Benefits and risks of orthokeratology treatment: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis reviews the evidence for the risks and benefits associated with orthokeratology (OK) treatment compared with other methods of myopia control in children and adults. METHODS: A systematic search of Cochrane Central Register of Controlled Trials, Pubmed, Embase and Ovid was conducted from database inception to 22nd August 2021. Studies that reported on risks, visual and ocular biometric effects of OK in patients > 5 years of age with myopia (- 0.75 to - 6.00D) were included. Main outcomes are change in axial length and any adverse event. RESULTS: Fourty-five papers were included in this systematic review and meta-analysis. The quality of data was variable and of moderate certainty, and selection bias likely skewed the results towards a relative benefit for OK. The rate of axial elongation in children was lower for OK treatment compared to other treatment modalities at one year (MD - 0.16 mm, 95% CI - 0.25 to - 0.07). Rate of change in axial length in children rebounded after OK discontinuation compared to participants who continued treatment (MD 0.10 mm, 95% CI 0.06 to 0.14). Adults and children wearing OK were up to 3.79 times more likely to experience an adverse event when compared with conventional contact lenses (OR 3.79, 95% CI 1.24 to ll.), though this evidence base is underdeveloped and requires additional well-designed studies for substantial conclusions to be drawn. CONCLUSIONS: OK arrests myopia progression while in use, however, there remain unanswered questions about the optimal duration of treatment, discontinuation effects and long-term risk for adverse events.

Determining the learning curve for a novel microsurgical procedure using histopathology.

PURPOSE: Wet laboratories are becoming an increasingly important training tool as part of a push to a proficiency-based training model. We created a microsurgical wet laboratory to investigate the utility of histopathology use in assessing surgical outcomes and determine the learning curve of a novel microsurgical procedure. METHODS: A microsurgical wet laboratory was established using pig eyes to simulate the human cornea. Three novice surgeons and an experienced surgeon performed an anterior cornea lamellar dissection and the duration of the procedure was recorded. With the aid of histological analysis, the thickness and characteristics of the dissected graft was recorded. The number of attempts to complete the experiment, defined as three successful dissections with mean thickness below 100 µm, was documented. RESULTS: The use of histopathology was highly successful allowing in-depth analysis of the dissected graft for each attempt. Trainees reached the endpoint of the study in 21, 26 and 36 attempts (mean: 28 attempts) whilst the corneal surgeon completed the experiment in 12 attempts (p = 0.07). Mean dissection thickness decreased over time for all participants. The mean dissection time for trainees was 10.6 ± 4.2 min compared to the corneal surgeon with a mean of 8.2 ± 3.1 min (p = 0.03). CONCLUSION: We propose a corneal wet laboratory model that allows for simple, efficient, and flexible microsurgical training. The use of histopathological analysis allows for careful graft analysis, providing objective feedback throughout the training exercise. Trainees demonstrated improvements in the three key aspects of the procedure: accuracy as evidenced by decreasing histological thickness, confidence by self-report and fluidity by decreasing duration of the procedure.

Open globe injuries: Epidemiology, visual and surgical predictive variables, prognostic models, and economic cost analysis.

BACKGROUND: Open globe injuries (OGI) represent a visually and economically devastating cause of vision loss. We examined the epidemiology, predictive variables, prognostic models, and economic cost of surgically managed OGI. METHODS: A retrospective tertiary centre study from 2008 to 2018 of 155 consecutive OGI in individuals aged 16 and older was performed. Medical records review, application of Ocular Trauma Score (OTS) and Classification and Regression Tree Analysis (CART) and cost analysis were undertaken. Key outcomes measured were visual acuity, number of operating theatre visits, prognostication using OTS and CART and estimated costs. RESULTS: Younger males at work with inadequate protective eyewear (89.1%) and falls in the elderly were overrepresented. Inferior visual outcomes were associated with a more severe OTS score, a larger injury zone, increasing age, the presence of retinal detachment, extraocular muscle involvement, intraocular foreign body, and globe rupture (R2  = 0.723, p < 0.001). Multiple operating theatre visits were required in the presence of retinal detachment, lens or orbit involvement, work-related injury, globe rupture, and a history of previous intraocular surgery (R2  = 0.0423, p < 0.001). Both OTS and CART prognosticated outcomes (p < 0.001). The OTS predicted for no vision (no light perception/enucleation/evisceration) and profound visual loss (worse than 6/120; specificity: both 100%, sensitivity: 88.2% and 88%) whereas the CART predicted for visual survival (light perception or better) and minimal-to-severe visual loss (6/120 or better; specificity: 88.5% and 81.7% , sensitivity: 97.7% and 100%). Estimated annual OGI cost for Australia was AUD48.1-60.5 million (USD37.3-47.0 million). CONCLUSIONS: The total cost of OGI is immense with young males and the elderly being disproportionately affected. Implementation of targeted government legislation and public health preventative measures may be cost-effective in ameliorating the significant burden.

