Outcomes of Ahmed glaucoma valve surgery performed by glaucoma fellows - A large retrospective study from Eastern India.

PURPOSE: Teaching and training of glaucoma fellows on the technique of Ahmed glaucoma valve (AGV) implantation surgery is very important. The purpose of this study was to describe the clinical outcomes and complications of AGV surgery performed by glaucoma fellows of a tertiary eye center from eastern India. METHODS: This was a retrospective study based on electronic medical records. Thirty-five eyes operated with AGV by five glaucoma fellows from January 2016 to November 2020 were included. Best-corrected visual acuity, intraocular pressure (IOP), and number of antiglaucoma medications (AGMs) were the study outcome measures. RESULTS: The mean (±standard deviation) age of the patients was 40.5 (±19.7) years. The follow-up period was 24.37 (±13.01) months. Both complete success (IOP <21 mmHg without additional AGM) and qualified success (IOP <21 mmHg with an additional AGM) were achieved in eight eyes each (22.8%). Failure of the surgery was noted in 19 eyes (54.3%) as there was a need for repeat surgery for IOP control in 12 eyes and a persistent IOP spike (IOP >21 mmHg with AGM beyond 3 months) in seven eyes. Despite a high rate of failure of the primary surgery, with the consultants' intervention, there was statistically significant improvement in vision and IOP in all patients (P < 0.01) at the last follow-up. CONCLUSION: AGV implantation is a challenging surgical skill to be acquired by the glaucoma fellows.

Outcomes of reimplantation of a new Glaucoma Drainage Device after explantation of an older implant from exposure-related complications.

Purpose: To describe the clinical outcome of a series of seven eyes with an explanation of an original Glaucoma Drainage Device (GDD) arising from the complication of plate exposure and consequent reimplantation of another GDD at a second setting. Methods: This was a retrospective, interventional, and non-comparative study at two tertiary eye care hospitals in eastern and southern India. Electronic medical record data of the seven eyes where a GDD was explanted and a 2nd GDD was reimplanted over October 2010 and May 2021 was analyzed. Statistical analysis was done by SPSS (ver. 26). Results: The first GDD survived for a mean of 168 days only till the plate got exposed and thereby got explanted. Possible predisposing factors noted were conjunctival and scleral thinning, ischemic conjunctiva, etc., The reimplantation surgery was technically easy in the absence of hypotony-opposite to what is reported in the literature. The final IOP (mean +/- SD) values (mm Hg) were 18.9 (+/-7.9), range = 10-30. The mean number of glaucoma medications reduced from 3.9 (+/-1.2; range, 2 to 5) after the explanation to 3.1 (+/-0.7; range, 2 to 4) after the 2nd GDD implantation, in the final follow-up. The second GDD was found to be stable till the last follow-up (mean = 1149 days). No other significant intraoperative or postoperative complications were seen. Conclusions: Reimplantation of a second GDD in a separate setting after explanations of an original implant due to exposure-related complication is both a safe and effective method.

Recipes for when physics fails: recovering robust learning of physics informed neural networks.

Physics-informed neural networks (PINNs) have been shown to be effective in solving partial differential equations by capturing the physics induced constraints as a part of the training loss function. This paper shows that a PINN can be sensitive to errors in training data and overfit itself in dynamically propagating these errors over the domain of the solution of the PDE. It also shows how physical regularizations based on continuity criteria and conservation laws fail to address this issue and rather introduce problems of their own causing the deep network to converge to a physics-obeying local minimum instead of the global minimum. We introduce Gaussian process (GP) based smoothing that recovers the performance of a PINN and promises a robust architecture against noise/errors in measurements. Additionally, we illustrate an inexpensive method of quantifying the evolution of uncertainty based on the variance estimation of GPs on boundary data. Robust PINN performance is also shown to be achievable by choice of sparse sets of inducing points based on sparsely induced GPs. We demonstrate the performance of our proposed methods and compare the results from existing benchmark models in literature for time-dependent Schrödinger and Burgers' equations.

Diurnal and seasonal variations of pCO2 and fluorescent dissolved organic matter (FDOM) in different polluted lakes.

