Intraoperative Retinal Changes May Predict Surgical Outcomes After Epiretinal Membrane Peeling.

Purpose: To investigate whether intraoperative retinal changes during epiretinal membrane (ERM) peeling affect anatomic or functional outcomes after surgery. Methods: We measured retinal thickness using an intraoperative optical coherence tomography (iOCT) device in patients undergoing pars plana vitrectomy with membrane peeling for idiopathic ERM. Changes in intraoperative central macular thickness (iCMT) were compared with postoperative improvements in CMT and best-corrected visual acuity (VA). Results: Twenty-seven eyes from 27 patients (mean age 68 years) underwent iOCT-assisted ERM peeling surgery. Before surgery, mean VA was logMAR 0.50 ± 0.36 (Snellen 20/63), and mean baseline CMT was 489 ± 82 µm. Mean iCMT before peeling was 477 ± 87 µm, which correlated well with preoperative CMT (P < 0.001). Mean change in iCMT was -39.6 ± 37 µm (range -116 to +77 µm). After surgery, VA improved to logMAR 0.40 ± 0.38 (Snellen 20/50) at month 1 and logMAR 0.27 ± 0.23 (Snellen 20/37) at month 3, whereas CMT decreased to 397 ± 44 µm and 396 ± 51 µm at months 1 and 3. Eyes that underwent greater amount of iCMT change (absolute value of iCMT change) were associated with greater CMT reduction at month 1 (P < 0.001) and month 3 (P = 0.010), whereas those with greater intraoperative thinning (actual iCMT change) showed a trend toward better VA outcomes at months 1 (P = 0.054) and 3 (P = 0.036). Conclusions: Intraoperative changes in retinal thickness may predict anatomic and visual outcomes after idiopathic ERM peeling surgery. Translational Relevance: Our study suggests that intraoperative retinal tissue response to ERM peeling surgery measured by iOCT may be a prognostic indicator for restoration of retinal architecture and for visual acuity outcomes.

Repeatability of Vascular Density Measurement of the Three Retinal Plexus Layers Using OCT Angiography in Pathologic Eyes (OCTA Vascular Density Repeatability of Three Plexus Layers).

PURPOSE: Although commercial optical coherence tomography angiography (OCTA) machines quantitate retinal vascular density (VD) by dividing the vasculature into superficial and deep capillary plexus (SCP, DCP), histology reveals three distinct plexus layers. This study tested the hypothesis that the VD measurement of three distinct retinal plexus layers obtained using custom segmentation has high repeatability comparable to that of automatically segmented SCP and DCP layers. MATERIALS AND METHODS: Forty-four participants (86 eyes) were enrolled - 54 eyes with retinal vasculopathy and 25 eyes with macular edema. Macular OCTA images (3x3 mm and 6x6 mm) were obtained twice within 30 minutes by the same personnel using the same instrument (AngioVue, Optovue, version 2018.0.0.18). The intraclass correlation coefficient (ICC) was calculated to access repeatability. RESULTS: The repeatability of VD for SCP and DCP was good-to-moderate (ICC=0.65-0.85) and minimally affected by image quality, retinal vasculopathy, or macular edema. The repeatability of the VD of the custom-segmented intermediate and deep plexus layers (cICP and cDCP) was poor/moderate (ICC=0.40-0.74) but better in the subset without macular edema using 3x3 mm scans with good images quality (ICC=0.58-0.93). Repeatability of cICP and cDCP VD measurement for 6x6 mm scans was poor (ICC≤0.5) in eyes with retinal vasculopathy and/or macular edema. CONCLUSION: Although repeatability of the VD measurement is high for the automatically segmented SCP and DCP, repeatability of VD is poor for the cICP and cDCP using larger scans in eyes with retinal vasculopathy and/or macular edema.

Phase I/II randomized study of proton beam with anti-VEGF for exudative age-related macular degeneration: long-term results.

