Angle-based minimally invasive glaucoma surgery in normal tension glaucoma: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis quantitatively examines the efficacy of angle-based minimally invasive glaucoma surgery (MIGS) in normal tension glaucoma (NTG). METHODS: A literature search was performed on Medline, Embase, PubMed, CINAHL and Cochrane Library from inception until 20 December 2022. Pilot, cohort, observational studies and randomised controlled trials including at least 5 subjects undergoing angle-based MIGS (trabecular-bypass devices, excisional trabeculotomy, goniotomy and ab-interno canaloplasty) for NTG, with or without cataract surgery, were included. Meta-analysis of continuous outcome using the meta routine in R version 2022.12.0+353 was performed to determine mean intraocular pressure (IOP) and anti-glaucoma medication (AGM) reduction post-operatively. RESULTS: Of the 846 studies initially identified, 15 studies with a pooled total of 367 eyes which underwent combined phacoemulsification and angle-based MIGS were included for final meta-analysis. Outcomes of the iStent were reported in 5 studies, iStent inject in 7 studies, Hydrus Microstent in 1 study, Kahook Dual Blade in 3 studies, and Trabectome in 2 studies. There was significant reduction in both IOP and AGM post-operatively at 6 months (2.44 mmHg, 95%CI: 1.83-3.06; 1.21 AGM, 95%CI: 0.99-1.44), 12 months (2.28 mmHg, 95%CI: 1.71-2.84; 1.18 AGM, 95%CI: 0.90-1.47), 24 months (2.10 mmHg, 95%CI: 1.51-2.68; 1.26 AGM, 95%CI: 0.85-1.68) and 36 months (2.43 mmHg, 95%CI: 1.71-3.15, 0.87 AGM, 95%CI: 0.21-1.53) (all p < 0.05). Subgroup analysis on combined phacoemulsification-iStent inject surgery demonstrated a reduction in both IOP (2.31 mmHg, 95%CI: 1.07-3.56, p < 0.001) and AGM (1.07 AGM, 95%CI: 0.86-1.29, p < 0.001) at 12 months post-operatively. CONCLUSIONS: Angle-based MIGS combined with phacoemulsification effectively reduces IOP and AGM in NTG eyes for up to 36 months after surgery.

Development of a knowledge broker group to support evidence-informed policy: lessons learned from Myanmar.

BACKGROUND: Globally, policy-makers face challenges to using evidence in health decision-making, particularly lack of interaction between research and policy. Knowledge-brokering mechanisms can fill research-policy gaps and facilitate evidence-informed policy-making. In Myanmar, the need to promote evidence-informed policy is significant, and thus a mechanism was set up for this purpose. This paper discusses lessons learned from the development of the Knowledge Broker Group-Myanmar (KBG-M), supported by the Johns Hopkins Bloomberg School of Public Health's Applied Mental Health Research Group (JHU) and Community Partners International (CPI). METHODS: Sixteen stakeholders were interviewed to explore challenges in formulating evidence-informed policy. Two workshops were held: the first to further understand the needs of policy-makers and discuss knowledge-brokering approaches, and the second to co-create the KBG-M structure and process. The KBG-M was then envisioned as an independent body, with former officials of the Ministry of Health and Sports (MoHS) and representatives from the nongovernmental sector actively engaging in the health sector, with an official collaboration with the MoHS. RESULTS: A development task force that served as an advisory committee was established. Then, steps were taken to establish the KBG-M and obtain official recognition from the MoHS. Finally, when the technical agreement with the MoHS was nearly complete, the process stopped because of the military coup on 1 February 2021, and is now on hold indefinitely. CONCLUSIONS: Learning from this process may be helpful for future or current knowledge-brokering efforts, particularly in fragile, conflict-affected settings. Experienced and committed advisory committee members enhanced stakeholder relationships. Responsive coordination mechanisms allowed for adjustments to a changing bureaucratic landscape. Coordination with similar initiatives avoided overlap and identified areas needing technical support. Recommendations to continue the work of the KBG-M itself or similar platforms include the following: increase resilience to contextual changes by ensuring diverse partnerships, maintain advisory committee members experienced and influential in the policy-making process, ensure strong organizational and funding support for effective functioning and sustainability, have budget and timeline flexibility to allow sufficient time and resources for establishment, organize ongoing needs assessments to identify areas needing technical support and to develop responsive corrective approaches, and conduct information sharing and collaboration between stakeholders to ensure alignment.

Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways.

