitalizations and Outcomes Between Two Temporal Waves of Admissions.

OBJECTIVE: The COVID-19 pandemic has disproportionately impacted minority communities, yet little data exists regarding whether disparities have improved at a health system level. This study examined whether sociodemographic disparities in hospitalization and clinical outcomes changed between two temporal waves of hospitalized COVID-19 patients. METHODS: This is a retrospective cohort study of primary care patients at Mass General Brigham (a large northeastern health system serving 1.27 million primary care patients) hospitalized in-system with COVID-19 between March 1, 2020, and March 1, 2021, categorized into two 6-month "wave" periods. We used chi-square tests to compare demographics between waves, and regression analysis to characterize the association of race/ethnicity and language with in-hospital severe outcomes (death, hospice discharge, intensive unit care need). RESULTS: Hispanic/Latino, Black, and non-English-speaking patients constituted 30.3%, 12.5%, and 29.7% of COVID-19 admissions in wave 1 (N = 5844) and 22.2%, 9.0%, and 22.7% in wave 2 (N = 4007), compared to 2019 general admission proportions of 8.8%, 6.3%, and 7.7%, respectively. Admissions from highly socially vulnerable census tracts decreased between waves. Non-English speakers had significantly higher odds of severe illness during wave 1 (OR 1.35; 95% CI: 1.10, 1.66) compared to English speakers; this association was non-significant during wave 2 (OR 1.01; 95% CI: 0.76, 1.36). CONCLUSIONS: Comparing two COVID-19 temporal waves, significant sociodemographic disparities in COVID-19 admissions improved between waves but continued to persist over a year, demonstrating the need for ongoing interventions to truly close equity gaps. Non-English-speaking language status independently predicted worse hospitalization outcomes in wave 1, underscoring the importance of targeted and effective in-hospital supports for non-English speakers.

When the Process Is the Problem: Racial/Ethnic and Language Disparities in Care Management.

OBJECTIVES: Achieving health equity requires addressing disparities at every level of care delivery. Yet, little literature exists examining racial/ethnic disparities in processes of high-risk care management, a foundational tool for population health. This study sought to determine whether race, ethnicity, and language are associated with patient entry into and service intensity within a large care management program. DESIGN: Retrospective cohort study. METHODS: Subjects were 23,836 adult patients eligible for the program between 2015 and 2018. Adjusting for demographics, utilization, and medical risk, we analyzed the association between race/ethnicity and language and outcomes of patient selection, enrollment, care plan completion, and care management encounters. RESULTS: Among all identified as eligible by an algorithm, Asian and Spanish-speaking patients had significantly lower odds of being selected by physicians for care management [OR 0.74 (0.58-0.93), OR 0.79 (0.64-0.97)] compared with White and English-speaking patients, respectively. Once selected, Hispanic/Latino and Asian patients had significantly lower odds compared to White counterparts of having care plans completed by care managers [OR 0.69 (0.50-0.97), 0.50 (0.32-0.79), respectively]. Patients speaking languages other than English or Spanish had a lower odds of care plan completion and had fewer staff encounters than English-speaking counterparts [OR 0.62 (0.44-0.87), RR 0.87 (0.75-1.00), respectively]. CONCLUSIONS: Race/ethnicity and language-based disparities exist at every process level within a large health system's care management program, from selection to outreach. These results underscore the importance of assessing for disparities not just in outcomes but also in program processes, to prevent population health innovations from inadvertently creating new inequities.

Improving care coordination and reducing ED utilization through patient navigation.

