The regulatory landscape of biosimilars: Algeria's efforts and progress made from 2006 to 2021.

Biologics are tremendously efficacious biological molecules that have enabled the treatment of many life-threatening diseases, which have previously been hard to treat. Biosimilars, also known as "follow-on biologics", are highly similar versions of another already approved biologic, called the Reference Product. The European Union has been a pioneer in the regulation of biosimilars. WHO guideline on evaluation of biosimilars published in 2009 was an important landmark in biosimilar regulations worldwide, and several countries have adopted its principles in the development of their own regulatory pathway for the approval of biosimilars. Most countries in the Middle East North Africa (MENA) region still lack official and scientific guidelines for biosimilar approval pathways. This article explores the regulatory situation of biosimilar registration pathways in Algeria and describes the progress made and the regulatory landscape changes for biosimilars in Algeria during the past ten years. Our findings indicate that the development of biosimilar regulation in Algeria went through three major phases between 2006 and 2021, during which there has been much progress in drafting guidance documents for biosimilars. Since 2016, Algeria has used the EMA, FDA and WHO guidelines as the basis for approval of several biosimilars and no national guidelines or regulations have been adopted to date. Additionally, there has been no regulation on substitution/interchangeability. The Algerian regulatory authority has gained considerable experience with approval and use of increasingly complex biosimilars over the past 5 years and has the potential to create its own biosimilar-specific regulatory pathway in the near future.

Cytosolic expression of functional Fab fragments in Escherichia coli using a novel combination of dual SUMO expression cassette and EnBase® cultivation mode.

AIMS: The Escherichia coli expression system is highly effective in producing recombinant proteins. However, there are some limitations in this system, especially in obtaining correctly folded forms of some complex proteins such as Fab fragments. To improve the solubility and folding quality of Fab fragments, we have examined the effect of simultaneous application of a SUMO fusion tag, EnBase® cultivation mode and a redox mutant strain in the E. coli expression system. METHODS AND RESULTS: A bicistronic gene construct was designed to express an antivascular endothelial growth factor (VEGF) Fab fragment as a model system. The construct contained a dual SUMO fusion gene fragment to encode SUMO-tagged heavy and light chains. While the expression of the construct in batch cultures of BL21 or SHuffle® transformants produced insoluble and unfolded products, the induction of the transformants in EnBase® medium resulted in soluble and correctly folded Fab fragment, reaching as high as 19% of the total protein in shuffle strain. The functional assays indicated that the biological activity of the target Fab is similar to the commercial anti-VEGF, Lucentis® . CONCLUSIONS: This study demonstrated that the combination of SUMO fusion technology, EnBase® cultivation system and recruiting a redox mutant of E. coli can efficiently enhance the solubility and productivity of recombinant Fab fragments. SIGNIFICANCE AND THE IMPACT OF THE STUDY: The presented strategy provides not only a novel method to produce soluble and active form of an anti-VEGF Fab but also may use in the efficient production of other antibody fragments.

Dark Adaptation in Patients with Primary Open-Angle Glaucoma, Pseudoexfoliation Glaucoma and Childhood Glaucoma.

Purpose To investigate the state of dark adaptation and macular blood flow in different forms of glaucoma. Methods Eighteen eyes of 18 patients with primary open-angle glaucoma, 14 eyes of 14 patients with pseudoexfoliation glaucoma, and 10 eyes of 10 patients with childhood glaucoma (CG) were examined by means of dark adaptometry, scanning-laser retinal flowmetry, and retinal tomography. Results All glaucomatous eyes had comparable optic disc excavation (one-way ANOVA, p = 0.138). Eyes with CG had significantly lower best-corrected visual acuity than the other groups (Tukey, all p < 0.0001). Macular perfusion was comparable in all three groups (one - way ANOVA, p = 0.08). The delay in rod-cone break time in the CG group was significantly higher than in the other groups (Tukey, all p < 0.0001). The scotopic sensitivity threshold in the CG group was significantly greater than in the other groups (Tukey, all p < 0.01). Conclusion This underlying dysfunction of dark adaptation may contribute, at least to some extent, to the decreased visual perception observed in patients with CG.

A randomized phase II trial of doxorubicin plus pemetrexed followed by docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant treatment of early breast cancer.

