Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser 727

International audienceChronic lymphoid leukemia (CLL) is characterized by the accumulation of functionally defective CD5-positive B lymphocytes. The clinical course of CLL is highly variable, ranging from a long-lasting indolent disease to an unpredictable and rapidly progressing leukemia requiring treatment. It is thus important to identify novel factors that reflect disease progression or contribute to its assessment. Here, we report on a novel STAT3-mediated pathway that characterizes CLL B cells-extended viability and oxidative stress control. We observed that leukemic but not normal B cells from CLL patients exhibit constitutive activation of an atypical form of the STAT3 signaling factor, phosphorylated on serine 727 (Ser 727) in the absence of detectable canonical tyrosine 705 (Tyr 705)-dependent activation in vivo. The Ser 727 -phosphorylated STAT3 molecule (pSTAT3Ser 727) is localized to the mitochondria and associates with complex I of the respiratory chain. This pSer 727 modification is further controlled by glutathione-dependent antioxidant pathway(s) that mediate stromal protection of the leukemic B cells and regulate their viability. Importantly, pSTAT3Ser 727 , but neither Tyr705-phosphorylated STAT3 nor total STAT3, levels correlate with prolonged in vivo CLL B cells survival. Furthermore, STAT3 activity contributes to the resistance to apoptosis of CLL, but not normal B cells, in vitro. These data reveal that mitochondrial (Mt) pSTAT3Ser 727 overactivity is part of the antioxidant defense pathway of CLL B cells that regulates their viability. Mt pSTAT3Ser 727 appears to be a newly identified cell-protective signal involved in CLL cells survival. Targeting pSTAT3Ser 727 could be a promising new therapeutic approach

Optometrists show rudimentary understanding of evidence-based practice but are ready to embrace it: can barriers be overcome?

Evidence-based practice (EBP) involves integration of the best available evidence from research, the patient's preferences or circumstances, the clinical environment and the health practitioner's expertise. There have been several qualitative studies of EBP in health-care but none has focused on the profession of optometry. Therefore, the aim of the present study was to assess optometrists' perceptions of EBP in optometry

Biophysical characteristics of the tear film in school-aged children

Purpose : The ocular surface and tear film in children are not as well characterised as in adults. Biophysical properties of tears are associated with their ability to spread on the ocular surface and reduce surface tension to form a stable tear film. The aim of this study was to investigate biophysical properties of tears in school-aged children and examine the relationship with age. Methods : Unstimulated tears were collected from 21 healthy children (age 6-14 years, 71% female) using glass capillary tubes. For each participant, tears were spread on the surface of an artificial tear solution reflecting the salt composition of tears and maintained at the physiological pH (7.4) and temperature (35°C) in a Langmuir trough. The tear film was compressed and expanded with two barriers and surface pressure was continually recorded with a pressure sensor to give pressure-area profiles. Pressure-area profiles were qualitatively compared between all participant tear samples. Maximum surface pressure at the highest compression for each participant sample was determined from profiles. Associations between maximum surface pressure and age were examined using Pearson correlation, and male and female samples were compared using Mann-Whitney U test. Profiles were also compared with a representative historical adult tear sample (35 y, female, normal ocular surface). Results : Pressure-area profiles of tear films of all participants indicated features of a stable, highly compressible liquid film with continuous increase in pressure without any collapse of the film. Profiles of child participants were similar and comparable to the profile of the historical adult sample. Group mean maximum surface pressure at the highest compression for child participants was 33 ± 3.5 mN/m. There were no significant relationships between maximum surface pressure and age (p=0.8) or sex (p=0.7). Conclusions : Biophysical characteristics of tears in school-aged children are comparable with adult tears and are not affected by age or sex. Many components including lipids and proteins contribute to the surface pressure of tears. Surface pressure of adult tears is known to be higher than surface pressure of lipid component alone because of additional contribution from proteins. Future investigations will examine the contribution of different components in children’s tears to overall tear stability