OBJECTIVES: Our study examines the impact of an emergency department (ED) patient navigation program for patients in a Medicaid accountable care organization across 3 hospitals in a large health system. Our program engages community health workers to (1) promote primary care engagement, (2) facilitate care coordination, and (3) identify and address patients' health-related social needs. STUDY DESIGN: Our study was a retrospective analysis of health care utilization and costs in the 30 days following the index ED visit, comparing individuals receiving ED navigation and matched controls. The primary outcome of interest was all-cause return ED visits, and our secondary outcomes were hospital admissions and completed primary care appointments. METHODS: Patients with ED visits who received navigation were matched to comparable patients with ED visits without an ED navigator interaction. Outcomes were analyzed using fixed effects logistic regression models adjusted for patient demographics, ED visit characteristics, and preceding utilization. Our primary outcome was odds of a return ED visit within 30 days, and our secondary outcomes were odds of a hospitalization within 30 days and odds of having primary care visit within 30 days. RESULTS: In our sample, there were 1117 ED visits by patients meeting our inclusion criteria with an ED navigator interaction, with 3351 matched controls. ED navigation was associated with 52% greater odds of a completed follow-up primary care appointment (odds ratio [OR], 1.52; 95% CI, 1.29-1.77). In patients with no ED visits in the preceding 6 months, ED navigation was associated with 32% decreased odds of repeat ED visits in the subsequent 30 days (OR, 0.68; 95% CI, 0.52-0.90). There was no statistically significant impact on return ED visits in those with higher baseline ED utilization. CONCLUSIONS: Our program demonstrates that high-intensity, short-term patient navigation in the ED can help reduce ED visits in those with low baseline ED utilization and facilitate stronger connections with primary care.

A novel near-peer reflective writing workshop.

BACKGROUND: Training in clinical medicine involves exposure to complex ethical and emotional situations. Reflection aids in the development of personal belief systems and improves self-awareness. Students may be reluctant to participate when reflection is mandatory and may be concerned about retaliation when the facilitator has a role in evaluations. Near-peers are institutional equals with more experience than the participants and may be well suited to facilitate reflection. METHODS: A quarterly near-peer-facilitated reflective writing workshop (RWW) was implemented in the mandatory clinical curriculum at a single institution. Qualitative feedback forms were solicited and were analysed through an iterative and inductive consensus process. An end-of-year web-based survey was distributed to test the hypotheses generated from our analysis of the feedback forms. RESULTS: There were 82 responses (80%) to the web-based survey and 266 (65%) feedback forms were collected. Although few students reported using writing as a coping mechanism, the RWW was viewed favourably, with 62% indicating that they would attend if optional. The structured prompts aided reflection. Students reported a higher likelihood of discussing difficult topics (doubts about medicine as a career, personal shortcomings, harassment and burnout) in sessions led by a near-peer than by a faculty member. The workshop created a safe space to reflect, increased a sense of camaraderie and helped normalise experiences. [The workshop] humanised the clinical experience, gave new perspective and reminded students of their positive personal accomplishments DISCUSSION: The near-peer-facilitated RWW is a novel intervention aimed at developing reflective practice and coping with the challenges of entering clinical medicine. It is highly structured and has been incorporated into the mandatory curriculum. It was well received by students, is generalisable and is easily implementable.

Detecting Opioid-Related Aberrant Behavior using Natural Language Processing.

The United States is in the midst of a prescription opioid epidemic, with the number of yearly opioid-related overdose deaths increasing almost fourfold since 20001. To more effectively prevent unintentional opioid overdoses, the medical profession requires robust surveillance tools that can effectively identify at-risk patients. Drug-related aberrant behaviors observed in the clinical context may be important indicators of patients at risk for or actively abusing opioids. In this paper, we describe a natural language processing (NLP) method for automatic surveillance of aberrant behavior in medical notes relying only on the text of the notes. This allows for a robust and generalizable system that can be used for high volume analysis of electronic medical records for potential predictors of opioid abuse.