Dysfunction of the cerebrovasculature plays an important role in vascular cognitive impairment (VCI). Lipotoxic injury of the systemic endothelium in response to hydrolyzed triglyceride-rich lipoproteins (TGRLs; TGRL lipolysis products) or a high-fat Western diet (WD) suggests similar mechanisms may be present in brain microvascular endothelium. We investigated the hypothesis that TGRL lipolysis products cause lipotoxic injury to brain microvascular endothelium by generating increased mitochondrial superoxide radical generation, upregulation of activating transcription factor 3 (ATF3)-dependent inflammatory pathways, and activation of cellular oxidative stress and apoptotic pathways. Human brain microvascular endothelial cells were treated with human TGRL lipolysis products that induced intracellular lipid droplet formation, mitochondrial superoxide generation, ATF3-dependent transcription of proinflammatory, stress response, and oxidative stress genes, as well as activation of proapoptotic cascades. Male apoE knockout mice were fed a high-fat/high-cholesterol WD for 2 months, and brain microvessels were isolated by laser capture microdissection. ATF3 gene transcription was elevated 8-fold in the hippocampus and cerebellar brain region of the WD-fed animals compared with chow-fed control animals. The microvascular injury phenotypes observed in vitro and in vivo were similar. ATF3 plays an important role in mediating brain microvascular responses to acute and chronic lipotoxic injury and may be an important preventative and therapeutic target for endothelial dysfunction in VCI.

Characterizing blood-brain barrier perturbations after exposure to human triglyceride-rich lipoprotein lipolysis products using MRI in a rat model.

PURPOSE: Previous studies indicated hyperlipidemia may be a risk factor for Alzheimer's disease, but the contributions of postprandial triglyceride-rich lipoprotein (TGRL) are not known. In this study, changes in blood-brain barrier diffusional transport following exposure to human TGRL lipolysis products were studied using MRI in a rat model. METHODS: Male Sprague-Dawley rats (∼180-250 g) received an i.v. injection of lipoprotein lipase (LpL)-hydrolyzed TGRL (n = 8, plasma concentration ≈ 150 mg human TGRL/dL). Controls received i.v. injection of either saline (n = 6) or LpL only (n = 6). The (1) H longitudinal relaxation rate R1 = 1/T1 was measured over 18 min using a rapid-acquired refocus-echo (RARE) sequence after each of three injections of the contrast agent Gd-DTPA. Patlak plots were generated for each pixel yielding blood-to-brain transfer coefficients, Ki , chosen for best fit to impermeable, uni-directional influx or bi-directional flux models using the F-test. RESULTS: Analysis from a 2-mm slice, 2-mm rostral to the bregma showed a 275% increase of mean Ki during the first 20 min after infusion of human TGRL lipolysis product that differed significantly compared with saline and LpL controls. This difference disappeared by 40 min mark. CONCLUSION: These results suggest human TGRL lipolysis products can lead to a transient increase in rat BBB permeability. Magn Reson Med 76:1246-1251, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Anterior chamber inflammation grading methods: A critical review.

Assessing anterior chamber inflammation is highly subjective and challenging. Although various grading systems attempt to offer objectivity and standardization, the clinical assessment has high interobserver variability. Traditional techniques, such as laser flare meter and fluorophotometry, are not widely used since they are time-consuming. With the development of optical coherence tomography with high sensitivity, direct imaging offers an excellent alternative to assess objectively inflammation with the potential for automated analysis. We describe various anterior chamber inflammation grading methods and discuss their utility, advantages, and disadvantages.

Correction: Translating drug resistant tuberculosis treatment guidelines to reality in war-torn Kandahar, Afghanistan: A retrospective cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0237787.].

Ocular manifestations in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a rare but important systemic disease with or without ocular manifestations. We describe 4 cases of IgAN presenting with scleritis and review the various ocular manifestations in patients with IgAN. We found 55 cases with ocular manifestations in patients with prior or newly-diagnosed IgAN described in 38 publications. The most common ocular manifestations of IgAN were episcleritis (23.6%), scleritis (16.4%), hypertensive retinopathy or retinal vasculopathy (20.0%), and uveitis (14.5%). The median age at presentation was 36.5 years, with 54.5% female patients. 61.8% had history of IgAN prior to ocular involvement, while 29.1% had ocular presentations as the first manifestation of IgAN. The majority received systemic corticosteroids and/or immunosuppressants. Additionally, we report 4 women with anterior scleritis and previous diagnosis of IgAN. All 4 were treated with topical and systemic corticosteroids. Three out of 4 patients had no recurrence for at least 1 year since the first presentation. IgAN is a rare but important systemic association to be considered in ocular inflammatory conditions. Timely recognition and comanagement of the disease with nephrologist could reduce disease morbidity.