Systematic review of the appropriateness of eye care delivery in eye care practice

Background: Health care systems are continually being reformed, however care improvement and intervention effectiveness are often assumed, not measured. This paper aimed to review findings from published studies about the appropriateness of eye care delivery, using existing published evidence and/or experts' practice and to describe the methods used to measure appropriateness of eye care. Methods: A systematic search was conducted using Medline, Embase and CINAHL (2006 to September 2016). Studies reporting the processes of eye care delivery against existing published evidence and/or experts' practice were selected. Data was extracted from published reports and the methodological quality using a modified critical appraisal tool. The primary outcomes were percentage of appropriateness of eye care delivery. This study was registered with PROSPERO, reference CRD42016049974. Results: Fifty-seven studies were included. Most studies assessed glaucoma and diabetic retinopathy and the overall methodological quality for most studies was moderate. The ranges of appropriateness of care delivery were 2-100% for glaucoma, 0-100% for diabetic retinopathy and 0-100% for other miscellaneous conditions. Published studies assessed a single ocular condition, a sample from a single centre or a single domain of care, but no study has attempted to measure the overall appropriateness of eye care delivery. Conclusions: These findings indicated a wide range of appropriateness of eye care delivery, for glaucoma and diabetic eye care. Future research would benefit from a comprehensive approach where appropriateness of eye care is measured across multiple conditions with a single methodology, to guide priorities within eye care delivery and monitor quality improvement initiatives.</p

Risk factors common to leading eye health conditions and major non-communicable diseases: a rapid review and commentary

Background: To gain an understanding of the intersection of risk factors between the most prevalent eye health conditions that are associated with vision impairment and non-communicable diseases (NCDs). Methods: A series of rapid reviews of reviews reporting on non-modifiable risk factors, age and sex, and modifiable risk factors, including social determinants, were conducted for five common eye health conditions that are the leading causes of vision impairment globally (refractive error including uncorrected refractive error, cataract, age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy) and five prevalent NCDs (cancer, cardiovascular disease, chronic respiratory disease, dementia, and depressive disorders). Articles published within approximately 5 years to the end of 2019 were identified through expert recommendation, PubMED, Ovid Medline, the Lancet Global Burden of Disease series, the International Agency for Research on Cancer and World Cancer Research Fund.    Results: Of 9,213 records identified, 320 records were eligible. Eye health conditions and NCDs share many risk factors. Increased age was found to be the most common shared risk factor, associated with increased risks of AMD, cataract, diabetic retinopathy, glaucoma, refractive error, cancer, cardiovascular disease, chronic obstructive pulmonary disease, and dementia. Other shared risk factors included smoking, obesity, alcohol consumption (mixed results), and physical activity was protective, though limited evidence was found for eye conditions. Social determinants are well documented as risk factors for NCDs. Conclusion: There is substantial overlap in common established risk factors for the most frequent vision impairing eye conditions and leading NCDs. Increasing efforts should be made to integrate preventative and risk reduction interventions to improve health, with greatest shared benefits for initiatives which aim to reduce smoking, improve diet, and promote physical activity.</ns3:p

Risk factors common to leading eye health conditions and major non-communicable diseases: a rapid review and commentary