This study aimed to assess pollution and daily-to-seasonal dynamics of the partial pressure of CO2 (pCO2) and CO2 degassing flux concerning the fluorescent dissolved organic matter (FDOM) from tropical lakes. A membrane-enclosed pCO2 sensor and water quality multimeter analyzer was deployed to continuously record daily and seasonal variations in pCO2 and CO2 degassing flux in three lakes in Savar, Dhaka. During both wet and dry seasons, all lake water was supersaturated with CO2 in contrast to the atmospheric equilibrium (~400 µatm). The pCO2 values in the lake water during the dry season were relatively low in comparison, and the pCO2 levels in the wet season were much higher due to external inputs of organic matter from watersheds and direct inputs of CO2 from soils or wetlands. The estimated water-to-air CO2 degassing flux in the different levels of polluted lakes varies with the pollution context. Study areas calculated the carbon flux and three lakes released respectively 86.75×107g CO2 year-1, 13.8×107g CO2 year-1, and 9.17×107g CO2 year-1. Three-dimensional excitation-emission matrix (3D-EEM) fluorescence spectroscopy combined with parallel factor (PARAFAC) analysis was used to investigate the distributions of fluorescent components in DOM. EEM-PARAFAC analysis identified humic-like, fulvic-like, protein-like, and more tyrosine-like FDOM components and their environmental dynamics. Terrestrial DOM may provide inputs to the terrestrial humic-like component in the lake water. In contrast, the biological activity of plankton-derived FDOM is the most likely source for the autochthonous humic-like component. FDOM and DO concentrations have negative correlations with pCO2, indicating that when the FDOM and DO level is decreased, the amount of pCO2 values increases.

Muscle-building supplement ß-hydroxy ß-methylbutyrate binds to PPARα to improve hippocampal functions in mice.

This study underlines the importance of ß-hydroxy ß-methylbutyrate (HMB), a muscle-building supplement in human, in increasing mouse hippocampal plasticity. Detailed proteomic analyses reveal that HMB serves as a ligand of peroxisome proliferator-activated receptor α (PPARα), a nuclear hormone receptor involved in fat metabolism, via interaction with the Y314 residue. Accordingly, HMB is ineffective in increasing plasticity of PPARα-/- hippocampal neurons. While lentiviral establishment of full-length PPARα restores the plasticity-promoting effect of HMB in PPARα-/- hippocampal neurons, lentiviral transduction of Y314D-PPARα remains unable to do that, highlighting the importance of HMB's interaction with the Y314 residue. Additionally, oral HMB improves spatial learning and memory and reduces plaque load in 5X familial Alzheimer's disease (5XFAD) mice, but not in 5XFADΔPPARα mice (5XFAD lacking PPARα), indicating the involvement of PPARα in HMB-mediated neuroprotection in 5XFAD mice. These results delineate neuroprotective functions of HMB and suggest that this widely used supplement may be repurposed for AD.

Suppression of Experimental Autoimmune Encephalomyelitis in Mice by ß-Hydroxy ß-Methylbutyrate, a Body-Building Supplement in Humans.

Although several immunomodulatory drugs are available for multiple sclerosis (MS), most present significant side effects with long-term use. Therefore, delineation of nontoxic drugs for MS is an important area of research. ß-Hydroxy ß-methylbutyrate (HMB) is accessible in local GNC stores as a muscle-building supplement in humans. This study underlines the importance of HMB in suppressing clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of MS. Dose-dependent study shows that oral HMB at a dose of 1 mg/kg body weight/d or higher significantly suppresses clinical symptoms of EAE in mice. Accordingly, orally administered HMB attenuated perivascular cuffing, preserved the integrity of the blood-brain barrier and blood-spinal cord barrier, inhibited inflammation, maintained the expression of myelin genes, and blocked demyelination in the spinal cord of EAE mice. From the immunomodulatory side, HMB protected regulatory T cells and suppressed Th1 and Th17 biasness. Using peroxisome proliferator-activated receptor (PPAR)α-/- and PPARß-/- mice, we observed that HMB required PPARß, but not PPARα, to exhibit immunomodulation and suppress EAE. Interestingly, HMB reduced the production of NO via PPARß to protect regulatory T cells. These results describe a novel anti-autoimmune property of HMB that may be beneficial in the treatment of MS and other autoimmune disorders.

Detection of Elevated Level of Tetrahydrobiopterin in Serum Samples of ME/CFS Patients with Orthostatic Intolerance: A Pilot Study.