Sodium Hyaluronate in the Treatment of Dry Eye Syndrome: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis compares sodium hyaluronate (HY) with non-HY based artificial tears in the treatment of dry eye syndrome. A literature search for clinical trials comparing HY against non-HY preparations was conducted across PubMed, Cochrane Central Register of Controlled Trials and Scopus databases from inception up to May 2016. Majority of the 18 studies selected for review showed superiority of HY in improving ocular staining and symptoms. Randomized controlled trials (RCTs) examining Schirmer's I (SH) and tear breakup time (TBUT) underwent further meta-analyses with calculation of pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs). 7 RCTs including 383 eyes randomized to HY and 596 eyes to non-HY preparations underwent meta-analysis for SH. 9 RCTs including 458 eyes randomized to HY and 651 eyes to non-HY preparations underwent meta-analysis for TBUT. By fixed-effects modelling, HY demonstrated greater improvement of SH compared to non-HY preparations (SMD, 0.238; 95% CI, 0.107 to 0.369; p < 0.001). By random-effects modelling, HY demonstrated less improvement of TBUT (SMD, -0.566; 95% CI, -1.099 to -0.0336; p = 0.037). In summary, neither preparation was shown to be consistently superior across all outcome measures. The difference in effect between preparations on SH and TBUT was not clinically significant.

No Time for Silence: An Urgent Need for Political Activism Among the Medical Community.

Despite being a major stakeholder in the U.S. health care system, the medical community has remained relatively mute in the debate over the future of the Patient Protection and Affordable Care Act (ACA). If the ACA were repealed, tens of millions of Americans would be in danger of losing their insurance, resulting in a significant increase in mortality. Because misinformation about the ACA is rampant, it is imperative that health care providers explain to the public what exactly the ACA is and how repeal will affect patients. Traditionally, many in the medical community have abstained from political advocacy for multiple reasons, including compromising the doctor-patient relationship, financial incentives, lack of experience with activism due to an absence of training in that area, and fear of political retaliation. Encouragingly, there are indications that the medical community is beginning to become more vocal. Medical students are one example, having formed a grassroots response to repeal. However, students need more guidance and support from experienced mentors to most effectively serve as patient advocates. This is no time for silence: On this life-or-death issue, the medical community cannot afford to remain mute.

Survey of Common Aesthetic Practices Among Oculofacial Surgeons in Parts of the Asia-Pacific.

PURPOSE: An anonymous Web-based survey was performed to assess the current practices, preferences, and complications of aesthetic procedures encountered by oculofacial surgeons in the Asia-Pacific. Results were compared with a similar study carried out in 2007 among members of the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS). DESIGN: This was a cross-sectional survey study. METHODS: The study survey was sent out via e-mail to 131 oculofacial surgeons in 14 countries in the Asia-Pacific. Survey questions included the demographics of survey respondents, practices, preferences, and complications of aesthetic procedures encountered by the surgeons. RESULTS: Seventy-four respondents (56.5%) attempted the survey between May and December 2012. Only completed surveys (43 surveys) were included in our analysis. Eighty-six percent of respondents performed aesthetic procedures in their practice. The top 3 most common nonsurgical procedures reported were injection of botulinum toxin (94.1% of respondents), tissue fillers (61.8%), and skin resurfacing (11.8%), whereas the top 3 most common surgical procedures reported were blepharoplasty (100% of respondents), brow lift (94.6%), and midface lift (29.7%). CONCLUSIONS: The majority of our study respondents performed aesthetic procedures in their practice. The percentage of practices that comprised aesthetics services was lower than that seen in the ASOPRS study. The percentage of respondents who performed injection of botulinum toxin, tissue fillers, brow lifts, and thread lifts were similar to those in the ASOPRS study; however, the percentage of respondents who performed ablative skin resurfacing was much lower.

Laser iridotomy and the corneal endothelium: a systemic review.

