Clinical characteristics in the misdiagnosis of cytomegalovirus retinitis: A retrospective analysis of eight patients.

Purpose: To highlight characteristics in the misdiagnosis of cytomegalovirus retinitis (CMVR). Methods: Misdiagnosed cases related to CMVR were analyzed retrospectively at the Department of Ophthalmology, Beijing Youan Hospital, from July 2017 to October 2019. The medical records were reviewed by two independent senior ophthalmologists and the patients' clinical characteristics were analyzed. Results: Eight patients (16 eyes) were identified with misdiagnoses related to CMVR. Six of the patients with CMVR were previously unaware of their human immunodeficiency virus (HIV) infection; one patient with CMVR concealed their history of HIV infection. The cases were initially misdiagnosed as diabetic retinopathy (1/7, 14.3%), branch retinal vein occlusion (1/7, 14.3%), ischemic optic neuropathy (1/7, 14.3%), Behçet's disease (1/7, 14.3%), iridocyclitis (2/7, 28.6%), and progressive outer retinal necrosis (1/7, 14.3%). One patient with binocular renal retinopathy and chronic renal insufficiency was misdiagnosed with CMVR. Four eyes (4/16, 25%) presented with pan-retinal involvement. Fourteen eyes (14/16, 87.5%) had optic disc or macular area involvement. At the final diagnosis, one patient was blind, and two patients had low vision. Seven AIDS patients showed an extremely low level of CD4+ T lymphocytes (median of 5 cells/µl; range 1-9 cells/µl). Conclusion: CMVR may be misdiagnosed in the absence of known immune suppression. CMVR and HIV screening cannot be overlooked if a young male patient presents with yellowish-white retinal lesions. These misdiagnosed patients had severe retinitis associated with poor vision.

Macular Changes Observed on Optical Coherence Tomography Angiography in Patients Infected With Human Immunodeficiency Virus Without Infectious Retinopathy.

Purpose: As the human immunodeficiency virus (HIV) pandemic is far from over, whether there are subclinical macular changes in HIV-positive patients is something that should not be overlooked. We aimed to apply optical coherence tomography angiography (OCTA) to assess the macular structure and microvasculature changes in patients with HIV without infectious retinopathy. Methods: HIV-positive and -negative participants were included and classified into three groups: HIV-negative, HIV-positive, and HIV-positive with microvasculopathy. OCTA parameters regarding macular structure and microvasculature were analyzed. Results: Compared with the HIV-negative group, the superficial retinal vessel density (VD) in the parafovea sectors and the whole Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and the choroidal vascularity index (CVI) in the whole ETDRS grid were significantly decreased in the HIV-positive and HIV-positive with microvasculopathy groups (p < 0.05). No differences were found in OCTA parameters between the HIV-positive and HIV-positive with microvasculopathy groups. Retinal, retinal nerve fiber layer-ganglion cell layer-inner plexiform layer (RNFL-GCL-IPL), RNFL, GCL-IPL, and INL thickness showed a negative association with the duration of HIV diagnosis or antiretroviral therapy (ART) (all p < 0.05). All OCTA microvasculature parameters showed no association with HIV-related clinical variables (all p > 0.05). Conclusions: Subclinical macular changes existed in HIV-infected patients without clinical infectious retinopathy. Substructures from inner retinal layers might be associated with HIV infection or ART duration.

High Blood Cytomegalovirus Load Suggests Cytomegalovirus Retinitis in HIV/AIDS Patients: A Cross-Sectional Study.

PURPOSE: To clarify the cut off value of blood CMV load to indicate CMV retinitis and its relationships with ocular features. METHODS: Patients were divided into non-CMV and CMV retinitis groups. A logistic regression model was applied to estimate the association of each variable with CMV retinitis. Spearman correlation was used to estimate the correlation between the blood and aqueous CMV load. RESULTS: Blood CMV load higher than 4log10 (OR, 6.897; CI: 2.813-16.910; P < .001) was the major predictor of CMV retinitis. Blood CMV load wasn't different between the initial and early stage (P = .066). No correlation was observed between the blood and aqueous CMV load (P = .083, r = 0.228). CONCLUSIONS: Blood CMV load higher than 4log10 is an important predictor for CMV retinitis in HIV/AIDS patients, but it couldn't indicate the ocular features. Ophthalmologic screening is still necessary.Abbreviations: CMV: Cytomegalovirus; CMVR: Cytomegalovirus retinitis; HIV: Human Immunodeficiency Virus; AIDS: Acquired Immune Deficiency Syndrome; ART: Antiretroviral therapy; EOD: End-organ diseases; PCR: Polymerase Chain Reaction; OR: Odds Ratio; CI: 95% Confidence Interval; IQR: Interquartile range.