BACKGROUND: Neoadjuvant systemic therapy (NST) before surgery is a standard option for patients with early breast cancer (EBC) that allows in vivo chemosensitivity testing. Given the promising activity of pemetrexed plus doxorubicin in metastatic breast cancer, it was reasonable to evaluate the utility of this combination as part of an NST regimen in EBC. PATIENTS AND METHODS: Patients with untreated operable T2-T4a-c N0-2 M0 breast cancer were randomly assigned to receive either four cycles of pemetrexed 500 mg/m(2) plus doxorubicin 60 mg/m(2) every 3 weeks (q3w) followed by four cycles of docetaxel 100 mg/m(2) q3w (AP-D) or four cycles of doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) q3w followed by four cycles of docetaxel 100 mg/m(2) q3w (AC-D). Surgery was carried out within 2 months after last chemotherapy. Primary end point was pathological complete response (pCR) rate in the breast. Secondary end points included clinical response rate, rate of histologically negative axillary lymph nodes, toxicity, and disease-free survival. RESULTS: From September 2005 to August 2007, 257 patients were randomly allocated to 17 sites. Median age was 48 and 49 years for AP-D and AC-D, respectively. Overall pCR rates were 16.5% for AP-D and 20.2% for AC-D. With AP-D, pCR rate was 17.8% for hormone receptor (HR)-negative patients and 15.9% for HR-positive patients. With AC-D, pCR rates were 42.9% and 7.8% for HR-negative and HR-positive patients, respectively. Clinical response rates were 59.5% in the AP-D group and 68.1% in the AC-D group. The rate of histologically negative axillary lymph nodes was 53% in both groups. Both treatments were well tolerated. Median disease-free survival is currently not mature. CONCLUSIONS: AP-D and AC-D are well tolerated and active as NST in EBC. Of note, AC-D had a higher pCR rate in HR-negative tumors, whereas AP-D had more activity if HRs were expressed.

Granulomatous uveitis and congenital cataract: a rare association.

INTRODUCTION: The association of a granulomatous uveitis and congenital cataract and is rarely observed in newborn children. We describe the history of two patients presenting simultaneously with these two features in the absence of a TORCH infection. PATIENTS AND METHODS: The first patient, a boy born in 1997, presented to our hospital two days after birth with multiples Koeppe's and Busacca's nodules and bilateral cataract. The second patient, a boy born in 2006, was referred two weeks after birth. He presented with a severe unilateral granulomatous uveitis, multiples iris nodules, a high intraocular pressure of 45 mmHg and a congenital cataract. THERAPY AND OUTCOME: Lens extraction produced a rapid resolution of uveitis in these two patients. TORCH infection was ruled out in both children by history, extensive serologies performed simultaneously in mother and child or PCR of ocular fluids. CONCLUSIONS: A congenital cataract associated with a granulomatous uveitis is an extremely rare association. The removal of the lens resulted in complete resolution of the inflammation: a phacogenic mechanism could be at the origin of ocular inflammation in both cases.

The correlation between Modified Ashworth Scale scores and the new index of alpha motoneurones excitability in post-stroke patients.

The Modified Ashworth Scale (MAS) is currently a widely used clinical scale to evaluate muscle spasticity. However, it lacks reliability and the validity, of the MAS as a clinical measure of muscle spasticity has been challenged. The aim of the present study was to examine the validity of the MAS in patients with wrist flexor spasticity after stroke by using the Hslope/Mslope (Hslp/Mslp) ratio as the new index of alpha motoneuron excitability. Twenty-seven adult patients (14 women and 13 men) with first ever stroke resulting in hemiplegia with a mean (SD, range) age of 57.9 (11.6, 37-75) were included in the study. The main outcome measures were the MAS for the clinical assessment of spasticity, and the Hslp/Mslp for the neurophysiological evaluation. There was not a significant correlation between the MAS scores and Hslp/Mslp ratio (r = 0.38, p > 0.05). The mean of the Hslp/Mslp did not show a hierarchical increase with the MAS scores. The findings indicate that the MAS is not a valid and ordinal level measure of muscle spasticity.

Neurophysiological examination of the Modified Modified Ashworth Scale (MMAS) in patients with wrist flexor spasticity after stroke.

