Topographic Differences in Superficial Macular Vessel Density in Eyes with Early Primary Open-Angle Glaucoma and Normal Tension Glaucoma.

INTRODUCTION: The aim of the study was to compare macular vascular microcirculation in early primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and normal subjects. METHODS: 99 patients with early glaucoma (99 eyes: 60 POAG and 39 NTG) and 78 normal subjects were included. All subjects underwent optical coherence tomography angiography scan at 6 × 6 mm macular area. Macular vessel density (VD) and perfusion density (PD) and 9 sectors were compared between the controls, POAG, and NTG groups. Linear regression analysis was used to investigate the relationship between VD and other variables including macular PD, signal strength (SS), and mean macular ganglion cell-inner plexiform layer (mGCIPL) thickness. RESULTS: Significant losses in total area of VD and PD were detected in POAG and NTG groups compared to the controls (all p < 0.01). There were no significant differences in all inner sectors of macular VD and PD between POAG and controls (all p > 0.05). Except for outer-nasal sector, all other outer sectors of macular VD and PD were significantly lower in POAG than in the controls (all p < 0.01). The inferior-inner sector and all outer sectors of VD and PD were significantly lower in NTG than in the controls (all p < 0.01). Macular VD was significantly correlated with macular PD (r = 0.99, p < 0.001), SS (r = 0.60, p < 0.001), and mGCIPL thickness (r = 0.51, p < 0.001). CONCLUSIONS: Macular microcirculation declined significantly in early POAG and NTG patients. Macular microcirculation loss in the NTG group was more central and nasal compared with that in the POAG group. A decrease in macular VD was correlated with lower macular PD, lower SS, and thinner mGCIPL thickness.

Superficial macular vessel density in eyes with mild, moderate, and severe primary open-angle glaucoma.

PURPOSE: The aim of this study is to report changes in and associations of macular vessel density (VD) and perfusion density (PD) using optical coherence tomography angiography (OCTA) in mild, moderate, and severe open-angle glaucoma. METHODS: One hundred thirty-three patients with open-angle glaucoma (133 eyes: 47 mild, 33 moderate, and 53 severe glaucoma) and 73 normal subjects (right eyes) were included in this cross-sectional study. All subjects underwent Cirrus OCTA measurements. One-way analysis of variance (ANOVA) was used to compare macular VD and PD between the controls and mild, moderate, and severe glaucoma groups. Multiple linear regression was performed with OCTA parameters as the predicted variable and age, gender, spherical equivalent (SE), intraocular pressure (IOP), mean deviation (MD), signal strength (SS), and mean macular ganglion cell-inner plexiform layer (mGCIPL) thickness as the predictor variables. RESULTS: The total area of VD showed significant differences between the controls vs. mild (p < 0.001) and moderate vs. severe glaucoma (p = 0.003); no significant difference was found between mild and moderate glaucoma (p = 1.000). Macular VD was associated with age (ß = -0.02, p = 0.003), MD (ß = 0.04, p = 0.001), SS (ß = 1.43, p < 0.001), and mGCIPL thickness (ß = 0.04, p = 0.002) but not with gender, SE, and IOP (all p > 0.05). CONCLUSIONS: Macular microcirculation declined significantly in mild and severe glaucoma. No significant difference was found between mild and moderate glaucoma. Decrease macular VD was independently associated with age, severe MD, lower SS, and thinner mGCIPL thickness.

Epithelial changes with corneal punctate epitheliopathy in type 2 diabetes mellitus and their correlation with time to healing.