Macular Structure and Microvasculature Changes in AIDS-Related Cytomegalovirus Retinitis Using Optical Coherence Tomography Angiography.

Background: Cytomegalovirus retinitis (CMVR) is a crucial blind-causing disease of AIDS-related ocular opportunistic infection. The CMVR lesions produced retinal necrosis. It is not entirely clear whether CMVR eyes without macular-involved necrotic lesions may have subtle macular damage. In this study, we conducted a cross-sectional study using optical coherence tomography angiography (OCTA) to evaluate macular microvasculature and structure in eyes with AIDS-related CMVR. Methods: Acquired immune deficiency syndrome (AIDS)-related CMVR patients (active and inactive CMVR) and healthy controls treated in the Department of Ophthalmology, Beijing Youan Hospital, Capital Medical University between August 25, 2019, and October 18, 2019, were recruited. All OCTA parameters, including the foveal avascular zone (FAZ), retinal vessel density (VD), choroidal vascularity index (CVI), retinal thickness, and choroidal thickness, were compared between groups after the signal strength was corrected. Results: Signal strength in the 3 × 3 and 6 × 6 mm scan patterns was significantly weaker in the inactive CMVR group than in the control group (both p < 0.001). After adjusting for signal strength, heterogeneity in the central fovea and parafoveal quadrants was present with a shift toward lower macular chorioretinal vasculature, decreased full choroidal thickness, and thicker retinal thickness in the active and inactive CMVR groups. The retinal nerve fiber layer (RNFL) and inner nuclear layer (INL) were significantly thicker in the active and inactive CMVR groups than in the control group (all p < 0.05). For photoreceptor-retinal pigment epithelium (PR-RPE) thickness, no significant differences were found in any quadrant between groups. Foveal avascular zone areas were not significantly different among the three groups (p = 0.053). Conclusions: Subtle macular structure and microvasculature damage still existed in CMVR eyes without macular-involved necrotic lesions. The results of our study are helpful for a deep understanding of the damage caused by CMVR.

Clinical efficacy of laser therapy in the prevention of retinal detachment in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis.

BACKGROUND: The aim of the present study was to evaluate the clinical efficacy of laser therapy in the prevention of retinal detachment in patients with acquired immunodeficiency syndrome (AIDS) and cytomegalovirus retinitis (CMVR). METHODS: A total of 96 eyes from 80 patients with AIDS and CMVR who received anticytomegalovirus (anti-CMV) treatment in the ophthalmology and infection centers of Beijing YouAn Hospital, between June 2016 and August 2018 were retrospectively investigated. The patients were randomly divided into a nonlaser group (50 eyes from 43 patients), who were treated with anti-CMV therapy, and a laser group (46 eyes from 37 patients), who were treated with a fundus laser method to close the retinopathy area after commencing the maintenance stage of anti-CMV treatment. Both groups were followed up for 24 months. The safety of laser therapy was observed, and the efficacy of the therapy was determined by evaluating the incidence of retinal detachment. RESULTS: The percentage of retinal detachment in the nonlaser group was 24% compared with 6.5% in the laser group (P=0.018). There was no significant difference between the two groups in the number of CD4+ T cells, the load of human immunodeficiency virus, or the time between the detachment and the end of the induction period. After laser therapy, 39.13% of patients exhibited keratic precipitates (KP), 30.43% had anterior chamber flare (±), 50% had anterior chamber flare (+), and 19.57% had anterior chamber flare (++). Intraocular pressure (IOP) increased in 3 eyes within 2 weeks of laser therapy. The retinal pigment reaction was not obvious in 8 eyes. CONCLUSIONS: The use of laser therapy in the main maintenance period of anti-CMV treatment can effectively reduce the incidence of retinal detachment in patients with AIDS and CMVR, and the therapy is safe and reliable.