Seasonal influences on CAPs exposures: differential responses in platelet activation, serum cytokines and xenobiotic gene expression.

Increasing evidence suggests a role for a systemic pro-coagulant state in the pathogenesis of cardiac dysfunction subsequent to inhalation of airborne particulate matter (PM). We evaluated platelet activation, systemic cytokines and pulmonary gene expression in mice exposed to concentrated ambient particulate matter (CAPs) in the summer of 2008 (S08) and winter of 2009 (W09) from the San Joaquin Valley of California, a region with severe PM pollution episodes. Additionally, we characterized the PM from both exposures including organic compounds, metals, and polycyclic aromatic hydrocarbons. Mice were exposed to an average of 39.01 µg/m(3) of CAPs in the winter and 21.7 µg/m3 CAPs in the summer, in a size range less than 2.5 µm for 6 h/day for 5 days per week for 2 weeks. Platelets were analyzed by flow cytometry for relative size, shape, CD41, P-selectin and lysosomal associated membrane protein-1 (LAMP-1) expression. Platelets from W09 CAPs-exposed animals had a greater response to thrombin stimulation than platelets from S08 CAPs-exposed animals. Serum cytokines were analyzed by bead based immunologic assays. W09 CAPs-exposed mice had elevations in IL-2, MIP-1α, and TNFα. Laser capture microdissection (LCM) of pulmonary vasculature, parenchyma and airways all showed increases in CYP1a1 gene expression. Pulmonary vasculature showed increased expression of ICAM-1 and Nox-2. Our findings demonstrate that W09 CAPs exposure generated a greater systemic pro-inflammatory and pro-coagulant response to inhalation of environmentally derived fine and ultrafine PM. Changes in platelet responsiveness to agonists, seen in both exposures, strongly suggests a role for platelet activation in the cardiovascular and respiratory effects of particulate air pollution.

Effect of sprint interval exercise on postexercise metabolism and blood pressure in adolescents.

The current study examined the effect of sprint interval exercise on postexercise oxygen consumption, respiratory-exchange ratio (RER), substrate oxidation, and blood pressure in adolescents. Participants were 10 normal-weight healthy youth (7 female), age 15-18 years. After overnight fasts, each participant undertook 2 trials in a random balanced order: (a) two 30-s bouts of sprint interval exercise on a cycle ergometer and (b) rested in the laboratory for an equivalent period. Time-matched measurements of oxygen consumption, RER, and blood pressure were made 90 min into recovery, and substrate oxidation were calculated over the time period. Total postexercise oxygen uptake was significantly higher in the exercise than control trial over the 90 min (mean [SD]: control 20.0 [6.0] L, exercise 24.8 [9.8] L; p=.030). After exercise, RER was elevated above control but then fell rapidly and was lower than control 30-60 min postexercise, and fat oxidation was significantly higher in the exercise than control trial 45-60 min postexercise. However, total fat oxidation did not differ between trials (control 4.5 [2.5] g, exercise 5.4 [2.7] g; p=.247). Post hoc tests revealed that systolic blood pressure was significantly lower than in control at 90 min postexercise (control 104 [10] mm Hg, exercise 99 [10] mm Hg; p<.05). These data indicate that acute sprint interval exercise leads to short-term increases in oxygen uptake and reduced blood pressure in youth. The authors suggest that health outcomes in response to sprint interval training be examined in children.

Cost optimisation analysis of the expanded programme for immunisation: balancing equity and coverage in Pakistan.

INTRODUCTION: With limited resources, attaining maximal average health service coverage can be at odds with maximising equity which attempts to promote greater reach among underserved populations. In this study, we examined the trade-offs in immunisation coverage levels and equity for children under 5 years of age in Pakistan across various subpopulations who can be targeted with different combinations of immunisation service modalities. METHODS: We conducted a detailed costing exercise across 16 geographically and demographically diverse districts in Pakistan. These data were the basis for (a) technical efficiency benchmarking via Data Envelopment Analysis to identify potential efficiency gains by location, delivery model and cost ingredient; (b) allocative efficiency optimisation modelling to understand how resource allocations could be optimised and to devise recommended budget allocations and operational metrics. Finally, the hypothetical overall efficiency gains attainable were estimated if available resources were allocated with the optimal emphases, and if service delivery models operated at productivity levels at the benchmarked frontier of efficiency. RESULTS: Benchmarking suggests that ~44% of delivery models are running efficiently and 37% are highly inefficient. While coverage and equity are usually at odds, surprisingly, the optimisation modelling revealed that substantial improvements in equity between subpopulations does not necessarily cost very much in overall immunisation coverage: theoretically, equity can be achieved while still attaining close to maximal immunisation coverage. Overall, analyses suggest greater emphases should be placed on outreach delivery models which particularly target rural areas and slum populations. CONCLUSION: The unit cost differentials within districts are not sufficiently large for there to be a large reduction in potential Fully Immunised Children coverage if one focuses on maximising equity. However, reallocations of programme budgets can have a significant impact on equity outcomes, particularly at current low spending amounts. Therefore, it is recommended to address equity as the key objective in national immunisation programming.