BACKGROUND: To study basal epithelial cell (BEC), sub-basal nerve plexus (SBN) and Langerhans cell (LC) density in patients with type 2 diabetes mellitus (T2DM) with corneal punctate epitheliopathy (CPE) and to assess their association with time to healing of CPE. METHODS: Retrospective study of in vivo confocal microscopy (IVCM) in 160 eyes from 160 patients with T2DM diagnosed with CPE due to a single cause. Key exclusion criteria included multiple-causes for CPE or treatment with autologous serum. A total of 149 eyes from 149 gender- age- and aetiolgy-matched patients with CPE without T2DM comprised the control group. Electronic records were reviewed for demographic features, history of T2DM and aetiology of CPE. Density of BEC, SBN and LC were compared between the two groups. RESULTS: The healing time in days for CPE with different aetiologies in the T2DM and control groups were as follows: dry eye (21.56 ± 2.41; 7.00 ± 2.19; P = 0.001); meibomian gland dysfunction (26.42 ± 6.04; 9.21 ± 2.55; P = 0.001); cataract extraction (38.00 ± 19.62; 25.83 ± 11.49; P = 0.043); drug induced (53.19 ± 18.83; 41.86 ± 23.87; P = 0.018) and exposure (38.25 ± 14.13; 29.00 ± 13.67; P = 0.026). LC density was 38.70 ± 9.65 cells/mm2 in the T2DM group comparedwith 25.53 ± 3.54 cells/mm2 in the controls (P = 0.001). SBN density was 11.76 ± 1.69 mm/mm2 in the T2DM group compared with 20.92 ± 1.43 mm/mm2 in the controls (P = 0.001). BEC density in the T2DM group was 4982 ± 1178 cells/mm2 compared with 5739 ± 394 cells/mm2 in the control group (P = 0.018). Age and duration of T2DM had no relationship with healing time (multiple linear regression, P = 0.618; P = 0.787). The density of LC in the T2DM group showed a negative correlation with SBN density (r = 0.350; R2 = 0.1225; P = 0.034). The density of SBN in the T2DM group showed a positive correlation with BEC density (r = 0.427; R2 = 0.1823; P = 0.008). The density of BEC in the T2DM group showed a negative correlation with healing time (r = 0.931; R2 = 0.8668; P = 0.001). CONCLUSIONS: Utilising IVCM, we have demonstrated increased LC and decreased SBN in patients with T2DM and CPE. Both may be related to lower BEC density and nuclei enhanced reflection. Furthermore, decreased BEC density may lead to delay in cornea epithelium healing in the T2DM group comparedwith controls. An immune-mediated response may play a role in delayed wound closure in patients with T2DM.

Age-related changes in and determinants of macular ganglion cell-inner plexiform layer thickness in normal Chinese adults.

IMPORTANCE: Consideration of age-related changes in macular ganglion cell-inner plexiform layer (mGCIPL) thickness are important for glaucoma progression analysis. BACKGROUND: To report age-related changes in and the determinants of high-definition optical coherence tomography (HD-OCT) measurements of mGCIPL thickness. DESIGN: Cross-sectional study. PARTICIPANTS: 326 healthy adults. METHODS: All subjects underwent Cirrus HD-OCT measurements of mGCIPL. One-way analysis of variance (ANOVA) was used to compare mGCIPL thickness between 7 decades based age groups and macular sectors. Multiple regression analysis determined the association between mGCIPL thickness and age, gender, intraocular pressure (IOP), peripapillary retinal nerve fibre layer thickness (pRNFL) and spherical equivalent. MAIN OUTCOME MEASURES: Change in mGCIPL thickness and determinants of thickness. RESULTS: Mean mGCIPL thickness in 295 subjects was 80.80 ± 6.42 µm. Mean mGCIPL decreased by 0.12 µm (95% CI [confidence interval], 0.09-0.16) with every year of age; 1.61 µm (95% CI, 0.08-2.41) per decade. It showed two steep declines with age, first in the fifth and next in the seventh decade with relative stability between them. mGCIPL thickness was associated with pRNFL thickness (ß = 0.30, P < 0.001) and IOP (ß = -0.19, P = 0.03) but not with gender (ß = -1.09, P = 0.116) or spherical equivalent (ß = -0. 24, P = 0.145). CONCLUSIONS AND RELEVANCE: Mean mGCIPL thickness showed a small age-related linear decrease with two steep drops in the fifth and seventh decades. Thinner mGCIPL was independently associated with age, thinner pRNFL and higher IOP. These factors should be considered if using mGCIPL to detect progression of glaucoma and other optic neuropathies characterized by the loss of retinal ganglion cells.

Association of intraocular pressure-related factors and retinal vessel diameter with optic disc rim area in subjects with and without primary open angle glaucoma.