BACKGROUND/OBJECTIVE: To determine if treatment of exudative age-related macular degeneration (eAMD) using proton beam therapy (PBT) combined with intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is safe and effective long term. SUBJECT/METHODS: Thirty eyes with newly diagnosed eAMD were enrolled in a phase I/II prospective, sham-controlled double-masked university study. Eyes were randomized 1:1:1-24 GyE, 16 GyE or sham radiation, and treated with three initial monthly intravitreal ranibizumab or bevacizumab. Subsequent anti-VEGF reinjection was based on monthly optical coherence tomography and examination for 2 years and standard of care thereafter. RESULTS: A total of 23 eyes completed 2-year study follow-up, of which 16 maintained monthly follow-up. Mean best-correct visual acuity (BCVA) at 2 years was similar among treatment groups (p > 0.05). The 24 GyE group required fewer anti-VEGF injections when compared with the sham group at 2 years (4.67 ± 1.9 vs 9.67 ± 3.5; p = 0.017). Extended follow-up (mean 4 years) available in 22 eyes showed persistent reduced need for anti-VEGF therapy among eyes treated with 24 GyE compared with sham radiation (2.0 ± 1.6 vs 4.84 ± 2.4 per year, p = 0.008). New and increasing geographic atrophy (GA), noted in some eyes in all treatment groups, resulted in decreased mean BCVA from baseline for the 24 GyE group on extended follow-up (p = 0.009). Possible mild radiation retinopathy noted in 15% of eyes was not visually significant. CONCLUSIONS: Initial treatment combining PBT (24 GyE) with intravitreal anti-VEGF therapy appears to decrease the need for anti-VEGF reinjection in eyes with newly diagnosed eAMD. Radiation retinopathy risk was low and does not appear visually significant. Long-term vision was limited by GA development especially in the 24 GyE group.

Long-term natural history of idiopathic epiretinal membranes with good visual acuity.

BACKGROUND/OBJECTIVES: To evaluate the long-term progression of idiopathic epiretinal membranes (iERMs) with good baseline visual acuity, and to identify predictors of visual decline. DESIGN: Retrospective case series SUBJECTS METHODS: We reviewed records of 145 eyes with iERM and best-corrected visual acuity (BCVA) of 20/40 or greater at presentation, including BCVA, lens status, and central macular thickness (CMT) at yearly visits; as well as anatomic biomarkers including vitreomacular adhesion, pseudohole, lamellar hole, intraretinal cysts, disorganization of the inner retinal layers (DRIL), and disruption of outer retinal layers. Linear mixed effects and mixed-effects Cox proportional hazards models were used to identify clinical and anatomic predictors of vision change and time to surgery. RESULTS: At presentation, mean BCVA was 0.17 ± 0.10 logMAR units (Snellen 20/30) and mean CMT was 353.3 ± 75.4 µm. After a median follow-up of 3.7 years (range 1-7 years), BCVA declined slowly at 0.012 ± 0.003 logMAR units/year, with phakic eyes declining more rapidly than pseudophakic eyes (0.019 ± 0.003 vs. 0.010 ± 0.004 logMAR units/year). Metamorphopsia, phakic lens status, lamellar hole, and inner nuclear layer cysts were associated with faster visual decline. Cumulative rates of progression to surgery were 2.9, 5.6, 12.2, and 21.1% at years 1-4. Visual symptoms, metamorphopsia, greater CMT, and disruption of outer retinal layers were associated with greater hazard for surgery. CONCLUSION: Eyes with iERM and visual acuity ≥ 20/40 experience slow visual decline, with 21% of eyes requiring surgery after 4 years. Clinical and anatomic predictors of vision loss may be distinct from factors associated with earlier surgical intervention.

Suicidality in psychiatrically hospitalized children and adolescents: Demographics, treatment, and outcome.

BACKGROUND: Despite the high prevalence of suicidality in psychiatrically hospitalized youth, its risk factors and impact on inpatient psychopharmacologic treatment are unknown. We identified characteristics associated with suicidality in psychiatrically hospitalized youth and determined the association of suicidality with subsequent psychopharmacologic interventions. METHODS: Medical records from consecutive psychiatric admissions to a large, acute care, urban, pediatric hospital were analyzed retrospectively (N = 1,309). Demographic, clinical, and treatment-related features of suicidal and nonsuicidal youth were characterized. Logistic regression identified predictors of suicidality, and multiple comparison analyses evaluated the association between suicidality and changes to antidepressant prescribing during inpatient course. RESULTS: Compared with nonsuicidal patients, inpatients who were suicidal were more likely to have a mood disorder or posttraumatic stress disorder, as well as Cannabis and alcohol use, were more commonly girls, and at least 13 years of age (all P ≤ .05). Hospitalization was shorter for suicidal patients, was more likely to be associated with antidepressant treatment (P ≤ .001), and among suicidal patients prescribed antidepressants at the time of admission, was associated with a greater likelihood of changing antidepressant treatment compared with nonsuicidal inpatients (P ≤ .05). CONCLUSIONS: These findings reveal differences between suicidal and nonsuicidal psychiatrically hospitalized youth and suggest that suicidality is associated with specific pharmacologic treatment approaches within this population.