Adenosine blocks IFN-gamma-induced phosphorylation of STAT1 on serine 727 to reduce macrophage activation.

Macrophages are activated by IFN-gamma, a proinflammatory and proatherogenic cytokine that mediates its downstream effects primarily through STAT1. IFN-gamma signaling induces phosphorylation of two STAT1 residues: Tyr(701) (Y701), which facilitates dimerization, nuclear translocation, and DNA binding; and Ser(727) (S727), which enables maximal STAT1 transcription activity. Immunosuppressive molecules such as adenosine in the cellular microenvironment can reduce macrophage inflammatory and atherogenic functions through receptor-mediated signaling pathways. We hypothesized that adenosine achieves these protective effects by interrupting IFN-gamma signaling in activated macrophages. This investigation demonstrates that adding adenosine to IFN-gamma-stimulated murine RAW 264.7 and human THP-1 macrophages results in unique modulation of STAT1 serine and tyrosine phosphorylation events. We show that adenosine inhibits IFN-gamma-induced STAT1 S727 phosphorylation by >30% and phosphoserine-mediated transcriptional activity by 58% but has no effect on phosphorylation of Y701 or receptor-associated JAK tyrosine kinases. Inhibition of the adenosine A(3) receptor with a subtype-specific antagonist (MRS 1191 in RAW 264.7 cells and MRS 1220 in THP-1 cells) reverses this adenosine suppressive effect on STAT1 phosphoserine status by 25-50%. Further, RAW 264.7 A(3) receptor stimulation with Cl-IB-MECA reduces IFN-gamma-induced STAT1 transcriptional activity by 45% and STAT1-dependent gene expression by up to 80%. These data suggest that A(3) receptor signaling is key to adenosine-mediated STAT1 modulation and anti-inflammatory action in IFN-gamma-activated mouse and human macrophages. Because STAT1 plays a key role in IFN-gamma-induced inflammation and foam cell transformation, a better understanding of the mechanisms underlying STAT1 deactivation by adenosine may improve preventative and therapeutic approaches to vascular disease.

Recalcitrant Pseudomonas Aeruginosa Keratitis with Hyphaema.

PURPOSE: To report a case of recalcitrant pseudomonas keratitis with a rare presentation of hyphaema. OBSERVATION: A 45-year-old female was noted to have contact lens-related pseudomonas keratitis with hyphaema. The organism was refractory to multiple antibiotics and only responded to Tazocin eye drops. CONCLUSION AND IMPORTANCE: Hyphaema is a rare presentation in bacterial keratitis and could represent infection with an especially virulent organism. Use of Aspirin could precipitate hyphaema in infective keratitis. Alternative antibiotic choices such as Tazocin, colistin, meropenem, and imipenem can be considered when standard therapy is ineffective for multidrug-resistant Pseudomonas keratitis.

Postpartum women's knowledge and planned use of contraception in Myanmar.

BACKGROUND: Maternal mortality in Myanmar is one of the highest in the WHO South-East Asian region. Additionally, the country has a high unmet need for contraception and low rates of uptake of long-acting reversible contraceptive methods (LARCs) including intrauterine devices (IUDs) and implants. Engagement with health professionals around the time of a birth is an ideal opportunity for women to access contraception but immediate postpartum provision is not widely offered in Myanmar. METHODS: We undertook a cross-sectional survey of women immediately postpartum at two hospitals in Yangon to investigate their knowledge, and past use of, contraceptive methods and their plans for postpartum contraception including perceptions of implants and IUDs. Four trained obstetrics staff collected data using electronic tablets between January 2017 and January 2018. RESULTS: Of the 1755 participants, 55.1% had used pills and 42.2% injectables. In contrast, only 0.5% had used an IUD and 0.3% an implant. Few women (4.4%) anticipated starting contraception immediately postpartum and only a minority would consider future use of an implant (36.9%) or an IUD (13.0%). Fear of side effects was the major barrier to future implant and IUD uptake, reported by 64.5% and 62.5%, respectively. CONCLUSIONS: Women in maternity care in Yangon have some awareness of IUDs and implants but many hold misconceptions about their side effects leading to reluctance to use. Reducing the unmet need for contraception and improving maternal outcomes in Myanmar could be achieved by improving education, policy and practice around immediate postpartum contraception provision, with a particular focus on LARC methods.