The Modified Modified Ashworth Scale (MMAS) is a clinical test for the measurement of spasticity. The aim of the present study was to examine the validity of the MMAS in patients with wrist flexor spasticity after stroke. 27 adult patients (14 women and 13 men) with first ever stroke resulting in hemiplegia with a mean (SD, range) age of 57.9 (11.6, 37-75) were included in the study. The outcome measures were the MMAS for the clinical assessment of spasticity, the Hslope/Mslope (Hslp/Mslp), and the H(max)/M(max) ratio for the neurophysiological evaluation. The mean of the Hslp/Mslp and the H(max)/M(max) were higher in patients with worse MMAS grades but the differences were not statistically significant. There was a significant positive correlation between the MMAS scores and Hslp/Mslp ratio as the new index of alpha motoneurone excitability or traditional index of H(max)/M(max) ratio (r = 0.39, p = 0.04). It is concluded that the MMAS to be a valid measure of spasticity after stroke.

A preliminary study into the criterion validity of the Modified Modified Ashworth Scale using the new measure of the alpha motoneuron excitability in spastic hemiplegia.

The Modified Ashworth Scale (MAS) is the most widely used clinical test for the measurement of muscle spasticity. This scale that suffers from limitations and lack of reliability and validity has recently been remodified. The aim of the present study is to investigate the criterion validity of the new Modified MAS(MMAS) in the upper limb in post-stroke hemiplegia, using the Hslope/Mslope (Hslp/Mslp) as a novel index of alpha motor neuron excitability. Prior to the validity study, the reliability of the MMAS was evaluated in 30 hemiplegic patients. The raters agreed on 23 patients (0. 76%). The MMAS had good inter-rater reliability (K= 0.63, SE = 0.11, p < 0.001) for the assessment of wrist flexors spasticity in hemiplegic patients. 12 adult patients (7 women and 5 men) with first ever stroke resulting in hemiplegia with a mean age of 58.9 +/- 11.9 years (range, 37-73) were included in the validity study. The outcome measures were the MMAS for the clinical assessment of spasticity, and the HslopelMslope and the Hmax/Mmax ratio for the electrophysiological evaluation. The results showed an increase in mean rank of Hslp / Mslp in patients with a score of 1, 2 or 3 on the MMAS. However, the difference among the groups was not significant (p > 0.05). There was also no relationship between the clinical scale of MMAS and either the traditional [Hmax / Mmax ratio (r = -0.06)] or the new index [Hslp / Mslp (r = 0.24)] of spinal excitability. This preliminary study recruited a small number of patients, and failed to confirm a linear correlation between these variables. A study with a large number of patients is suggested to clarify the outcome.

All-trans retinoic acid preconditioning enhances proliferation, angiogenesis and migration of mesenchymal stem cell in vitro and enhances wound repair in vivo.

OBJECTIVES: Stem cell therapy is considered to be a suitable alternative in treatment of a number of diseases. However, there are challenges in their clinical application in cell therapy, such as to reduce survival and loss of transplanted stem cells. It seems that chemical and pharmacological preconditioning enhances their therapeutic efficacy. In this study, we investigated effects of all-trans retinoic acid (ATRA) on survival, angiogenesis and migration of mesenchymal stem cells (MSCs) in vitro and in a wound-healing model. MATERIALS AND METHODS: MSCs were treated with a variety of concentrations of ATRA, and mRNA expression of cyclo-oxygenase-2 (COX-2), hypoxia-inducible factor-1 (HIF-1), C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 2 (CCR2), vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and Ang-4 were examined by qRT-PCR. Prostaglandin E2 (PGE2) levels were measured using an ELISA kit and MSC angiogenic potential was evaluated using three-dimensional tube formation assay. Finally, benefit of ATRA-treated MSCs in wound healing was determined with a rat excisional wound model. RESULTS: In ATRA-treated MSCs, expressions of COX-2, HIF-1, CXCR4, CCR2, VEGF, Ang-2 and Ang-4 increased compared to control groups. Overexpression of the related genes was reversed by celecoxib, a selective COX-2 inhibitor. Tube formation and in vivo wound healing of ATRA-treated MSCs were also significantly enhanced compared to untreated MSCs. CONCLUSION: Pre-conditioning of MSCs with ATRA increased efficacy of cell therapy by activation of survival signalling pathways, trophic factors and release of pro-angiogenic molecules.

