Background Oocyte activation deficiency (OAD) is attributed to the majority of cases underlying failure of intracytoplasmic sperm injection (ICSI) cycles, the standard treatment for male factor infertility. Oocyte activation encompasses a series of concerted events, triggered by sperm-specific phospholipase C zeta (PLCζ), which elicits increases in free cytoplasmic calcium (Ca2+) in spatially and temporally specific oscillations. Defects in this specific pattern of Ca2+ release is directly attributable to most cases of OAD. Ca2+ release can be clinically mediated via assisted oocyte activation (AOA), a combination of mechanical, electrical and/or chemical stimuli which artificially promote an increase in the levels of intracytoplasmic Ca2+. However, concerns regarding safety and efficacy underlie potential risks that must be addressed before such methods can be safely widely used. Objective and Rationale Recent advances in current AOA techniques warrant a review of the safety and efficacy of these practices, to determine the extent to which AOA may be implemented in the clinic. Importantly, the primary challenges to obtaining data on the safety and efficacy of AOA must be determined. Such questions require urgent attention before widespread clinical utilisation of such protocols can be advocated. Search Methods A literature review was performed using databases including PubMed, Web of Science, Medline etc. using assisted oocyte activation, oocyte activation deficiency, calcium ionophores, intra-cytoplasmic sperm injection, phospholipase c zeta, oocyte activation, failed fertilisation, and fertilisation failure as keywords. Relevant articles published until June 2019 were analysed and included in the review, with an emphasis on studies assessing large scale efficacy and safety. Outcomes Contradictory studies on the safety and efficacy of AOA do not yet allow for the establishment of AOA as standard practice in the clinic. Heterogeneity in study methodology, inconsistent sample inclusion criteria, non-standardised outcome assessments, restricted sample size and animal model limitations render AOA strictly experimental. The main scientific concern impeding AOA utilisation in the clinic is the non-physiological method of Ca2+ release mediated by most AOA agents, coupled with a lack of holistic understanding regarding the physiological mechanism(s) underlying Ca2+ release at oocyte activation. Limitations, reasons for caution The number of studies with clinical relevance using AOA remains significantly low. A much wider range of studies examining outcomes using multiple AOA agents are required. Wider Implications In addition to addressing the five main challenges of studies assessing AOA safety and efficacy, more standardized, large-scale, multi-centre studies of AOA, as well as long term follow-up studies of children born from AOA, would provide evidence for establishing AOA as a treatment for infertility. The delivery of an activating agent that can more accurately recapitulate physiological fertilisation, such as recombinant PLCζ, is a promising prospect for the future of AOA. Further to PLCζ, many other avenues of physiological oocyte activation also require urgent investigation to assess other potential physiological avenues of AOA. Study Funding/Competing Interests DG was supported by Stanford University’s Bing Overseas Study Program. JK was supported by a Healthcare Research Fellowship Award (HF-14-16) made by Health and Care Research Wales (HCRW), alongside a National Science, Technology, and Innovation plan (NSTIP) project grant (15-MED4186-20) awarded by the King Abdulaziz City for Science and Technology (KACST). The authors have no competing interests to declare. Lay Summary At fertilisation, oocyte activation is triggered by sperm-specific phospholipase C zeta (PLCζ) by releasing calcium in specific patterns within the oocyte. A deficiency in this process underlies most cases of fertilisation failure in mammals. This process of calcium release can be clinically mimicked via assisted oocyte activation (AOA), involving a combination of mechanical, electrical and/or chemical stimuli. Recent advances in AOA techniques warrant a review of the safety and efficacy of these practices and of how AOA may be clinically implemented in the clinic. Herein, following a detailed literature review examining studies assessing large scale efficacy and safety, the main concern impeding clinical AOA implementation is its non-physiological nature, coupled with a lack of holistic understanding of physiological mechanism(s) underlying calcium release at fertilisation. We find that numerous questions require urgent attention before widespread clinical utilisation of such protocols can be advocated. We hope that this article will be able to aid the burgeoning number of researchers investigating the clinical efficacy of such methodology in further refining the practice until large scale utilisation can be achieved and accepted.
Background/Objectives We provide global averages and standard deviations for ocular biometry—axial length (AL), corneal radius of curvature (CR), anterior chamber depth (ACD), lens thickness (LT), white to white (WTW), and central corneal thickness (CT). We hope a better understanding of normal and abnormal values will help clinicians gain further insight into their surgical outcomes, especially for off-target eyes. Subjects/Methods We searched the MEDLINE database using keywords “axial length, corneal power, anterior chamber depth, lens thickness, white to white, and corneal thickness.” We included studies that reported averages and standard deviations on eye biometry for at least 1300 eyes. Global weighted averages and standard deviations were calculated using the Cochrane method. Results Fourteen studies were included, originating from Asia (Japan, Singapore, Myanmar, Iran, South Korea, China), Europe (Germany, United Kingdom, Portugal), Australia, and North America (United States). Global ocular biometry metrics were: AL—23.49 mm ± 1.35 mm, CR—7.69 mm ± 0.28 mm, ACD—3.10 mm ± 0.47 mm, WTW—11.80 mm ± 0.42 mm, LT—4.37 mm ± 0.43 mm, and CT—544 μm ± 38 μm. Total eyes per value ranged from 19,538 to 90,814. Conclusions We report global ocular biometry averages and standard deviations. No eyes were from studies in Africa or South America, highlighting the need to publish eye biometry data from these continents. We hope that promoting a deeper understanding of biometry values will help clinicians gain insight into surgical outcomes and drive innovations in lens calculations.
We report a case of a child with secondary open-angle glaucoma who developed 6.5 diopters (D) of corneal flattening upon the addition of Rhopressa (0.02% netarsudil dimesylate solution) eye drops to a preexisting treatment regimen of timolol and latanoprost. This change in corneal power reversed after netarsudil, a rho-kinase inhibitor, was discontinued and replaced with Vyzulta (0.024% latanoprostene bunod ophthalmic solution). The 4-year-old female patient presented with bilateral secondary open-angle glaucoma from Paired Box 6 (PAX6)-related aniridia, aphakia, and persistent fetal vasculature. She was started on netarsudil to treat elevated intraocular pressure (IOP) in her right eye, which was not adequately controlled by latanoprost and timolol. Over 4 months, she developed 6.5D of corneal flattening in her right eye. Netarsudil was stopped and the corneal flattening reversed. There is evidence to support the ability of rho kinase inhibitors to increase the healing of the corneal endothelium in addition to their intended IOP-lowering effects. Rho kinase inhibitors may increase cell proliferation and adhesion within the corneal endothelium, hence decreasing apoptosis and promoting cell preservation. If there was an excess of cell proliferation; however, this might induce stromal cells to abnormally secrete enzymes or proteins, such as TGFβ-induced proteins. This could result in corneal fibrosis, thereby flattening the cornea. Further investigation is required to explore this phenomenon and elucidate its mechanism of action. Corneal flattening may be considered as a potential side effect of the use of netarsudil, particularly in young pediatric patients.
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