IMPORTANCE: The data may support the notion that the intra-ocular pressure (IOP)-related factors and vascular factors were implicated concurrently in glaucomatous optic nerve damage. BACKGROUND: To study the association of intraocular pressure (IOP)-related factors, IOP, trans-lamina cribrosa pressure difference (TLCPD), cerebrospinal fluid pressure (CSFP) and retinal vessel diameters (RVD), central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE) with neuro-retinal rim area (RA). DESIGN: A population-based, cross-sectional study. PARTICIPANTS: A total of 6830 people aged 30 years and over. METHODS: All participants underwent a comprehensive eye examination, fundus photograph-based measurements of RVD and Heidelberg retinal tomogram (HRT) measurement of optic disc. MAIN OUTCOME MEASURES: RA, CRAE, CRVE, IOP, body mass index (BMI), CSFP and TLCPD. RESULTS: Primary open-angle glaucoma (POAG) was diagnosed using two separate methods: 67 from expert consensus, and 125 from the International Society of Geographical and Epidemiologic Ophthalmology (ISGEO) classification. After excluding of those with high myopia or without gradable HRT images, 4194 non-glaucoma and 40 POAG were analysed for determinants of RA. On multivariable analysis determinants of reduced RA were POAG (P < 0.001), higher IOP (P = 0.03), higher refractive error (P < 0.01), longer axial length (P = 0.01), CRVE (P < 0.001), lower BMI (P = 0.015), older age (P < 0.001) smaller disc area (P < 0.001) and higher TLCPD (P = 0.03). When age and/or BMI were omitted from the model, reduced RA was also associated with lower CSFP (P < 0.001). CONCLUSIONS AND RELEVANCE: Reduced RA is associated with narrow CRVE and higher IOP or lower CSFP. The data supports the concurrent role of IOP-related and vascular factors in glaucomatous optic nerve damage.

Peripapillary retinal nerve fibre layer thickness and its association with refractive error in Chinese children: the Anyang Childhood Eye Study.

BACKGROUND: To report the thickness of the peripapillary retinal nerve fibre layer (pRNFL) in Chinese children and examine its association with refractive error, axial length (AL) and optic disc parameters. DESIGN: Population-based cross-sectional study. PARTICIPANTS: A total of 2893 seven-year-old children from 11 randomly selected primary schools in Anyang, central China. METHODS: Participants underwent ophthalmic examinations including optical biometry, cycloplegic autorefraction and spectral-domain ocular coherence tomography. MAIN OUTCOME MEASURES: Retinal nerve fibre layer thickness in 16 radial sections, cycloplegic spherical equivalent, AL. RESULTS: The mean (SD) average RNFL thickness was 102.01(8.02) µm. The average RNFL thickness decreased with smaller disc area (r = 0.18, R2 = 0.03, P < 0.0001), bigger cup area (r = -0.11, R2 = 0.01, P < 0.0001), smaller rim area (r = 0.28, R2 = 0.08, P < 0.0001), smaller nerve head volume (r = 0.27, R2 = 0.07, P < 0.0001), longer AL (r = -0.15, R2 = 0.02, P < 0.0001) and a negative spherical equivalent (r = 0.11, R2 = 0.01, P < 0.0001). Hyperopic children had a thicker RNFL than emmetropic children [102.45(8.13) µm vs. 100.81 (7.18) µm, P < 0.001]. Myopic children had thinner RNFL than emmetropic children [99.17 (7.69) µm vs. 100.81 (7.18) µm, P < 0.05]. CONCLUSION: Retinal nerve fibre layer thickness decreased with increasing AL, higher myopia, bigger cup area, smaller disc and rim area, and a smaller nerve head volume, but the coefficient of determination for all these associations was small. The RNFL in myopes was significantly thinner than emmetropes or hyperopes, but with small absolute differences. The study provides RNFL values for healthy 7-year-old Chinese children. Follow up of this cohort to observe the change of RNFL thickness with myopia and possible change in detected associations with age is planned.

Understanding the causation of primary angle closure disease using the sufficient component cause model.