Maternal Exposure to Dibutyl Phthalate (DBP) or Diethylstilbestrol (DES) Leads to Long-Term Changes in Hypothalamic Gene Expression and Sexual Behavior.

Xenobiotic exposure during pregnancy and lactation has been linked to perinatal changes in male reproductive outcomes and other endocrine parameters. This pilot study wished to assess whether brief maternal exposure of rats to xenobiotics dibutyl phthalate (DBP) or diethylstilbestrol (DES) might also cause long-term changes in hypothalamic gene expression or in reproductive behavior of the resulting offspring. Time-mated female Sprague Dawley rats were given either DBP (500 mg/kg body weight, every second day from GD14.5 to PND6), DES (125 µg/kg body weight at GD14.5 and GD16.5 only), or vehicle (n = 8-12 per group) and mild endocrine disruption was confirmed by monitoring postnatal anogenital distance. Hypothalamic RNA from male and female offspring at PND10, PND24 and PND90 was analyzed by qRT-PCR for expression of aromatase, oxytocin, vasopressin, ER-alpha, ER-beta, kisspeptin, and GnRH genes. Reproductive behavior was monitored in male and female offspring from PND60 to PND90. Particularly, DES treatment led to significant changes in hypothalamic gene expression, which for the oxytocin gene was still evident at PND90, as well as in sexual behavior. In conclusion, maternal xenobiotic exposure may not only alter endocrine systems in offspring but, by impacting on brain development at a critical time, can have long-term effects on male or female sexual behavior.

Low systemic vitamin D as a potential risk factor in primary open-angle glaucoma: a review of current evidence.

Currently, intraocular pressure is the only modifiable risk factor for glaucoma; thus, identifying other modifiable determinants may have far-reaching outcomes. There has been increasing interest in vitamin D status and glaucoma pathogenesis as low vitamin D has been identified by some studies as an independent risk factor for glaucoma. Although the exact mechanism of vitamin D in glaucoma remains uncertain, there is sufficient evidence to continue research in this area. There is a potential physiological role for vitamin D as an anti-inflammatory agent in the oxidative stress-driven pathogenesis of primary open-angle glaucoma, and further studies are required to evaluate the temporal and causal relationship. Ocular vitamin D status in the tear, aqueous and vitreous fluid is a prospective gap in research.

LiQD Cornea: Pro-regeneration collagen mimetics as patches and alternatives to corneal transplantation.

Transplantation with donor corneas is the mainstay for treating corneal blindness, but a severe worldwide shortage necessitates the development of other treatment options. Corneal perforation from infection or inflammation is sealed with cyanoacrylate glue. However, the resulting cytotoxicity requires transplantation. LiQD Cornea is an alternative to conventional corneal transplantation and sealants. It is a cell-free, liquid hydrogel matrix for corneal regeneration, comprising short collagen-like peptides conjugated with polyethylene glycol and mixed with fibrinogen to promote adhesion within tissue defects. Gelation occurs spontaneously at body temperature within 5 min. Light exposure is not required-particularly advantageous because patients with corneal inflammation are typically photophobic. The self-assembling, fully defined, synthetic collagen analog is much less costly than human recombinant collagen and reduces the risk of immune rejection associated with xenogeneic materials. In situ gelation potentially allows for clinical application in outpatient clinics instead of operating theaters, maximizing practicality, and minimizing health care costs.