Practical Lessons from Protocol I for the Management of Diabetic Macular Edema.

Protocol I, a multicenter randomized clinical trial, compared the visual outcomes of patients treated with 0.5 mg intravitreal ranibizumab with either prompt or deferred (by 24 weeks laser), 4 mg intravitreal triamcinolone with prompt laser, or sham injection with prompt laser for the treatment of center-involving diabetic macular edema (DME). A total of 854 adult patients with type I or II diabetes and any level of non-proliferative diabetic retinopathy or proliferative retinopathy with adequate panretinal photocoagulation, with best-corrected visual acuity (BCVA) of 78 to 24 ETDRS letters (Snellen equivalent of 20/32 to 20/320) and visual loss attributed to macular edema, or retinal thickening with central subfield thickness of at least 250 µm by OCT were enrolled. The main outcomes relevant for practicing clinicians are as follows. (1) Intravitreal ranibizumab treatment provides superior visual outcomes compared to conventional laser treatment. (2) Adjunctive laser treatment does not appear to provide substantial visual benefit compared to ranibizumab treatment alone, but may reduce the number of injections required to resolve DME. Deferral of laser is likely beneficial in patients with worse initial visual acuity. (3) Intravitreal triamcinolone provides similar visual outcomes compared to intravitreal ranibizumab in pseudophakic patients but is associated with a clinically important increased risk of increased intraocular pressure (IOP), need for glaucoma medications, and need for glaucoma surgery. (4) Delayed initiation of intravitreal ranibizumab therapy provides improved visual outcome among patients initially treated with conventional laser photocoagulation or triamcinolone, but the magnitude of the benefit is not as great as is observed when ranibizumab treatment is initiated promptly. (5) The number of ranibizumab injections required to achieve the desired visual outcome decreases substantially after the first year, with the majority of patients not requiring further treatment after 3 years. (6) Patients who do not have a rapid response to ranibizumab still display long-term benefit to continued therapy, although perhaps less than those with immediate improvement. (7) Intravitreal ranibizumab is not only effective in reducing retinal edema and improving BCVA among patients with DME, it is also a disease modifying therapy and induces improvement of the diabetic retinopathy severity score by 2 or more steps in approximately one third of patients. Triamcinolone injection also induces improvement in diabetic retinopathy severity in DME patients, but perhaps to a lesser degree. (8) No increased risk of systemic adverse events was observed among patients treated with intravitreal ranibizumab compared to sham-injected controls or triamcinolone-treated patients, but the low frequency of adverse events, restrictive enrollment criteria, and specific posology employed in this study limit the generalization of this conclusion to patients routinely encountered in clinical practice. (9) There was no clinically important increased risk of major ocular complications among patients treated with intravitreal ranibizumab (including the risk of glaucoma), although endophthalmitis is a potentially devastating outcome should it occur. In addition to the risk of endophthalmitis, intravitreal triamcinolone injection was associated with clinically important increased risk of cataract progression and increased IOP.

Practical Lessons from Protocol T for the Management of Diabetic Macular Edema.