An automated curation procedure for addressing chemical errors and inconsistencies in public datasets used in QSAR modelling.

The increasing availability of large collections of chemical structures and associated experimental data provides an opportunity to build robust QSAR models for applications in different fields. One common concern is the quality of both the chemical structure information and associated experimental data. Here we describe the development of an automated KNIME workflow to curate and correct errors in the structure and identity of chemicals using the publicly available PHYSPROP physicochemical properties and environmental fate datasets. The workflow first assembles structure-identity pairs using up to four provided chemical identifiers, including chemical name, CASRNs, SMILES, and MolBlock. Problems detected included errors and mismatches in chemical structure formats, identifiers and various structure validation issues, including hypervalency and stereochemistry descriptions. Subsequently, a machine learning procedure was applied to evaluate the impact of this curation process. The performance of QSAR models built on only the highest-quality subset of the original dataset was compared with the larger curated and corrected dataset. The latter showed statistically improved predictive performance. The final workflow was used to curate the full list of PHYSPROP datasets, and is being made publicly available for further usage and integration by the scientific community.

Childhood Pre-B acute lymphoblastic leukemia and glutathione S-transferase omega 1 and 2 polymorphisms.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy among children and makes up 23% of total childhood cancers worldwide. Pre-B ALL is one of the most common ALLs, comprising about 80% of childhood cases. A variety of genes are involved in metabolizing carcinogens. These gene polymorphisms can result in less efficient or overly-down metabolic pathways, which may contribute to the susceptibility to develop cancer. Glutathione S-transferase omega (GSTO) is a new known class among GSTs superfamily. GSTO1 and GSTO2 polymorphisms have been reported to be related to several types of disease. We assessed the association between GSTO1 and GSTO2 polymorphisms and childhood pre-B ALL risk in Iran. METHODS: This case-control study analyzed GSTO1 A140D (rs. 4925) and GSTO2 N142D (rs. 156697) gene polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism method, in 100 patients and 120 healthy controls. RESULTS: The genotype frequencies were not significantly different between patients and healthy controls. Odds ratio (95% confidence intervals) for mutant homozygotes were 1.54 (0.628-3.778) and 0.791 (0.349-1.793) for GSTO1 A140D and GSTO2 N142D, respectively. CONCLUSION: This study found no significant association between Pre-B ALL and GSTO1 A140D and GSTO2 N142D polymorphisms.

Deferoxamine preconditioning to restore impaired HIF-1α-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats.

OBJECTIVES: Both excessive and insufficient angiogenesis are associated with progression of diabetic complications, of which poor angiogenesis is an important feature. Currently, adipose-derived stem cells (ADSCs) are considered to be a promising source to aid therapeutic neovascularization. However, functionality of these cells is impaired by diabetes which can result from a defect in hypoxia-inducible factor-1 (HIF-1), a key mediator involved in neovascularization. In the current study, we sought to explore effectiveness of pharmacological priming with deferoxamine (DFO) as a hypoxia mimetic agent, to restore the compromised angiogenic pathway, with the aid of ADSCs derived from streptozotocin (STZ)-induced type 1 diabetic rats ('diabetic ADSCs'). MATERIALS AND METHODS: Diabetic ADSCs were treated with DFO and compared to normal and non-treated diabetic ADSCs for expression of HIF-1α, VEGF, FGF-2 and SDF-1, at mRNA and protein levels, using qRT-PCR, western blotting and ELISA assay. Activity of matrix metalloproteinases -2 and -9 were measured using a gelatin zymography assay. Angiogenic potential of conditioned media derived from normal, DFO-treated and non-treated diabetic ADSCs were determined by in vitro (in HUVECs) and in vivo experiments including scratch assay, three-dimensional tube formation testing and surgical wound healing models. RESULTS: DFO remarkably enhanced expression of noted genes by mRNA and protein levels and restored activity of matrix metalloproteinases -2 and -9. Compromised angiogenic potential of conditioned medium derived from diabetic ADSCs was restored by DFO both in vitro and in vivo experiments. CONCLUSION: DFO preconditioning restored neovascularization potential of ADSCs derived from diabetic rats by affecting the HIF-1α pathway.