This study aims to systemically review the effect of laser iridotomy on the corneal endothelium. Searches were performed for studies that either compared corneal endothelial cell density/count, corneal thickness and morphology pre- and postiridotomy, or evaluated the postiridotomy development of corneal decompensation. There were 26 eligible studies. Our review shows that the effect of laser iridotomy on the corneal endothelium has been investigated with varying results. Although it has been demonstrated to be a relatively safe procedure, there is still the potential long-term risk of corneal decompensation, for which a corneal transplantation may be indicated eventually. The longest interval between laser iridotomy and corneal decompensation reported was 8 years. Mechanisms proposed for endothelial damage include direct focal injury, thermal damage, mechanical shock waves, iris pigment dispersion, transient rise in intraocular pressure, inflammation, turbulent aqueous flow, time-dependent shear stress on endothelium, chronic breakdown of blood-aqueous barrier and damage from bubbles that settled onto the endothelium. Inherent risk factors identified were iridotrabecular contact, current or prior acute angle closure, pigmented irides, small iris-to-endothelium distance, pre-existing endothelial disease and diabetes. Intervention-related risk factors include laser type, delivery and quantity. The significance of the risk factors and their direct association with the development of corneal decompensation remain to be determined. Understanding these risk factors may allow physicians to counsel their patients better. They may offer opportunities for preventive strategies, allowing us to ensure that a procedure performed to prevent disease progression and visual loss does not cause further morbidity.

Periorbital muscle atrophy associated with topical bimatoprost therapy.

Topical Bimatoprost is a common and popular prostaglandin analog used as an ocular hypotensive agent in the treatment of glaucoma. Side effects include ocular hyperaemia, ocular pruritus, and periocular and iris pigmentary changes. Perioribital lipodystrophy is another well-documented outcome associated with chronic use of topical bimatoprost, which results in periorbital hallowing, upper eyelid sulcus deepening, eyelid retraction and enophthalmos. We report an unusual case of periocular muscle atrophy and weakness from unilateral topical bimatoprost use. Our patient had primary angle closure and experienced a right upper eyelid ptosis 2 months after she started to use topical bimatoprost in that eye. Clinical measurements of her eyelids clearly showed reduction in the function of her right levator muscle, suggesting that effects of topical bimatoprost may not be limited to periorbital fat. She was advised to stop topical bimatoprost and right ptosis correction surgery with levator muscle advancement was performed successfully. Ophthalmologists and patients should be aware of this potential rare side effect of topical bimatoprost, as it may be potentially disfiguring, especially with monocular use. However, its exact mechanism of action needs to be clarified further.

The epidemiology and incidence of cytomegalovirus retinitis in the HIV population in Singapore over 6 years.

PURPOSE: We report the epidemiologic trend of cytomegalovirus (CMV) retinitis among human immunodeficiency virus (HIV) patients in Singapore. METHODS: Our study included a retrospective case series of HIV patients with newly diagnosed CMV retinitis (CMVR) at the Singapore CDC between 2005 and 2010. Demographics, symptoms, signs, and laboratory results, including CD4 counts, were collected. Prevalence and disease trends over time were measured. RESULTS: Of 224 new patients, 92.9% were male and 96.0% were on antiretroviral therapy (ART). Median age was 43.0 years, with a median CD4 count of 38.0 cells/µL at HIV diagnosis. There was a decline in CD4 counts at diagnosis, and median duration of ART initiation from HIV diagnosis generally was earlier. Overall incidence rate was 10.4 cases per 1000 person-years (PY) and the mortality rate was 19.4 per 1000 PY. Mean survival time was 160.2 months (95% confidence interval [CI] 150.3-170.2). The 25 patients who died during the study period were older at the time of CMVR diagnosis (P = 0.003) and had lower CD4 counts (P = 0.030). Worse prognoses were associated with older age (hazard ratio [HR] 1.06, 95% CI 1.02-1.10) and shorter time lag from HIV to CMVR diagnosis (HR 0.97, 95% CI 0.95-0.99). Patients who did not receive highly active antiretroviral treatment (HAART) had a higher mortality risk (HR 4.70, 95% CI 1.54-14.33). CONCLUSIONS: The incidence rate of CMVR was decreasing with earlier initiation of ART and lower CD4 counts at HIV diagnosis. Poor prognostic factors included older age, shorter time lag from HIV to CMVR diagnosis, and the absence of HAART. Constant ophthalmologic surveillance until immune reconstitution is recommended.