Translating drug resistant tuberculosis treatment guidelines to reality in war-torn Kandahar, Afghanistan: A retrospective cohort study.

INTRODUCTION: Afghanistan is affected by one of the world's longest protracted armed conflicts, frequent natural disasters, disease outbreaks and large population movements and it suffers from a high burden of tuberculosis (TB), including rifampicin-resistant TB (RR-TB). The study shows Médecins Sans Frontières' experiences with care for patients with RR-TB in Kandahar Province. We describe the uptake of RR-TB treatment, how World Health Organisation criteria for the choice between the short and an individualized regimen were implemented, and treatment outcomes. METHODS: This is a retrospective cohort analysis of routinely collected data from RR-TB patients enrolled in care from 2016 until 2019. Descriptive analysis was performed to present characteristics of patients and treatment outcomes. Multivariable Cox analysis was performed to identify risk factors for having an unfavourable treatment outcome. RESULTS: Out of 146 enrolled RR-TB patients, 112 (76.7%) started treatment: 41 (36.6%) and 71 (63.4%) with the short and individualized treatment regimen, respectively. Of 82 with results for fluoroquinolone susceptibility, 39 (47.6%) had fluoroquinolone-resistant TB. Seven patients with initially fluoroquinolone-resistant TB and three pregnant women started the short regimen and 18 patients eligible for the short regimen started the injectable-free individualized regimen. Overall, six-month smear and culture conversion were 98.7% and 97.1%, respectively; treatment success was 70.1%. Known initial fluoroquinolone resistance (aHR 3.77, 95%CI:1.53-9.27) but not choice of regimen predicted having an unfavourable outcome. CONCLUSION: Even though criteria for the choice of treatment regimen were not applied strictly, we have achieved acceptable outcomes in this cohort. To expand RR-TB care, treatment regimens should fit provision at primary health care level and take patient preferences into account.

Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design.

Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.

5-Aminomethylbenzimidazoles as potent ITK antagonists.

Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.

Burma Terrane part of the Trans-Tethyan Arc during collision with India according to palaeomagnetic data.

Convergence between the Indian and Asian plates has reshaped large parts of Asia, changing regional climate and biodiversity. Yet geodynamic models fundamentally diverge on how convergence was accommodated since the India-Asia collision. Here we report paleomagnetic data from the Burma Terrane, at the eastern edge of the collision zone and famous for its Cretaceous amber biota, to better determine the evolution of the India-Asia collision. The Burma Terrane was part of a Trans-Tethyan island arc and stood at a near-equatorial southern latitude at ~95 Ma, suggesting island endemism for the Burmese amber biota. The Burma Terrane underwent significant clockwise rotation between ~80-50 Ma, causing its subduction margin to become hyper-oblique. Subsequently, it was translated northward on the Indian Plate, by an exceptional distance of at least 2000 km, along a dextral strike-slip fault system in the east. Our reconstructions are only compatible with geodynamic models involving a first collision of India with a near-equatorial Trans-Tethyan subduction system at ~60 Ma, followed by a later collision with the Asian margin.

Mice lacking alpha-tocopherol transfer protein gene have severe alpha-tocopherol deficiency in multiple regions of the central nervous system.

Ataxia with vitamin E deficiency is caused by mutations in alpha-tocopherol transfer protein (alpha-TTP) gene and it can be experimentally generated in mice by alpha-TTP gene inactivation (alpha-TTP-KO). This study compared alpha-tocopherol (alpha-T) concentrations of five brain regions and of four peripheral organs from 5 months old, male and female, wild-type (WT) and alpha-TTP-KO mice. All brain regions of female WT mice contained significantly higher alpha-T than those from WT males. alpha-T concentration in the cerebellum was significantly lower than that in other brain regions of WT mice. These sex and regional differences in brain alpha-T concentrations do not appear to be determined by alpha-TTP expression which was undetectable in all brain regions. All the brain regions of alpha-TTP-KO mice were severely depleted in alpha-T. The concentration of another endogenous antioxidant, total glutathione, was unaffected by gender but was decreased slightly but significantly in most brain regions of alpha-TTP-KO mice. The results show that both gender and the hepatic alpha-TTP, but not brain alpha-TTP gene expression are important in determining alpha-T concentrations within the brain. Interestingly, functional abnormality (ataxia) develops only very late in alpha-TTP-KO mice in spite of the severe alpha-tocopherol deficiency in the brain starting at an early age.