PURPOSE: To review the results of Diabetic Retinopathy Clinical Research Network Protocol T, as applied to clinical practice. METHODS: Review of major publications reporting the results of Protocol T, a randomized single-masked (in year-1 only), multicenter clinical trial comparing aflibercept, bevacizumab, and ranibizumab as treatment option for center-involving diabetic macular edema (DME). The main outcome measures were change in visual acuity (VA), central subfield thickness (CST) on optical coherence tomography, cost effectiveness, burden of care, and safety. RESULTS: A total of 660 participants (mean age 61 ± 10 years, 47% women, 65% Caucasian) were randomized to treatment with aflibercept (n = 224), ranibizumab (n = 218), or bevacizumab (n = 218). The majority of patients (90%) had type II diabetes, with an average duration of 17 ± 11 years. About half the patients had baseline ETDRS VA of 20/32 to 20/40, and half had ETDRS VA of 20/50 to 20/320 in all 3 cohorts. Patients in all 3 cohorts received a similar number of injections during the study period (9-10 in year-1; 5-6 in year-2). The year-1 improvement in ETDRS letters was significantly higher for aflibercept than for ranibizumab and bevacizumab in patients with baseline VA 20/50 or worse (p = 0.003 and p < 0.001, respectively), but was no different in patients with better baseline VA of 20/32 to 20/40 (p = 0.69). By year-2, among patients with poorer baseline VA, there was a difference in mean letters gained between aflibercept and bevacizumab (p = 0.02), but no difference between aflibercept and ranibizumab (p = 0.18). At year-2, there was no clinically meaningful difference in VA improvement (i.e., gain or loss of ≥10 or ≥15 letters) among any of the agents (p > 0.74). Bevacizumab was less effective than the other agents in decreasing CST at years-1 and -2 in the overall cohort of patients (p < 0.001). However, bevacizumab is substantially cheaper and much more cost-effective (when comparing expense and quality of life measures) than aflibercept and ranibizumab. The cost of other agents would have to decrease by 80-90% to be cost-effective relative to bevacizumab. Intravitreal administration of anti-VEGF therapy has relatively few ocular and systemic side effects, but caution may be warranted for patients with a recent history or high risk of myocardial infarction or stroke. CONCLUSIONS: Aflibercept, bevacizumab, and ranibizumab are highly effective treatments for DME. Bevacizumab is more cost-effective than aflibercept and ranibizumab. Intravitreal administration of drugs is relatively safe; however, intravitreal administration may be associated with severe systemic side effects in a small percentage of patients, particularly in those with a prior history of or high risk of Anti-Platelet Trialists' Collaboration events.

Application of Clinical Trial Results to Clinical Practice.

Two critical questions one must answer as one applies the results of a clinical trial to clinical practice are: (1) Regardless of whether the trial result is likely to be replicated or reproduced in a second large-scale trial, are the results likely to be reproduced in one's practice? (2) Regardless of whether the experimental treatment was better than the alternative on average for a population of patients, are the results clinically important for a given patient in one's practice? To determine if a study result is likely to be reproduced in one's clinical practice, it may be helpful to answer 5 questions: (1) Have steps been taken to minimize bias? (2) Is the result likely due to the treatment? (3) Is the result unlikely due to chance? (4) Is the study population representative of one's patients? (5) Is the totality of evidence consistent? If the answer to all 5 questions is "yes," then we posit that the trial result is likely to be reproduced in one's practice. If not, the likelihood of reproducibility is low. If the answer is yes to all questions except the last, then reproducibility in one's practice is not clear and depends on the strength of the prior versus the current evidence. If the prior evidence is strong, such as multiple pivotal randomized clinical trials, and if the current trial result is not consistent with the previous studies, then the current result may not be reproduced in one's practice. To determine if a study result is clinically important, a 3-step approach is suggested. Step 1. Decide, a priori, what a clinically meaningful difference between 2 treatments would be. This choice defines regions of beneficial, harmful, and trivial outcomes. Step 2. Identify the confidence intervals (CIs). Determine whether the 95% CI mostly includes the range of clinically beneficial outcomes and lies outside the range of clinically harmful outcomes. If these conditions are met, the result is probably clinically important, but the result may or may not be statistically significant. Put the CIs and the regions of benefit/harm together to make a decision about clinically important effects. Step 3. Assess the proportion of eyes with clinically meaningful changes in vision. The proportion of "responders" among patients receiving a given treatment reflects the likelihood of one's patient having a clinically meaningful response to the treatment. In summary, not all statistically significant results are reproduced, even those of carefully designed clinical trials. Determining if a study result is likely to be reproduced in one's practice is even more problematic. The 5-question test may help in this regard. The 5-question test attempts to assess whether steps have been taken to: minimize bias; avoid confounding; ensure adequate statistical power to support precision in the estimates of population parameters; insure external validity of the trial result; and determine whether there is a convergence of evidence consistent with the trial's major findings. To determine if a statistically significant result is likely to be clinically important, a 3-step approach may be useful, focusing on CIs and the proportion of eyes with clinically meaningful changes in vision. Application of clinical trial results to clinical practice requires critical analysis of the extant literature and good clinical judgment.