Clinical Features of Ocular Pathology in Patients with Acquired Immunodeficiency Syndrome and Syphilis.

INTRODUCTION: The present study aimed to analyze the clinical features of ocular pathology in patients with acquired immunodeficiency syndrome (AIDS) combined with syphilis. METHODS: A total of 129 patients with AIDS and syphilis who first visited the Department of Ophthalmology in Beijing YouAn Hospital between 2012 and 2019 were included in the study. All patients underwent ophthalmologic examinations, such as best-corrected visual acuity (BCVA), slit lamp, intraocular pressure, dilated fundus examination, and color fundus photography as well as systemic examinations related to AIDS and syphilis. The patients were divided into four groups according to fundus disease: a normal fundi group, an HIV-related microvascular retinopathy (MVR) group, a cytomegalovirus retinitis (CMVR) group, and a syphilis-related retinopathy group. RESULTS: The incidence of fundus disease was 70.7%. There were 36 patients with normal fundi (29.3%), 40 with HIV-related MVR (31.0%), 25 with CMVR (19.4%) (including 11 cases of CMVR with syphilis-related retinopathy), 26 (20.2%) with syphilis-related retinopathy, 1 (0.78%) case with acute retinal necrosis, and 1 (0.78%) case with PORN. The median blood CD4 + T-cell count in the syphilis-associated retinopathy group was 357.5 cells/µl, which was significantly higher than in the other groups; this difference was statistically significant. In the CMVR group, 11 cases with concomitant syphilis-associated retinopathy had lower BCVA and 10 (90.9%) had active inflammatory manifestations in the anterior segment. CONCLUSION: The incidence of ocular pathology was high in patients co-infected with AIDS and syphilis, which might manifest in a variety of ocular manifestations; some patients may also have multiple ocular changes, which should be given great clinical attention.

Effect of Anti-CMV Therapy at Different Stages on Retinal Detachment in Patients with AIDS and CMVR.

INTRODUCTION: The present study aimed to investigate the effect of anti-cytomegalovirus (anti-CMV) therapy at different stages on retinal detachment in patients with acquired immunodeficiency syndrome (AIDS) and cytomegalovirus retinitis (CMVR). METHODS: Ninety-seven patients with AIDS and CMVR diagnosed and treated at the Ophthalmology and Infection Center of Beijing You'an Hospital, affiliated with Capital Medical University, from November 2017 to January 2020 were retrospectively analyzed. Of the 138 eyes included, 30 eyes with concomitant retinal detachment were enrolled as the study subjects. The eyes with retinal detachment were divided into a pre-induction group, an intra-induction group, and a post-induction group of anti-CMV therapy. The occurrence and characteristics of retinal detachment at different stages of anti-CMV therapy were observed. RESULTS: Retinal detachment occurred in 30 of the 138 eyes of 97 patients, with an incidence of retinal detachment of 21.74%. Retinal detachment occurred in eight eyes in the pre-induction group, with an incidence of 26.67%, and in four eyes in the intra-induction group, with an incidence of 13.33%. The difference in incidence between the two groups was statistically significant (P = 0.000). Retinal detachment occurred in 18 eyes in the post-induction group, with an incidence of 60%. The difference in incidence between the intra-induction group and the post-induction group was statistically significant (P = 0.001). CONCLUSION: The incidence of retinal detachment at the intra-induction stages of anti-CMV therapy was lower than that at the pre-induction stage, and retinal detachment during the anti-CMV therapy predominantly occurred after the end of the induction stage.

Utility of Ultra-Wide-Field Imaging for Screening of AIDS-Related Cytomegalovirus Retinitis.