BACKGROUND: Several risk factors have been associated with primary angle closure disease, but their actual role in causation of an individual case is not clear. DESIGN: Concept paper. PARTICIPANTS/SAMPLES: No patient participation. METHODS: The sufficient component cause model is briefly explained in the context of primary angle closure disease. The framework is used to conceptualize the role of individual mechanisms of disease. The possibility of personalized treatment for primary angle closure disease is discussed in this context. MAIN OUTCOME MEASURES: Qualitative concepts in disease causality may refine research and treatment in primary angle closure disease. RESULTS: The minimum set of conditions that are sufficient for primary angle closure disease to occur is considered the sufficient component cause model for that individual case. Described risk factors (including genes) as well as currently unknown influences play a role in the model. There may be many such models and all complementary components in any sufficient-cause model must be present for disease to occur. Interruption of any one component in that model can be used for treatment. Pupillary block is likely a component of most such models and may currently be considered a universally necessary component of these models. CONCLUSIONS: The sufficient component cause model can be used as a framework to explain the role of individual mechanisms of causation and treatment of primary angle closure disease. It also aids understanding of the proportion of disease due to specific causes.

Management algorithms for primary angle closure disease.

In contrast to primary open angle glaucoma, preventive interventions in primary angle closure disease (PACD) can sometimes be definitive. Data from randomized, controlled trials - and where this is not available - principles grounded in known biology, biological plausibility, logic, preferred practice and personal experience have been synthesized to develop explicit clinical algorithms for management of the spectrum of PACD. The mainstay of first-line intervention is usually a laser iridotomy: a commonly necessary but sometimes insufficient manoeuvre in PACD. The crucial stepwise considerations after iridotomy are: whether the angle is open or closed; whether the IOP can be medically controlled; the extent of PAS, and the presence of visually significant cataract. Indication for subsequent interventions--which may include iridoplasty, cataract surgery, trabeculectomy or phacotrabeulectomy--are herein based on an arbitrary threshold (180 degrees) for angle opening and extent of PAS following initial treatment.

Incidence of hypotony and sympathetic ophthalmia following trans-scleral cyclophotocoagulation for glaucoma and a report of risk factors.

OBJECTIVE: To report the incidence and risk factors for hypotony and estimate the risk of sympathetic ophthalmia following diode laser trans-scleral cyclophotocoagulation (TSCPC). DESIGN: Retrospective study using data from a private tertiary glaucoma clinic and review of the literature. PARTICIPANTS: Seventy eyes of 70 patients with refractory glaucoma who received TSCPC treatment. METHODS: Review of the records of consecutive patients who underwent TSCPC by a single ophthalmic surgeon and review of the literature. MAIN OUTCOME MEASURES: Hypotony (including phthisis bulbi), sympathetic ophthalmia. RESULTS: Seven eyes (10%; CI 5-19%) developed hypotony and included 4 eyes that developed phthisis. Higher total energy delivered during TSCPC treatment was associated with an increased risk of hypotony: eyes that developed hypotony received a mean total energy of 192.5 ± 73.2 joules, compared to a mean of 152.9 ± 83.2 joules in hypotony-free cases. The risk of sympathetic ophthalmia estimated from a review of the published literature and current series was one in 1512, or 0.07% (CI 0.03%-0.17%). CONCLUSIONS: Total laser energy is one of several risk factors that act in a sufficient component cause-model to produce hypotony in an individual patient. The small sample size precluded inference for other individual putative risk factors but titrating laser energy may help decrease the occurrence of hypotony. The risk of sympathetic ophthalmia calculated from the literature is likely an overestimate caused by publication bias.

Five-year incidence of primary glaucoma and related risk factors - The Handan eye study.

PURPOSE: To determine the 5-year incidence of primary glaucoma and its associated risk factors in rural northern China. METHODS: Population-based cohort study. A total of 5184 participants aged 30 years and older, without glaucoma at baseline, were subjected to comprehensive standardized interviews and ophthalmic and systemic examinations at baseline and after a 5-year interval in the Handan Eye Study. Incident glaucoma was diagnosed by a consensus panel of five senior glaucoma specialists. Univariate and multivariable logistic regression analyses were performed to identify the baseline risk factors that could predict the incidence of glaucoma. RESULTS: During the 5-year follow-up, incident primary glaucoma developed in 82 subjects (1.6%; 95% confidence interval [CI], 1.2%-1.9%). The age- and gender-standardized incidence of glaucoma among subjects ≥40 years old was 2.1% (0.4% annually), calculated according to the 2010 Chinese census. A higher age (odds ratio [OR], 1.06; 95% CI, 1.04-1.09; p < 0.001), higher intraocular pressure (IOP) (OR, 1.11; 95% CI, 1.02-1.20; p = 0.017), and vertical cup disc ratio (VCDR) ≥ 0.60 (OR, 5.30; 95% CI, 3.22-8.73; p < 0.001) were found to be associated with an increased risk of incident glaucoma. For each year, older age and each mmHg higher IOP, the risks of primary glaucoma increased by 1.2% and 2.0% per year, respectively. CONCLUSION: We reported the 5-year incidence of primary glaucoma in a rural Chinese population and found that older age, higher IOP, and VCDR ≥ 0.60 at baseline could help in identifying those at highest risk of disease development.