Posterior Segment Intraocular Foreign Bodies: A 10-Year Review.

PURPOSE: To describe the characteristics of open-globe injuries with posterior segment intraocular foreign bodies (IOFBs). DESIGN: Retrospective chart review study. PARTICIPANTS: Patients treated for posterior segment IOFB injuries. METHODS: Retrospective analysis of all patients with posterior segment IOFBs from 2003 to 2014 was conducted. Data including demographics, mechanism of injury, type of IOFB, method of diagnosis, presenting examination, medical and surgical treatment, visual outcomes, and complications were recorded. MAIN OUTCOME MEASURES: Visual acuity (VA); anatomically successful retinal reattachment; need for additional surgery; frequency of post-traumatic complications, such as sympathetic ophthalmia (SO), endophthalmitis, and enucleations; and accuracy of Ocular Trauma Score (OTS). RESULTS: Thirty-one patients (28 male; mean age, 36.6 years; 42% Hispanic) had posterior segment IOFB injuries, 23 (74%) of which were construction work related. Twenty-five IOFBs (81%) were metallic. Twenty-four IOFBs (77%) had Zone I entry. Computed tomography (CT) scan detected an IOFB in 21 of 22 eyes in which it was performed, with 1 scan highly suspicious for an IOFB. Average size of the IOFB was 10 mm3; size or initial VA did not have any correlation with final VA. The OTS had 60% accuracy in predicting final VA (n = 20). The majority of patients had traumatic cataract and vitreous hemorrhage (VH) on presentation (77% and 61%, respectively); 65% had a retinal tear or retinal detachment (RD), and these patients had worse final VA than those with no retinal pathology. Average time from injury to IOFB removal was 3 days because of the delay in presentation to our facility; 27 of 31 patients (87%) had IOFBs removed within 24 hours of presentation with pars plana vitrectomy (PPV) and either gas or silicone oil tamponade. Patients were admitted for an average of 4 days of intravenous antibiotics. The most common complication was recurrent RD in 11 patients (35%), which portended worse final VA. One patient (3%) developed SO. There were no cases of postoperative endophthalmitis or enucleation. CONCLUSIONS: Open-globe injuries with posterior segment IOFBs have a guarded visual prognosis, particularly when associated with RD. Increased awareness of the importance of eye protection can help minimize the occurrence of these injuries.

Corneal Haze as Prognostic Indicator of Intraocular Pressure in Primary Congenital Glaucoma.

PURPOSE: To perform a longitudinal analysis on the association of corneal haze with intraocular pressure (IOP) in eyes with primary congenital glaucoma (PCG) over 3 years. PATIENTS AND METHODS: Charts of all patients diagnosed with glaucoma of childhood from 2002 to 2012 at our institution were retrospectively reviewed. Inclusion criteria were age 18 years and below, plus elevated IOP or characteristic clinical signs. Exclusion criteria were eyes with secondary glaucoma or corneal haze not from PCG and patients with prior ocular surgery or incomplete follow-up. RESULTS: Of 79 eyes with childhood glaucoma during this period, 36 eyes had PCG [25 patients; 15 male (60.0%), 14 bilateral (56.0%)]. Eighteen eyes (13 patients) presented with corneal haze, whereas 18 eyes (12 patients) did not. Eyes with haze were diagnosed at a younger age than eyes without haze (0.79 vs. 5.2 y, P<0.02). During year 1, eyes with haze underwent significantly more IOP-lowering procedures and used significantly fewer IOP-lowering medications. Multivariate analysis revealed that corneal haze increased IOP by 4.63 mm Hg when controlling for treatment over time (P<0.01). Eyes with haze had lower survival curves and a failure hazard of 1.3 times that of eyes without haze. These eyes had a lower proportion of qualified successes than eyes without haze at year 1 (P<0.05) but this was reversed at year 3 (P<0.02). CONCLUSIONS: Eyes with PCG-related corneal haze generally presented more severely than did those without haze, but postmanagement outcomes may be similar to those in eyes without haze.

Intraocular foreign bodies: A review.