The role of reactive oxygen species in the pathogenesis and treatment of retinal diseases.

Reactive oxygen species (ROS) normally play an important physiological role in health regulating cellular processes and signal transduction. The amount of ROS is usually kept in fine balance with the generation of ROS largely being offset by the body's antioxidants. A tipping of this balance has increasingly been recognised as a contributor to human disease. The retina, as a result of its cellular anatomy and physical location, is a potent generator of ROS that has been linked to several major retinal diseases. This review will provide a summary of the role of oxidative stress in the pathogenesis of diabetic retinopathy, age-related macular degeneration, myopia, retinal vein occlusion, retinitis pigmentosa and retinopathy of prematurity. Therapies aimed at controlling oxidative stress in these diseases are also examined.

Late-gestation maternal dietary methyl donor and cofactor supplementation in sheep partially reverses protection against allergic sensitization by IUGR.

Perinatal exposures are associated with altered risks of childhood allergy. Human studies and our previous work suggest that restricted growth in utero (IUGR) is protective against allergic disease. The mechanisms are not clearly defined, but reduced fetal abundance and altered metabolism of methyl donors are hypothesized as possible underlying mechanisms. Therefore, we examined whether late-gestation maternal dietary methyl donor and cofactor supplementation of the placentally restricted (PR) sheep pregnancy would reverse allergic protection in progeny. Allergic outcomes were compared between progeny from control pregnancies (CON; n = 49), from PR pregnancies without intervention (PR; n = 28), and from PR pregnancies where the dam was fed a methyl donor plus cofactor supplement from day 120 of pregnancy until delivery (PR + Methyl; n = 25). Both PR and PR + Methyl progeny were smaller than CON; supplementation did not alter birth size. PR was protective against cutaneous hypersensitivity responses to ovalbumin (OVA; P < 0.01 in singletons). Cutaneous hypersensitivity responses to OVA in PR + Methyl progeny were intermediate to and not different from the responses of CON and PR sheep. Cutaneous hypersensitivity responses to house dust mites did not differ between treatments. In singleton progeny, upper dermal mast cell density was greater in PR + Methyl than in PR or CON (each P < 0.05). The differences in the cutaneous allergic response were not explained by treatment effects on circulating immune cells or antibodies. Our results suggest that mechanisms underlying in utero programming of allergic susceptibility by IUGR and methyl donor availability may differ and imply that late-gestation methyl donor supplementation may increase allergy risk.

Effects of induced placental and fetal growth restriction, size at birth and early neonatal growth on behavioural and brain structural lateralization in sheep.

Poor perinatal growth in humans results in asymmetrical grey matter loss in fetuses and infants and increased functional and behavioural asymmetry, but specific contributions of pre- and postnatal growth are unclear. We therefore compared strength and direction of lateralization in obstacle avoidance and maze exit preference tasks in offspring of placentally restricted (PR: 10M, 13F) and control (CON: 23M, 17F) sheep pregnancies at 18 and 40 weeks of age, and examined gross brain structure of the prefrontal cortex at 52 weeks of age (PR: 14M, 18F; CON: 23M, 25F). PR did not affect lateralization direction, but 40-week-old PR females had greater lateralization strength than CON (P = .021). Behavioural lateralization measures were not correlated with perinatal growth. PR did not alter brain morphology. In males, cross-sectional areas of the prefrontal cortex and left hemisphere correlated positively with skull width at birth, and white matter area correlated positively with neonatal growth rate of the skull (all P < .05). These studies reinforce the need to include progeny of both sexes in future studies of neurodevelopmental programming, and suggest that restricting in utero growth has relatively mild effects on gross brain structural or behavioural lateralization in sheep.

Programming the brain: Common outcomes and gaps in knowledge from animal studies of IUGR.