A polymorphism in the CYP1B1 promoter is functionally associated with primary congenital glaucoma.

Primary congenital glaucoma (PCG) is a childhood autosomal-recessive disorder caused by developmental defects in the trabecular meshwork and anterior chamber angle. These defects cause raised intraocular pressure (IOP) that damages the optic nerve and if left untreated, results in irreversible blindness. Mutations in CYP1B1 gene at the GLC3A locus (2p21) are associated with PCG. However, there has been very limited exploration of its promoter region. We resequenced the CYP1B1 promoter in a large cohort (n = 835) that included patients with PCG (n = 301), other primary glaucomas (primary open-angle glaucoma: n = 115 and primary angle closure glaucoma: n = 100) and unaffected controls (n = 319). We functionally characterized one associated variant by luciferase reporter assay using the trabecular meshwork (TM3) cell line. We found evidence of strong (P = 6.01 × 10(-4)) association of rs2567206 (T2805C) SNP in PCG and not in other primary glaucomas. Luciferase assay indicated a ∼90% reduction in CYP1B1 promoter activity in the risk-allele (C) compared to the other allele (T). The association of the risk allele was stronger in cases harboring homozygous CYP1B1 mutations (P = 3.42 × 10(-12)). The risk haplotype 'C-C-G' in the promoter had a strong non-random association to the previously characterized risk haplotype 'C-G-G-T-A' in the coding region. The independent effect of genotype at the promoter T2805C locus (P = 0.001), and the interaction effect of genotypes at the promoter and coding region mutations loci (P = 0.001) were significant for the presenting IOP of the worst affected eye. This is the first study that unequivocally shows the functional involvement of a CYP1B1 promoter variant in PCG.

There is insufficient evidence to recommend lens extraction as a treatment for primary open-angle glaucoma: an evidence-based perspective.

Cataract extraction in primary open-angle glaucoma has not been thought to provide a clinically useful or predictable decrease in IOP. This concept has now been challenged, with the opposite belief being promulgated: namely, that lens exchange should be considered as treatment for glaucoma. This revelation could bring a significant change in the glaucoma treatment paradigm. There are no randomised controlled trials to guide the role of lens extraction in primary open-angle glaucoma. The available evidence suggests at most a modest reduction in IOP from cataract extraction - greater in the presence of pseudoexfoliation - which is likely to be of marginal benefit, and only in milder forms of open-angle glaucoma. There is currently no evidence of any quality to suggest that lens extraction routinely represents a clinically useful treatment for primary open-angle glaucoma.

Retinal nerve fiber layer thickness in amblyopia.

Purpose: To report retinal nerve fiber layer thickness (RNFLT) in eyes with amblyopia compared with contralateral healthy eyes. Methods: In this cross-sectional study, we included patients with anisometropic amblyopia, strabismic amblyopia, and mixed amblyopia. All subjects underwent complete ophthalmic examination, including RNFLT measurement with time-domain OCT (Stratus OCT) and scanning laser polarimeter (GDX VCC). A paired "t" test was used to compare average and quadrant-wise RNFL thickness between the amblyopic and contralateral normal eyes. In addition, an analysis of variance test was used to compare various RNFL thickness parameters between the three groups. Results: A total of 33 eyes of 33 subjects with anisometropic amblyopia, 20 eyes of 20 subjects with strabismic amblyopia, and 38 eyes of 38 subjects with mixed amblyopia were included. In the anisometropic amblyopia group, the average RNFLT in the amblyopic eye was 98.2 µm and 99.8 µm in the fellow normal eye (P = 0.5), the total foveal thickness was 152.82 µm (26.78) in the anisometropic eye and 150.42 µm (23.84) in the fellow eye (P = 0.38). The difference between amblyopic and contralateral normal eye for RNFL and macular parameters was statistically insignificant in all three groups. The RNFL thickness in four quadrants was similar in the amblyopic and non-amblyopic eye between all three groups and statistically non-significant. Conclusion: Our study showed that RNFL thickness was similar in amblyopic and non-amblyopic eyes between all three amblyopia groups.