Streptomycin biosynthesis and its regulation in Streptomycetes.

New insights into the gene orders, structures, evolution, and functions of streptomycin (Sm) biosynthetic genes (str) were gained via hybridization studies, determination of nucleotide sequences, and measurement of expression in the str gene clusters of Streptomyces griseus and S. glaucescens. Both str clusters showed considerable divergence in macro and micro structure. Genes putatively involved in pathways leading to the (dihydro-)streptose and N-methyl-L-glucosamine moieties of Sm were identified. Additional regulatory elements, such as gene strS and conserved TTA codons in the N-terminal sections of reading frames, are reported. Evidences for the involvement of physiological state, signal transduction, and activators in the control of Sm production are presented.

The reactions of patients and doctors in the united arab emirates towards smoking.

One hundred male U.A.E. nationals (50 smokers and 50 non-smokers) rated their own risk for developing heart disease, developing arthritis and having an automobile accident; and the risks facing the average smoker and average non-smoker. Smokers in the U.A.E., like smokers in the U.K., exhibited "constrained optimism." Non-smokers, unlike non-smokers in the U.K., were "pessimistic" about their chances of developing heart disease and having an accident. Eighty-two male doctors, 41 smokers and 41 non-smokers, were asked to respond to two hypothetical patients (one with long-term obesity newly diagnosed as being hypertensive, the other a long-term smoker newly diagnosed as having lung cancer). Compared with smoker doctors, doctors who themselves did not smoke expected to feel more uncomfortable when managing the smoker patient, and perceived him as more responsible for his condition. Possible reasons for these results, their implications and ways of pursuing the issues raised are discussed.

Molecular aspect on the interaction of zinc-ofloxacin complex with deoxyribonucleic acid, proposed model for binding and cytotoxicity evaluation.

Recently, several studies have shown that the metal-fluoroquinolone complexes have more antibacterial and cytotoxic effects in comparison with free fluoroquinolones. These results may introduce new drugs for chemotherapy with fewer side effects. In this work a bidentated zinc (II) complex with ofloxacin (OZC) was synthesized and cytotoxicity activities and DNA binding of the resulted complex was studied. The in-vitro anti proliferative and cytotoxic effects of the free ofloxacin (OFL) and OZC against MCF-7, CaCo2 and SKNMC cell lines were tested by using Trypan blue and lactate dehyrogenase (LDH) assay methods. Results revealed that the OZC exhibits better anti proliferative and cytotoxic activities as compared with the OFL. This may be due to the more interaction of OZC with DNA. Therefore, the interaction of OZC with DNA was investigated by using voltammetry, UV-Vis, fluorescence, FT-IR and circular dichroism spectroscopy methods, and the equilibrium binding constant (Kb), binding site size, and thermodynamic parameters were measured. The results revealed that the OZC interacts with DNA via two modes: electrostatic and outside hydrogen binding. The proposed DNA binding modes may support the greater in-vitro cytotoxicity of OZC compared to OFL alone.

Continuous 24-hour intraocular pressure monitoring for glaucoma--time for a paradigm change.

Glaucoma is the main cause of irreversible blindness and intraocular pressure (IOP) is its only modifiable risk factor. The importance of robust lowering of IOP for prevention of glaucoma onset and progression is well established. Although IOP is a dynamic parameter with individual circadian rhythms, current management usually relies on single IOP measurements during regular clinic hours performed a few times a year. Recent technological advances have provided clinicians with tools for continuous IOP monitoring during a 24 hour period in an ambulatory setting. There are two approaches being investigated. The first is permanent IOP monitoring through an implantable sensor and the other is temporary monitoring through a contact lens sensor. In this article, we discuss the shortcomings of the current gold standard for tonometry (Goldmann Applanation Tonometry) and the current experience with the first commercially available continuous 24 hour IOP monitoring technology (SENSIMED Triggerfish®); a telemetric contact lens sensor produced by a Swiss start-up company (Sensimed AG, Lausanne, Switzerland). Recent studies suggest that 24 hour continuous monitoring of IOP can be integrated into clinical practice and have the potential to contribute to the reduction of glaucoma-related vision loss.