IUGR in humans is associated with impaired pre- and postnatal neurodevelopment, and subsequent postnatal cognition, resulting in lower IQ, poorer memory, visuomotor and executive function skills, as well as behavioural and attentional problems. Experimental models of IUGR are needed to allow direct testing of causality and interventions, and have benefits in reducing both confounding by comorbidities such as prematurity, and variation due to environment and genetics. This review describes and discusses experimental models of IUGR in which neurodevelopmental and cognitive outcomes of IUGR have been reported. We consider the timing of neurodevelopment relative to birth and to the period of restriction, as well as the effects of each experimental perturbation on the fetal environment and development, before discussing neurodevelopmental and cognitive outcomes for progeny as fetuses, neonates and into adolescent and adult life. Experimental IUGR induces broadly similar outcomes to human IUGR, with altered brain morphology, in particular grey matter loss and discordant trajectory of white matter development, and poorer cognition and memory reported in various studies. Nevertheless, there remain gaps in knowledge of neurodevelopment in experimental models. We end the review with recommendations for the design of future studies to further investigate the mechanisms underlying adverse neurodevelopmental consequences of IUGR, and to evaluate interventions that may subsequently improve outcomes of IUGR in humans.

Placental and fetal growth restriction, size at birth and neonatal growth alter cognitive function and behaviour in sheep in an age- and sex-specific manner.

Intrauterine growth restriction and slow neonatal growth in humans are each associated with poorer learning, memory and cognitive flexibility in childhood and adulthood. The relative contributions of pre- and post-natal growth to cognitive outcomes are unclear, however. We therefore compared performance in learning, memory and reversal tasks using a modified Y-maze at 18 and 40 weeks of age in offspring of placentally-restricted (PR: 10 M, 13 F) and control (23 M, 17 F) ovine pregnancies. We also investigated relationships between size at birth, neonatal growth rates and cognitive outcomes. PR had limited effects on cognitive outcomes, with PR males requiring more trials to solve the initial learning task than controls (P=0.037) but faster completion of reversal tasks in both sexes at 18 weeks of age. In males, neonatal growth rate correlated inversely with numbers of trials and total time required to solve memory tasks at 40 weeks of age. In females, bleat frequency in the first reversal task at 18 weeks of age correlated positively with birth weight (r=0.734, P<0.05) and neonatal growth rate (r=0.563, P<0.05). We conclude that PR induces limited effects on cognitive outcomes in sheep, with some evidence of impaired learning in males, but little effect on memory or cognitive flexibility in either sex. Rapid neonatal growth predicted improved memory task performance in males, suggesting that strategies to optimize neonatal growth may have long-term cognitive benefits but that these may be sex-specific.

Effect of placental restriction and neonatal exendin-4 treatment on postnatal growth, adult body composition, and in vivo glucose metabolism in the sheep.

Intrauterine growth restriction (IUGR) increases the risk of adult type 2 diabetes (T2D) and obesity. Neonatal exendin-4 treatment can prevent diabetes in the IUGR rat, but whether this will be effective in a species where the pancreas is more mature at birth is unknown. Therefore, we evaluated the effects of neonatal exendin-4 administration after experimental restriction of placental and fetal growth on growth and adult metabolic outcomes in sheep. Body composition, glucose tolerance, and insulin secretion and sensitivity were assessed in singleton-born adult sheep from control (CON; n = 6 females and 4 males) and placentally restricted pregnancies (PR; n = 13 females and 7 males) and in sheep from PR pregnancies that were treated with exendin-4 as neonates (daily sc injections of 1 nmol/kg exendin-4; PR + exendin-4; n = 11 females and 7 males). Placental restriction reduced birth weight (by 29%) and impaired glucose tolerance in the adult but did not affect adult adiposity, insulin secretion, or insulin sensitivity. Neonatal exendin-4 suppressed growth during treatment, followed by delayed catchup growth and unchanged adult adiposity. Neonatal exendin-4 partially restored glucose tolerance in PR progeny but did not affect insulin secretion or sensitivity. Although the effects on glucose tolerance are promising, the lack of effects on adult body composition, insulin secretion, and insulin sensitivity suggest that the neonatal period may be too late to fully reprogram the metabolic consequences of IUGR in species that are more mature at birth than rodents.

Do I turn left or right? Effects of sex, age, experience and exit route on maze test performance in sheep.