Development of angle closure and associated risk factors: The Handan eye study.

PURPOSE: To investigate the development of angle closure from baseline open angle and associated risk factors in a rural Chinese population through a longitudinal study over a 5-year period. METHODS: Subjects aged ≥30 years and older with bilateral open angles at baseline of the Handan Eye Study who participated in the follow-up and had undergone both baseline and follow-up gonioscopic examinations were included. Subjects with any form of angle closure, glaucoma, incisional ocular surgery or other conditions that could influence the results were excluded. The development of angle closure was defined as the presence of primary angle closure suspect (PACS) or primary angle closure (PAC)/primary angle closure glaucoma (PACG) during the follow-up in normal subjects with baseline bilateral open angles. Logistic regression was performed to identify the baseline risk factors for the development of angle closure. RESULTS: A total of 457 subjects with bilateral open angles at baseline aged 53.0 (45.5, 58.0) years were enrolled. 94.7% of the included cases developed PACS, 5.3% developed PAC and no one developed PACG after 5 years. In logistic regression, significant risk factors for the development of angle closure were shallower central anterior chamber depth (ACD) (p = 0.002) and narrower mean angle width (p < 0.001). CONCLUSIONS: This study reports the development from baseline open angle to angle closure after a 5-year follow-up. We confirm that the mean angle width and central ACD were independent predictive risk factors for the development of any form of angle closure.

Role of confocal microscopy in the diagnosis of fungal and acanthamoeba keratitis.

PURPOSE: To investigate the role of confocal microscopy as a diagnostic modality in microbial keratitis and to determine inter- and intraobserver variation in the analysis and interpretation of confocal microscopy findings. DESIGN: Prospective, double masked, nonrandomized, observational clinical trial. PARTICIPANTS: We included 146 consecutive patients with clinically suspected microbial keratitis. METHODS: Confocal microscopy and microbiology evaluation of study participants. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of confocal microscopy in diagnosing fungal and Acanthamoeba keratitis compared with microbiologic evaluation, as well as the intra- and interobserver variation in interpretation of confocal scans. RESULTS: We included 148 cases of infiltrative keratitis. Of the 103 microbiologically proven cases of Acanthamoeba or fungal keratitis, the confocal microscope was able to identify fungal filaments or Acanthamoeba cysts in 91 cases with either fungal or Acanthamoeba keratitis with a sensitivity of 88.3% (95% confidence interval [CI], 82.2-94.5) and a specificity of 91.1% (95% CI, 82.8-99.4). The interobserver agreement in interpreting the scans was good (kappa = 0.6; phi = 0.617). The intraobserver agreement was kappa = 0.795 and phi = 0.807. CONCLUSIONS: The confocal microscope seems to be an accurate and reliable diagnostic modality in the etiologic diagnosis of fungal and Acanthamoeba keratitis.

Clear lens extraction in angle closure glaucoma.

PURPOSE OF REVIEW: Clear lens extraction is being advocated for primary angle closure disease (PACD). It is important that this advocacy should be based on a sound, peer-reviewed evidence base. This review attempts to establish the extent of that evidence and provide some management guidelines. RECENT FINDINGS: There are only three reports that incorporate clear lens extraction (CLE) for angle closure: numbers are sparse and none compare modern phacoemulsification to alternative treatments for primary angle closure glaucoma or provide enough detail to guide clinical decisions. A Cochrane review in 2006 found that there was no evidence to support lens extraction as treatment for primary angle closure glaucoma (PACG). More recent randomized controlled trials have provided support for cataract extraction--although not specifically for CLE--as treatment for part of the spectrum of PACD. A recent review has attempted to provide guidelines for application of CLE in PACG by extrapolating from this evidence. SUMMARY: There are currently no randomized controlled trials supporting the use of CLE as treatment for PACG. A benefit from the procedure is biologically plausible and extrapolation from existing randomized trials to a few specific situations may be possible. Any potential benefit must be carefully weighed against the risks of intervention.