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a multisystem chronic illness characterized by severe muscle fatigue, pain, dizziness, and brain fog. Many patients with ME/CFS experience orthostatic intolerance (OI), which is characterized by frequent dizziness, light-headedness, and feeling faint while maintaining an upright posture. Despite intense investigation, the molecular mechanism of this debilitating condition is still unknown. OI is often manifested by cardiovascular alterations, such as reduced cerebral blood flow, reduced blood pressure, and diminished heart rate. The bioavailability of tetrahydrobiopterin (BH4), an essential cofactor of endothelial nitric oxide synthase (eNOS) enzyme, is tightly coupled with cardiovascular health and circulation. To explore the role of BH4 in ME/CFS, serum samples of CFS patients (n = 32), CFS patients with OI only (n = 10; CFS + OI), and CFS patients with both OI and small fiber polyneuropathy (n = 12; CFS + OI + SFN) were subjected to BH4 ELISA. Interestingly, our results revealed that the BH4 expression is significantly high in CFS, CFS + OI, and CFS + OI + SFN patients compared to age-/gender-matched controls. Finally, a ROS production assay in cultured microglial cells followed by Pearson correlation statistics indicated that the elevated BH4 in serum samples of CFS + OI patients might be associated with the oxidative stress response. These findings suggest that the regulation of BH4 metabolism could be a promising target for understanding the molecular mechanism of CFS and CFS with OI.

Outcomes of "Complex" Cataract Surgeries Performed by Long-Term Glaucoma Fellows in a Tertiary Eye Centre from Eastern India.

Purpose: To evaluate the outcomes of operating on "complex cataracts" by the glaucoma fellows. Patients and Methods: This was a retrospective study done at a tertiary referral eye care centre in eastern India. After obtaining IRB approval, a retrospective chart review of all patients who underwent "complex" cataract surgery by one of four long-term (2 years) glaucoma fellows between January 2016 and November 2020 was conducted. 'Complex' was defined as cataracts complicated with pseudoexfoliation syndrome, phacodonesis with or without blunt ocular trauma, posterior polar cataract, small pupil, co-existent corneal opacity or uveal coloboma, post-glaucoma filtering surgery, post-vitreoretinal surgery, co-existent glaucoma or post-laser iridotomy and monocular patients. Results: Out of a total of 677 eyes done by the glaucoma fellows during the study period, 83 eyes had complex cataract surgery and completed the six-week post-operative follow-up. Intraoperative surgical complications like posterior capsular rent or vitreous loss were noted in 36 of the cases. Thirty of the eyes were left aphakic. Despite a high rate of complications, the LogMAR best-corrected visual acuity (mean ± standard deviation) improved from the preoperative level of 1.7 (±0.5) to 1.0 (± 0.8) at post-operative six weeks, significant at p < 0.001. As far as the surgeon's experience was concerned-less than or more than a year since joining the fellowship-there was statistically no difference in the final visual acuity. The group with greater experience had shorter surgical time and lesser complications though this difference was not statistically significant. Conclusion: This is the first study in the literature reporting the outcomes of "complex" cataract surgery performed by glaucoma fellows. Though high rates of postoperative complications were noted in this study, the mean best-corrected visual acuity improved significantly in all eyes after the surgery.

Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases.

Historically, COVID-19 emerges as one of the most devastating diseases of humankind, which creates an unmanageable health crisis worldwide. Until now, this disease costs millions of lives and continues to paralyze human civilization's economy and social growth, leaving an enduring damage that will take an exceptionally long time to repair. While a majority of infected patients survive after mild to moderate reactions after two to six weeks, a growing population of patients suffers for months with severe and prolonged symptoms of fatigue, depression, and anxiety. These patients are no less than 10% of total COVID-19 infected individuals with distinctive chronic clinical symptomatology, collectively termed post-acute sequelae of COVID-19 (PASC) or more commonly long-haul COVID. Interestingly, Long-haul COVID and many debilitating viral diseases display a similar range of clinical symptoms of muscle fatigue, dizziness, depression, and chronic inflammation. In our current hypothesis-driven review article, we attempt to discuss the molecular mechanism of muscle fatigue in long-haul COVID, and other viral diseases as caused by HHV6, Powassan, Epstein-Barr virus (EBV), and HIV. We also discuss the pathological resemblance of virus-triggered muscle fatigue with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Evaluating perspective and quality of life of glaucoma patients during the COVID-19 pandemic in India: Results of a telephone survey.