Proliferation and differentiation potential of cryopreserved human skin-derived precursors.

OBJECTIVES: Skin-derived precursors are recognized to be a potentially autologous and accessible source of neural precursor cells for drug screening or cell-based treatments, in many neurological disorders. Thus, it is necessary to investigate appropriate methods for cryopreservation of such human skin-derived precursors (hSKPs). The aim of this study was to evaluate different cryopreservation techniques for retention of hSKPs to discover an optimized protocol. MATERIALS AND METHODS: We cryopreserved hSKPs treated with 0%, 10%, 20%, 30% and 40% foetal bovine serum (FBS) and three concentrations of dimethylsulphoxide (DMSO) 5%, 10% and 15%, with two different storage periods in liquid nitrogen (2 days: short-term storage; and 2 months: long-term storage). Then, we assessed survival and proliferation levels of the cells after freeze-thaw processes, by viability measurement and colony-forming assay. For detecting hSKPs, we used immunocytochemistry and RT-PCR assessments. RESULTS: Our findings indicated that hSKPs cryopreserved in 5% DMSO without FBS, had better survival and proliferation potentials compared to other working formulations. With various concentrations of cryoprotectants over different time periods, hSKPs retained their differentiation potentiality and were able to differentiate into neurons (NFM and ßΙΙΙ tubulin-positive), glial cells (GFAP-positive) and smooth muscle cells (SMA-positive). CONCLUSIONS: Results revealed that in only 5% DMSO, hSKPs could be cryopreserved for long-term storage with considerable survival and proliferation levels, without losing multipotency.

Reconditioning of the trabeculo-descemet's membrane with the 532-nm Nd : YAG (SLT) laser after deep sclerectomy.

The purpose of this study was to evaluate the intraocular pressure (IOP)-lowering effect of modified goniopuncture with the 532-nm Nd : YAG selective laser trabeculoplasty (SLT) laser on eyes after deep sclerectomy with collagen implant (DSCI). This was an interventional cased series. The effects of modified goniopuncture on eyes with insufficient IOP-lowering after DSCI were observed. Goniopuncture was performed using a Q-switched, frequency-doubled 532-nm Nd : YAG laser (SLT-goniopuncture, SLT-G). Outcome measures were amount of IOP-lowering and rapidity of decrease after laser intervention. In all, 10 eyes of 10 patients with a mean age of 71.0±7.7 (SD) years were treated with SLT-G. The mean time of SLT-G after DSCI procedure was 7.1±10.9 months. SLT-G decreased IOP from an average of 16.1±3.4 mm Hg to 14.2±2.8 mm Hg (after 15 min), 13.6±3.9 mm Hg (at 1 day), 12.5±4.1 mm Hg (at 1 month), and 12.6±2.5 (at 6 months) (P<0.0125). There were no complications related to the intervention. Patients in this series achieved an average 22.5% of IOP reduction after SLT-G. The use of the SLT laser appears to be an effective and safe alternative to the traditional Nd : YAG laser for goniopuncture in eyes after DSCI, with potential advantages related to non-perforation of trabeculo-descemet's membrane (TDM).

Assessment of rates of structural change in glaucoma using imaging technologies.

PURPOSE: To review the ability of current imaging technologies to provide estimates of rates of structural change in glaucoma patients. PATIENTS AND METHODS: Review of literature. RESULTS: Imaging technologies, such as confocal scanning laser ophthalmoscopy (CSLO), scanning laser polarimetry (SLP), and optical coherence tomography (OCT), provide quantifiable and reproducible measurements of the optic disc and parapapillary retinal nerve fibre layer (RNFL). Rates of change as quantified by the rim area (RA) (for CSLO) and RNFL thickness (for SLP and OCT) are related to glaucoma progression as detected by conventional methods (eg, visual fields and optic disc photography). Evidence shows that rates of RNFL and RA loss are significantly faster in progressing compared with non-progressing glaucoma patients. CONCLUSION: Measurements of rates of optic disc and RNFL change are becoming increasingly precise and individualized. Currently available imaging technologies have the ability to detect and quantify progression in glaucoma, and their measurements may be suitable end points in glaucoma clinical trials.