PURPOSE: To explore the potential use of ultra-wide-field (UWF) imaging for screening of cytomegalovirus retinitis (CMVR) in AIDS patients. METHODS: Ninety-four patients whose CD4 count was below 200 cells/µL were enrolled in a prospective study. Each patient underwent UWF imaging and indirect ophthalmoscopy. The main outcome measures were the concordance and detection rates of these 2 approaches and the sensitivity and specificity of UWF imaging. RESULTS: Twenty-seven eyes in 18 patients were diagnosed with CMVR by the indirect ophthalmoscopy. UWF imaging missed the diagnosis in 1 eye because of a zone 3 CMVR lesion. The UWF image showed several CMVR patterns and locations: hemorrhagic necrotizing lesion, granular lesion, frosted branch angiitis, and optic neuropathy lesion. The concordance of the 2 approaches was excellent for the diagnosis of CMVR, classification of CMVR pattern, and location of CMVR. The detection rates of UWF imaging and indirect ophthalmoscopy were 14.0% (26/186; 95% CI 0.089-0.190) and 14.5% (27/186; 95% CI 0.094-0.196), respectively (p = 1.000). The sensitivity and specificity of UWF imaging were 96.3 and 100%, respectively. CONCLUSIONS: UWF imaging is capable of documentation of different CMVR lesions and AIDS-related CMVR screening when examination by an ophthalmologist is not available.

Effect of individualized therapy for AIDS patients with cytomegalovirus retinitis in intravitreal ganciclovir injections.

The effect of intravitreal ganciclovir injection combined with intravenous infusion on acquired immune deficiency syndrome (AIDS) patients with cytomegalovirus retinitis (CMVR) was investigated. A total of 32 eyes in 23 AIDS patients diagnosed as CMVR from 2017 to 2018 were included in the retrospective study. All patients underwent induction therapy by using intravenous drip of the anti-cytomegalovirus (CMV) agent ganciclovir (5 mg/kg q12h) combined with intravitreal ganciclovir injection (3 mg/time, 2 times/wk). The visual acuity, fundus photographs, lesion location, and number of intravitreal injections were observed preoperatively and postoperatively. Totally 14 eyes were cured during induction therapy. The number of injections [4.13 (2 to 6)] in CMVR patients with peripherally fundus lesions were significantly lower than those with central lesions [4.89 (2 to 6)]. The individualized therapy of intravitreal ganciclovir injections for AIDS patients with CMVR can effectively reduce the numbers of intravitreal injections.

A comparative study on retinal thickness of the macular region among AIDS patients with normal ocular fundus, HIV-related microvascular retinopathy patients, and cytomegalovirus retinitis patients.

The present study aims to measure the retinal thickness of the macular region of AIDS patients with normal ocular fundus, HIV-related microvascular retinopathy patients and cytomegalovirus retinitis (CMVR) patients by optical coherence tomography, and generalize the characteristics of retinal thickness of these 3 groups of patients.In this retrospective case series, the study object comprised of 111 AIDS patients who received diagnosis and treatment in the Ophthalmology Department of Beijing Youan Hospital. There are 33 patients in the AIDS normal ocular fundus group, 47 patients in the HIV-related microvascular retinopathy group, and 31 patients in the CMVR group. The retinal thickness of the macular region of these above patients was measured. The main indicators were retinal thickness of 9 macular partitions, best corrected visual acuity, CD4+ T lymphocyte count, and the start of highly active antiretroviral therapy.In the CMVR group, except for the nasal-outer and temporal-outer sectors, the thickness of the affected eye of the rest of the regions was greater than that of healthy eye (P < .05). Furthermore, there was a difference in thickness of the superior-outer and inferior-outer sectors between the AIDS normal ocular fundus group and HIV-related microvascular retinopathy group. The difference in thickness of the superior-inner sector between patients in the AIDS normal ocular fundus group and CMVR group was not statistically significant, while the difference in thickness of the rest of the regions was statistically significant. The difference in thickness of various regions between patients in the HIV-related microvascular retinopathy group and CMVR group was statistically significant.The retinal thickness of patients in the CMVR group generally increased, the retinal thickness of superior-outer and inferior-outer sections of patients in the HIV-related microvascular retinopathy group increased, when compared to the AIDS normal ocular fundus group. These optical coherence tomography (OCT) examination results present its own characteristics in different eye diseases in AIDS patients, and different stages of eye disease.

Visual acuity and subfoveal choroidal thickness: the Beijing Eye Study.