Purpose: The past few years have been difficult in the lives of most glaucoma patients in view of the COVID-19 pandemic. Our aim was to find out patients' perspective and disruption of their quality of life during the COVID-19 pandemic by conducting a telephone survey among glaucoma patients. Methods: This was a cross-sectional study involving the glaucoma patients of a tertiary eye care hospital in India. Patients who had completed at least five years of follow-up before 2020 were randomized by a random number generator. A validated (forward-backward translation and completed pilot analysis) set of 14 questionnaires was administered to the patients, the latter of whom were telephonically interviewed by one of the investigators in February 2022. The entire data was audio-recorded. Statistical Package for the Social Sciences (SPSS) version 26 was used. Results: Out of 1141 patients with >5 years of follow-up, 103 were selected by randomization. A large group of 46 patients (44.6%) admitted to glaucoma affecting their daily activities. Only 12 (11.6%) admitted to being irregular with their drops. Thirty-four (33%) patients felt that their glaucoma was deteriorating and 31 (30.1%) had fear of blindness. Ninety-five patients (92.7%) felt that they were safe under the care of the treating doctor. There were 46 (44.6%) out of 103 patients who did not turn up for follow-up for six months or more. Lockdown (36.2%) and travel-expenses (27.6%) were the two most common reasons for the loss to follow-up visits. Conclusion: Nearly half of the long-term glaucoma patients were lost to follow-up during the COVID-19 pandemic. Glaucoma affecting daily lives and fear of losing vision turned out to be significant observations in the telephone survey. This fear seemed to be ameliorated by the majority still feeling safe by being in touch with their doctor for continued care even during the COVID-19 pandemic.

Glaucoma screening skills among general ophthalmologists - How general should it be?

Purpose: To compare the glaucoma assessment skills among general ophthalmologists in their referral patients over 5 years. Methods: This was a retrospective auditing of the electronic medical record database. Details of consecutive new glaucoma patients seen in the glaucoma services of a tertiary eye care institute in 2013 and 2018 were collected. Details of each patient included the clinical presentation, baseline intra-ocular pressure (IOP), type and severity of glaucoma, referral details, gonioscopy, HVF (Humphrey visual field) data, and the number of medications. Statistical tests used were the Chi-square test and T test using SPSS version 22. Results: Of 28,886 medical records screened, 211 and 568 new glaucoma patients were retrieved in 2013 and 2018, respectively. The patients presenting in 2018 were younger (58.1 ± 15.4 years) at presentation than in 2013 (65.6 ± 15.2 years), P < 0.01, and also had higher baseline IOP (IOP ≥40 mm Hg was found in 9.5% in 2018 versus 2.4% in 2013; P < 0.01). The percentage of eyes with presenting visual acuity worse than 20/400 or 20/600 was higher in the patients presenting in 2018 (22.2% vs. 15.1%; P = 0.03). Although primary glaucoma predominated in both periods, the number of eyes referred to as disc suspects showed an increase in 2018 (4.7% to 14.4%; P < 0.01). Among 195 and 517 referrals in 2013 and 2018, respectively, the documentation of clinical findings were dismally poor in both the groups in terms of absent gonioscopy (99% vs. 98.2%, P = 0.4), absent disc details (89.6% vs. 91%, P = 0.5), or absent visual field analysis (79.1% vs. 74.8%, P = 0.2). However, the missing IOP values were significantly better in the latter year (77.3% vs. 57.2%; P < 0.01). Conclusion: The increase in the number of new glaucoma patients and referrals did not show a corresponding improvement in documentation of findings except for IOP recording among general ophthalmologists. Hence, we need to re-emphasize the training of general ophthalmologists on basic glaucoma evaluation to improve their referral ability.

Treadmill exercise reduces α-synuclein spreading via PPARα.

This study underlines the importance of treadmill exercise in reducing α-synuclein (α-syn) spreading in the A53T brain and protecting nigral dopaminergic neurons. Preformed α-syn fibril (PFF) seeding in the internal capsule of young A53T α-syn mice leads to increased spreading of α-syn to substantia nigra and motor cortex and concomitant loss of nigral dopaminergic neurons. However, regular treadmill exercise decreases α-syn spreading in the brain and protects nigral dopaminergic neurons in PFF-seeded mice. Accordingly, treadmill exercise also mitigates α-synucleinopathy in aged A53T mice. While investigating this mechanism, we have observed that treadmill exercise induces the activation of peroxisome proliferator-activated receptor α (PPARα) in the brain to stimulate lysosomal biogenesis via TFEB. Accordingly, treadmill exercise remains unable to stimulate TFEB and reduce α-synucleinopathy in A53T mice lacking PPARα, and fenofibrate, a prototype PPARα agonist, reduces α-synucleinopathy. These results delineate a beneficial function of treadmill exercise in reducing α-syn spreading in the brain via PPARα.

Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE).

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy. A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells. Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.