Brain development and function are susceptible to perturbation by environmental factors. Sheep are increasingly being used as a neurodevelopmental model due to timing similarities with humans, but effects of age, experience and sex on cognition are not well characterised in this species. We therefore studied memory and reversal learning in sheep using a modified Y-maze at two ages: naive 18 weeks old (18N: 23 male, 17 female), experienced 40 week old sheep that had previously been tested at 18 weeks (40E: 22 male, 17 female), and naive 40 weeks old (40N: 4 male, 10 female). Younger naive animals (18N) required more trials and time to solve the first reversal task (task R1) than 40E (P=0.007 and P<0.001 respectively). Experience also improved outcomes, with 40N sheep requiring more time to solve tasks L (P=0.034) and R1 (P=0.002) than 40E. Increasing age (40N cf. 18N) decreased bleat frequency in tasks R1, M2 and R2 (each P<0.05). In 40N females, outcomes also differed by exit method in task R1, with those that exited via an indirect route taking less time to pass tasks R1 (P=0.009) and R2 (P=0.015) than those that used a direct route. Age plus experience improved learning outcomes, demonstrating knowledge retention for 22 weeks in this species, whilst age alone affected mostly behavioral responses. These results provide comparison data, and can be utilised to improve experimental design, for studies of neurodevelopment in the sheep.

Placental restriction of fetal growth reduces cutaneous responses to antigen after sensitization in sheep.

Prenatal and early childhood exposures are implicated as causes of allergy, but the effects of intrauterine growth restriction on immune function and allergy are poorly defined. We therefore evaluated effects of experimental restriction of fetal growth on immune function and allergic sensitization in adolescent sheep. Immune function (circulating total red and white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and the antibody response to Clostridial vaccination) and responses to house dust mite (HDM) allergen and ovalbumin (OVA) antigen sensitization (specific total Ig, IgG1, and IgE antibodies, and cutaneous hypersensitivity) were investigated in adolescent sheep from placentally restricted (PR, n = 23) and control (n = 40) pregnancies. Increases in circulating HDM-specific IgE (P = 0.007) and OVA-specific IgE (P = 0.038) were greater in PR than control progeny. PR did not alter total Ig, IgG1, or IgM responses to either antigen. PR increased OVA-specific but not HDM-specific IgA responses in females only (P = 0.023). Multiple birth increased Ig responses to OVA in a sex-specific manner. PR decreased the proportion of positive cutaneous hypersensitivity responders to OVA at 24 h (P = 0.030) but had no effect on cutaneous responses to HDM. Acute wheal responses to intradermal histamine correlated positively with birth weight in singletons (P = 0.023). Intrauterine growth restriction may suppress inflammatory responses in skin downstream of IgE induction, without impairment in antibody responses to a nonpolysaccharide vaccine. Discord between cutaneous and IgE responses following sensitization suggests new mechanisms for prenatal allergy programming.

Models of in vitro spermatogenesis.

Understanding the mechanisms that lead to the differentiation of male germ cells from their spermatogonial stem cells through meiosis to give rise to mature haploid spermatozoa has been a major quest for many decades. Unlike most other cell types this differentiation process is more or less completely dependent upon the cells being located within the strongly structured niche provided by mature Sertoli cells within an intact seminiferous epithelium. While much new information is currently being obtained through the application and description of relevant gene mutations, there is still a considerable need for in vitro models with which to explore the mechanisms involved. Not only are systems of in vitro spermatogenesis important for understanding the basic science, they have marked pragmatic value in offering ex vivo systems for the artificial maturation of immature germ cells from male infertility patients, as well as providing opportunities for the transgenic manipulation of male germ cells. In this review, we have summarized literature relating to simplistic culturing of germ cells, co-cultures of germ cells with other cell types, especially with Sertoli cells, cultures of seminiferous tubule fragments, and briefly mention the opportunities of xenografting larger testicular pieces. The majority of methods are successful in allowing the differentiation of small steps in the progress of spermatogonia to spermatozoa; few tolerate the chromosomal reduction division through meiosis, and even fewer seem able to complete the complex morphogenesis which results in freely swimming spermatozoa. However, recent progress with complex culture environments, such as 3-d matrices, suggest that possibly success is now not too far away.