Background: To gain an understanding of the intersection of risk factors between the most prevalent eye health conditions that are associated with vision impairment and non-communicable diseases (NCDs). Methods: A series of rapid reviews of reviews reporting on non-modifiable risk factors, age and sex, and modifiable risk factors, including social determinants, were conducted for five common eye health conditions that are the leading causes of vision impairment globally (refractive error including uncorrected refractive error, cataract, age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy) and five prevalent NCDs (cancer, cardiovascular disease, chronic respiratory disease, dementia, and depressive disorders). Articles published within approximately 5 years to the end of 2019 were identified through expert recommendation, PubMED, Ovid Medline, the Lancet Global Burden of Disease series, the International Agency for Research on Cancer and World Cancer Research Fund.    Results: Of 9,213 records identified, 320 records were eligible. Eye health conditions and NCDs share many risk factors. Increased age was found to be the most common shared risk factor, associated with increased risks of AMD, cataract, diabetic retinopathy, glaucoma, refractive error, cancer, cardiovascular disease, chronic obstructive pulmonary disease, and dementia. Other shared risk factors included smoking, obesity, alcohol consumption (mixed results), and physical activity was protective, though limited evidence was found for eye conditions. Social determinants are well documented as risk factors for NCDs. Conclusion: There is substantial overlap in common established risk factors for the most frequent vision impairing eye conditions and leading NCDs. Increasing efforts should be made to integrate preventative and risk reduction interventions to improve health, with greatest shared benefits for initiatives which aim to reduce smoking, improve diet, and promote physical activity.</ns4:p

Strategies to address inequity of uncorrected refractive error in the Western Pacific: A modified Delphi process.

PURPOSE: Uncorrected refractive error is the leading cause of vision impairment globally; however, little attention has been given to equity and access to services. This study aimed to identify and prioritise: (1) strategies to address inequity of access to refractive error services and (2) population groups to target with these strategies in five sub-regions within the Western Pacific. METHODS: We invited eye care professionals to complete a two-round online prioritisation process. In round 1, panellists nominated population groups least able to access refractive error services, and strategies to improve access. Responses were summarised and presented in round 2, where panellists ranked the groups (by extent of difficulty and size) and strategies (in terms of reach, acceptability, sustainability, feasibility and equity). Groups and strategies were scored according to their rank within each sub-region. RESULTS: Seventy five people from 17 countries completed both rounds (55% women). Regional differences were evident. Indigenous peoples were a priority group for improving access in Australasia and Southeast Asia, while East Asia identified refugees and Oceania identified rural/remote people. Across the five sub-regions, reducing out-of-pocket costs was a commonly prioritised strategy for refraction and spectacles. Australasia prioritised improving cultural safety, East Asia prioritised strengthening school eye health programmes and Oceania and Southeast Asia prioritised outreach to rural areas. CONCLUSION: These results provide policy-makers, researchers and funders with a starting point for context-specific actions to improve access to refractive error services, particularly among underserved population groups who may be left behind in existing private sector-dominated models of care

TFOS DEWS III Digest Report

This digest summarises the interdisciplinary research in dry eye disease (DED) published since the 2017 TFOS DEWS II reports. It comprises seven topics including Sex, Gender, and Hormones, Epidemiology, Pathophysiology, Tear Film, Pain and Sensation, Iatrogenic and Clinical Trial Design and explores how each of these inform diagnostic methodology, disease subtype and management of DED. Sex- and gender-related differences significantly influence the ocular surface due to hormones, sex chromosomes, sex-specific autosomal factors, epigenetics, care-seeking behaviors, and service utilization. Epidemiological data reveal that DED prevalence varies by age and sex, influenced by diagnostic criteria and the multifactorial nature of the disease. New risk factors for DED include environmental, iatrogenic, systemic diseases and lifestyle domains. Pathophysiological distinctions between Aqueous Deficient Dry Eye (ADDE) and Evaporative Dry Eye (EDE) have been clarified. EDE is characterized by a muted inflammatory response at the ocular surface, meibomian gland dysfunction and conceivably phenotypic changes in corneal epithelial cells. There is an expanding role for metabolic, hormonal, physical, neural and cellular stresses, including hyperosmolarity, mitochondrial stress, and neurogenic inflammation. Advancements in tear film research recommend new approaches to understanding DED pathogenesis and identifying biomarkers, such as microRNAs. Ocular pain perception is linked to structural integrity of corneal nerves, functional capacities of neurons, and activity of the central and peripheral nervous systems. Iatrogenic DED can result from medications, contact lenses, and surgical procedures. Clinical trials now emphasize aligning design and endpoints with DED subtypes and therapeutic mechanisms, with new therapeutics and trial designs under consideration