Visual function tests for glaucoma practice - What is relevant?

Glaucoma represents one of the most important ocular diseases causing irreversible ganglion cell death. It is one of the most common causes of visual impairment and morbidity in the elderly population. There are various tests for measuring visual function in glaucoma. While visual field remains the undisputed method for screening, diagnosis, and monitoring disease progression, other tests have been studied for their utility in glaucoma practice. This review discusses some of the commonly used tests of visual function that can be routinely used in clinics for glaucoma management. Among the various modalities of testing visual function in glaucoma, this review highlights the tests that are most clinically relevant.

Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer.

Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p402) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p402. The level of p40 was also larger than p402 in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4+IFNγ+ and CD8+IFNγ+ T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor ß (TGFß) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice.

Oleamide, a Sleep-Inducing Supplement, Upregulates Doublecortin in Hippocampal Progenitor Cells via PPARα.

BACKGROUND: Doublecortin (DCX), a microtubule associated protein, has emerged as a central biomarker of hippocampal neurogenesis. However, molecular mechanisms by which DCX is regulated are poorly understood. OBJECTIVE: Since sleep is involved with the acquisition of memory and oleamide or 9-Octadecenamide (OCT) is a sleep-inducing supplement in human, we examined whether OCT could upregulate DCX in hippocampal progenitor cells (HPCs). METHODS: We employed real-time PCR, western blot, immunostaining, chromatin immunoprecipitation, lentiviral transduction in HPCs, and the calcium influx assay. RESULTS: OCT directly upregulated the transcription of Dcx in HPCs via activation of peroxisome proliferator-activated receptor α (PPARα), a lipid-lowering transcription factor. We observed that, HPCs of Ppara-null mice displayed significant impairment in DCX expression and neuronal differentiation as compared to that of wild-type mice. Interestingly, treatment with OCT stimulated the differentiation process of HPCs in wild-type, but not Ppara-null mice. Reconstruction of PPARα in mouse Ppara-null HPCs restored the expression of DCX, which was further stimulated with OCT treatment. In contrast, a dominant-negative mutant of PPARα significantly attenuated the stimulatory effect of OCT on DCX expression and suppressed neuronal differentiation of human neural progenitor cells. Furthermore, RNA microarray, STRING, chromatin immunoprecipitation, site-directed mutagenesis, and promoter reporter assay have identified DCX as a new target of PPARα. CONCLUSION: These results indicate that OCT, a sleep supplement, directly controls the expression of DCX and suggest that OCT may be repurposed for stimulating the hippocampal neurogenesis.

Upregulation of IL-1 Receptor Antagonist by Aspirin in Glial Cells via Peroxisome Proliferator-Activated Receptor-Alpha.

BACKGROUND: Neuroinflammation is a recognized aspect of Alzheimer's disease (AD) and other neurological illnesses. Interleukin 1 receptor antagonist (IL-1Ra) is an anti-inflammatory molecule, which inhibits inflammatory molecules in different cells including brain cells. However, mechanisms for upregulating IL-1Ra in brain cells are poorly understood. OBJECTIVE: Since aspirin is a widely available pain reliever that shows promise beyond its known pain-relieving capacity, we examined whether aspirin could upregulate the IL-1Ra in the brain. METHODS: We employed PCR, real-time PCR, western blot, immunostaining, chromatin immunoprecipitation (ChIP), and lentiviral transduction in glial cells. 5xFAD mice, an animal model of AD, were treated with aspirin orally via gavage. RESULTS: Aspirin increased the expression of IL-1Ra mRNA and protein in primary mouse astrocytes and mouse BV-2 microglial cells. While investigating the mechanism, we found that the IL-1Ra gene promoter harbors peroxisome proliferator response element (PPRE) and that aspirin upregulated IL-1Ra in astrocytes isolated from peroxisome proliferator-activated receptor-beta knockout (PPARß-/-), but not PPARα-/-, mice. Moreover, we observed that aspirin bound to tyrosine 314 residue of PPARα to stimulate IL-1Ra and that aspirin treatment also increased the recruitment of PPARα to the IL-1Ra promoter. Accordingly, aspirin increased IL-1Ra in vivo in the brain of wild type and PPARß-/-, but not in PPARα-/- mice. Similarly, aspirin treatment also increased astroglial and microglial IL-1Ra in the cortex of 5xFAD, but not 5xFAD/PPARα-/- mice. CONCLUSION: Aspirin may reduce the severity of different neurological conditions by upregulating IL-1Ra and reducing the inflammation.