Intraocular foreign body injuries may result in a wide range of intraocular pathology and visual outcomes based on the mechanism of injury, type of foreign body, and subsequent complications. We have reviewed the literature to describe the epidemiology and mechanisms of such injuries; types of foreign bodies; imaging tools for diagnosis; current trends in management, presurgical, and surgical interventions; as well as visual prognosis and potential complications. The purpose of this review is to familiarize clinicians with the recent advances in diagnosis and management of such injuries.

The Economic Burden of Childhood Glaucoma.

PURPOSE: To date, there are limited data on the economic burden of childhood glaucoma, a relatively rare but visually debilitating disease. The purpose of this study is to evaluate the immediate costs of illness associated with childhood glaucoma during the first 4 years after presentation. METHODS: Data on age, sex, surgical interventions, visits, examinations under anesthesia, and medications were collected yearly following presentation in patients with childhood glaucoma. Inclusion criteria included diagnosis of primary or secondary childhood glaucoma, age less than 21 years, and follow-up of 4 years. A total of 23 patients (39 eyes) were included. Cost analysis used 2013 hospital-specific charges and US average hourly wage to calculate outcomes of total, direct, and indirect costs (significance level P<0.05). RESULTS: The annual cost of care of childhood glaucoma averaged $21,441.61 per patient, representing 1100% of annual costs in adult glaucoma and an increase of 800% in annual costs of health care per pediatric patient. The average total 4-year cost of care was $85,074.96 per patient. Surgical interventions and examinations under anesthesia were the greatest contributors to costs, representing 69.0% and 23.2% of total 4-year costs, respectively. The annual costs of care for childhood glaucoma were highest in the first year compared with subsequent years, averaging $46,293.62 per patient (P<0.05). CONCLUSIONS: Childhood glaucoma carries a substantial economic burden with the highest costs occurring in the first year after presentation. The greatest contributors to cost of illness are surgical interventions and examinations and anesthesia.

Characteristics of Children With Primary Congenital Glaucoma Receiving Trabeculotomy and Goniotomy.

PURPOSE: To describe the groups of patients who received trabeculotomy or goniotomy for the treatment of primary congenital glaucoma (PCG) regarding age at treatment, intraocular pressure (IOP) outcome, and medication burden. METHODS: A retrospective chart review of patients with PCG seen at Rutgers New Jersey Medical School, Newark, New Jersey, from 1998 to 2012 was conducted. Inclusion criteria were patients who received trabeculotomy or goniotomy with at least 9 months of follow-up. Presenting examination, surgical intervention, IOP, and number of medications at 1 and 2 years postoperatively were recorded. Absolute and qualified success, defined as IOP greater than 5 and less than 21 mm Hg without and with medications, respectively, was determined. RESULTS: Fifty eyes of 29 patients were diagnosed as having PCG. Of those, 25 eyes received trabeculotomy or goniotomy, with 19 fulfilling inclusion criteria. Average age at the time of trabeculotomy was 8 months versus 21 months for patients undergoing goniotomy. Mean IOP was significantly reduced (P < .001) for both trabeculotomy and goniotomy by 29.5% at 1 year and 33.3% at 2 years. There was no significant difference in IOP control between trabeculotomy and goniotomy groups. Patients in the goniotomy group were treated with significantly more medications before and after surgery compared to patients receiving trabeculotomy (P < .01), resulting in a greater rate of absolute success in trabeculotomy at 1 and 2 years. CONCLUSIONS: Patients with PCG who underwent trabeculotomy had higher IOP and were treated at an earlier age than those who had goniotomy. Both effectively lowered IOP up to 2 years with greater medication burden in patients receiving goniotomy.

Multimodal imaging in a severe case of hydroxychloroquine toxicity.

Retinal toxicity from hydroxychloroquine (HCQ) can be detected most readily on fundus autofluorescence, spectral-domain optical coherence tomography, and multifocal electroretinogram. The authors describe a case of a 60-year-old woman with a history of systemic lupus erythematosus undergoing HCQ treatment for 30 years who presented with visual loss over several years. Examination and multimodal imaging showed bilateral retinal pigment epithelium (RPE) changes in a bull's-eye distribution associated with cystoid macular edema. A novel imaging modality, multi-spectral imaging, appeared sensitive in detecting a bull's-eye pattern of RPE disturbance involving the entire macular region of both eyes. Cessation of drug was advised with close follow-up.