PURPOSE: To examine the association between best corrected visual acuity (BCVA) and subfoveal choroidal thickness. DESIGN: Population-based study. METHODS: The Beijing Eye Study 2011 included 3468 subjects with ages of 50+ years. The participants underwent an ophthalmologic examination including spectral-domain optical coherence tomography with enhanced depth imaging for measurement of choroidal thickness. BCVA was measured as logarithm of the minimal angle of resolution. RESULTS: Of the 3468 participants, choroidal measurements were available for 3233 (93.2%) subjects. In multivariate analysis, better BCVA was significantly associated with thicker subfoveal choroid (P < 0.001) in general and a subfoveal choroid thicker than 30 µm (P < 0.001) in particular, after adjusting for younger age (P < 0.001), higher level of education (P < 0.001), taller body stature (P < 0.001), higher body mass index (P = 0.005), absence of glaucoma (P = 0.001), absence of diabetic retinopathy (P < 0.001), absence of late-stage age-related macular degeneration (P < 0.001), and axial length shorter than 26.0 mm (P < 0.001) (correlation coefficient r:0.56). If eyes with glaucoma, diabetic retinopathy, late-stage age-related macular degeneration or myopic retinopathy were excluded, better BCVA was still significantly associated with thicker subfoveal choroid (P < 0.001) and subfoveal choroid thicker than 30 µm (P < 0.001) in multivariate analysis. In a reverse manner, thicker subfoveal choroid was associated with better BCVA (P < 0.001) after adjusting for younger age (P < 0.001), male gender (P < 0.001), longer axial length (P < 0.001), and higher corneal curvature radius (P < 0.001). CONCLUSIONS: Better visual acuity is strongly associated with thicker subfoveal choroid independent of additional factors, such as age, axial length, education level, and major ocular diseases.

Subfoveal choroidal thickness in diabetes and diabetic retinopathy.

PURPOSE: To examine subfoveal choroidal thickness (SFCT) in patients with diabetes mellitus and patients with diabetic retinopathy. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6 ± 9.8 years (range, 50-93 years). METHODS: A detailed ophthalmic examination was performed including spectral-domain optical coherence tomography (OCT) with enhanced depth imaging for measurement of SFCT and fundus photography for the assessment of diabetic retinopathy. MAIN OUTCOME MEASURES: Subfoveal choroidal thickness. RESULTS: Fasting blood samples, fundus photographs, and choroidal OCT images were available for 2041 subjects (58.8%), with 246 subjects (12.1 ± 0.7%) fulfilling the diagnosis of diabetes mellitus and 23 subjects having diabetic retinopathy. Mean SFCT did not differ significantly between patients with diabetes mellitus and nondiabetic subjects (266 ± 108 vs. 261 ± 103 µm; P=0.43) nor between patients with diabetic retinopathy and subjects without retinopathy (249 ± 86 vs. 262 ± 104 µm; P = 0.56). After adjustment for age, sex, axial length, lens thickness, anterior chamber depth, corneal curvature radius, and best-corrected visual acuity, SFCT was associated with a higher glycosylated hemoglobin (HbA1c) value (P<0.001; regression coefficient B, 8.18; 95% confidence interval [CI], 4.02-12.3); standardized coefficient ß, 0.08) or with the presence of diabetes mellitus (P = 0.001; B, 21.3; 95% CI, 9.12-33.5) but not with presence of diabetic retinopathy (P = 0.61) or stage of diabetic retinopathy (P = 0.14). As a corollary, after adjusting for age, region of habitation, body mass index, systolic and diastolic blood pressure, and level of education, diabetes mellitus was associated with a thicker SFCT (P<0.001). In contrast, neither presence of diabetic retinopathy (P = 0.61) nor stage of diabetic retinopathy (P = 0.09) were associated significantly with SFCT after adjusting for body mass index, diastolic and systolic blood pressure, and level of education and after adjusting for blood glucose concentrations, HbA1c value, diagnosis of diabetes mellitus, and systolic and diastolic blood pressure, respectively. CONCLUSIONS: Patients with diabetes mellitus had a slightly, but statistically significantly, thicker subfoveal choroid, whereas presence and stage of diabetic retinopathy were not associated additionally with an abnormal SFCT. Whereas diabetes mellitus as a systemic disease leads to a slight thickening of the choroid, diabetic retinopathy as an ocular disorder was not associated with choroidal thickness abnormalities after adjusting for the presence of diabetes mellitus. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Reproducibility of subfoveal choroidal thickness measurements with enhanced depth imaging by spectral-domain optical coherence tomography.

PURPOSE: To measure the interobserver reproducibility and intra-observer reproducibility of subfoveal choroidal thickness measurements performed by enhanced depth imaging of spectral-domain optical coherence tomography (EDI-OCT) in a population-based setting. METHODS: The Beijing Eye Study 2011 was a population-based study performed in rural and urban regions of Greater Beijing. The study included 3468 individuals with a mean age of 64.6 ± 9.8 years (range, 50-93 years). The participants underwent EDI-OCT and the subfoveal choroidal thickness (SFCT) was measured. To examine the interobserver variability, all images were assessed by two examiners independently of each other within 2 months. To examine the intra-observer reproducibility, a smaller study sample consisting of 21 eyes of 21 healthy subjects from the Tongren Eye Center was included in the study. These latter subjects were scanned 10 times with 1 minute breaks between each examination. The SFCT was measured by the same observer within 2 weeks. The intrasession within subject SD, the coefficient of variation, and the intraclass correlation coefficient (ICC) were calculated. RESULTS: EDI-OCTs were performed for 3233 subjects. Mean SFCT measured by grader one and grader two were 254.6 ± 107.3 µm and 253.8 ± 107.4 µm, respectively, with a mean difference of 3.14 ± 13.1 µm (95% confidence interval, 0.0, 24.0). Bland-Altman plot showed 1.9% (61/3233) points outside the 95% limits of agreement. For the assessment of the intra-observer reproducibility, the ICC was 1.00 (P < 0.001, and the mean coefficient of variation was 0.85% ± 1.48%). CONCLUSIONS: Under routine examination conditions, SFCT measurements by EDI-OCT showed a high intra-observer reproducibility and interobserver reproducibility.

Subfoveal choroidal thickness: the Beijing Eye Study.

PURPOSE: To study subfoveal choroidal thickness (SFCT) in adult Chinese subjects and its correlation with ocular biometric parameters, refractive error, and age. DESIGN: Population-based longitudinal study. PARTICIPANTS: The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years (range, 50-93 years). METHODS: A detailed ophthalmic examination was performed, including spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging for measurement of SFCT. MAIN OUTCOME MEASURES: Subfoveal choroidal thickness. RESULTS: The SFCT measurements were available for 3233 subjects (93.2%). Mean SFCT was 253.8±107.4 µm (range, 8-854 µm). In multivariate analysis, SFCT increased with younger age (P<0.001; correlation coefficient r=4.12; beta coefficient=0.37), shorter axial length (P<0.001; r=44.7; beta coefficient=0.46), male gender (P<0.001; r=28.5; beta coefficient=-0.13), deeper anterior chamber depth (P<0.001; r=39.3; beta coefficient=0.13), thicker lens (P<0.001; r=26.8; beta coefficient=0.08), flatter cornea (P<0.001; r=46.0; beta coefficient=0.11), and better best-corrected visual acuity (BCVA) (logarithm of minimal angle of resolution; P=0.001; r=48.4; beta coefficient=0.06). In multivariate analysis, SFCT was not significantly associated with blood pressure, ocular perfusion pressure, intraocular pressure, cigarette smoking, alcohol consumption, serum concentrations of lipids and glucose, diabetes mellitus, and arterial hypertension. In the myopic refractive error range of more than -1 diopter (D), SFCT decreased by 15 µm (95% confidence interval [CI], 11.9-18.5) for every increase in myopic refractive error of 1 D, or by 32 µm (95% CI, 37.1-26.0) for every increase in axial length of 1 mm. For each year increase in age, the SFCT decreased by 4.1 µm (95% CI, 4.6-3.7) (multivariate analysis). CONCLUSIONS: Subfoveal choroidal thickness with a mean of 254±107 µm in elderly subjects with a mean age of 65 years decreased with age (4 µm per year of age) and myopia (15 µm per diopter [D] of myopia). It was also associated with male gender and the ocular biometric parameters of a deeper anterior chamber and thicker lens. The association between SFCT and BCVA indicates a functional aspect of SFCT. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.