Retinal artery occlusion in young patients without typical cardiovascular risk factors: etiologies, prognosis, and suggested work-up.

PURPOSE: To understand the etiology, work-up, and secondary systemic and ocular events of retinal artery occlusion (RAO) in young patients (≤ 45 years old) without typical cardiovascular risk factors. METHODS: Retrospective longitudinal case series of 18 young patients with RAO and without typical cardiovascular risk factors evaluated at the University of Michigan Medicine Health System between the year 2000 and 2022. Laboratory and imaging studies performed at the time of RAO diagnosis, along with systemic and ocular events during follow-up, were recorded. These data were combined with data from a literature review of 74 similar patients experiencing a RAO. RESULTS: Fifteen (83%) of patients were female and 10 (56%) suffered a branch retinal artery occlusion (BRAO). 56% of patients had one risk factor associated with cryptogenic stroke, most commonly a migraine history (33%). The most frequent etiology of RAO was vasculitis (28%), followed by idiopathic (22%) and patent foramen ovale (PFO, 17%). Three out of four patients with idiopathic RAOs developed new migraines around the time of RAO diagnosis, whereas none of the patients with a clear etiology had new onset migraines (n = 14). No patients suffered a stroke or myocardial infarction (MI) in the follow-up period (average 3.6 years ± 3.2 years). Two patients (11%) suffered a repeat RAO, both of whom were diagnosed with a vasculitis. Patients with isolated retinal vasculitis required repeat fluorescein angiograms for up to 2 years after the initial event to definitively identify the vasculitic etiology of the RAO. When our data are pooled with similarly healthy patients from previously published RAO series, structural/functional cardiac abnormalities and vasculitides are the most common identifiable etiologies for RAOs in this group. CONCLUSION: The most common identifiable etiologies of RAO in young patients with low cardiovascular risk are structural/functional cardiac abnormalities and vasculitides, with a small range of additional causes/associations accounting for remaining cases. We suggest a focused work-up algorithm to rapidly identify etiologies in this group while minimizing unnecessary testing. The long-term risk of systemic or ocular secondary events in these patients is low regardless of the etiology of their RAO.

Sagittal Full-Spine vs. Sectional Cervical Lateral Radiographs: Are the Measurements of Cervical Alignment Interchangeable?

(1) Background: This study assessed the relationship between cervical spine parameters taken on standing full-spine lateral radiographic images compared to sectional lateral cervical radiographs. (2) Methods: Full-spine (FS) and sectional lateral cervical (LC) radiographs from four spine treatment facilities across the USA retrospectively provided data collected on 220 persons to assess the comparison of three sagittal cervical radiographic measurements between the two views. The measures included cervical lordosis using the absolute rotation angle from C2-C7, sagittal cervical translation of C2-C7, and atlas plane angle to horizontal. Linear correlation and R2 models were used for statistical comparison of the measures for the two views. (3) Results: The mean values of the three measurements were statistically different from each other: C2-C7 translation (FS = 19.84 ± 11.98 vs. LC = 21.18 ± 11.8), C2-C7 lordosis (FS = -15.3 ± 14.63 vs. LC = -18.32 ± 13.16), and atlas plane (FS = -19.99 ± 8.88 vs. LC = -22.56 ± 8.93), where all values were p < 0.001. Weak-to-moderate-to-strong correlations existed between the full-spine and sectional lateral cervical radiographic variables. The R2 values varied based on the measurement were R2 = 0.768 (p < 0.001) for sagittal cervical translation of C2-C7 (strong), R2 = 0.613 (p < 0.001) for the absolute rotation angle C2-C7 (moderate), and R2 = 0.406 (p < 0.001) for the atlas plane line (weak). Though a linear correlation was identified, there were consistent intra-person differences between the measurements on the full spine versus sectional lateral cervical radiographic views, where the full-spine view consistently underestimated the magnitude of the variables. (4) Conclusion: Key sagittal cervical radiographic measurements on the full spine versus sectional lateral cervical radiographic views show striking intra-person differences. The findings of this study confirm that full spine versus sectional lateral cervical radiographic views provide different biomechanical magnitudes of cervical sagittal alignment, and caution should be exercised by health care providers as these are not interchangeable. We recommend the LC view for measurement of cervical sagittal alignment variables.

Machine learning on alignment features for parent-of-origin classification of simulated hybrid RNA-seq.

BACKGROUND: Parent-of-origin allele-specific gene expression (ASE) can be detected in interspecies hybrids by virtue of RNA sequence variants between the parental haplotypes. ASE is detectable by differential expression analysis (DEA) applied to the counts of RNA-seq read pairs aligned to parental references, but aligners do not always choose the correct parental reference. RESULTS: We used public data for species that are known to hybridize. We measured our ability to assign RNA-seq read pairs to their proper transcriptome or genome references. We tested software packages that assign each read pair to a reference position and found that they often favored the incorrect species reference. To address this problem, we introduce a post process that extracts alignment features and trains a random forest classifier to choose the better alignment. On each simulated hybrid dataset tested, our machine-learning post-processor achieved higher accuracy than the aligner by itself at choosing the correct parent-of-origin per RNA-seq read pair. CONCLUSIONS: For the parent-of-origin classification of RNA-seq, machine learning can improve the accuracy of alignment-based methods. This approach could be useful for enhancing ASE detection in interspecies hybrids, though RNA-seq from real hybrids may present challenges not captured by our simulations. We believe this is the first application of machine learning to this problem domain.

Drug Approval for the Treatment of Geographic Atrophy: How We Got Here and Where We Need to Go.

PURPOSE: To discuss the clinical trial results leading to the US Food and Drug Administration (FDA) approval of anti-complement therapies for geographic atrophy (GA), perspectives on functional data from the GA clinical trials, and how lessons from the FDA approval may guide future directions for basic and clinical research in AMD. DESIGN: Selected literature review with analysis and perspective METHODS: We performed a targeted review of publicly available data from the clinical trials of pegcetacoplan and avacincaptad for the treatment of GA, as well as scientific literature on the natural history of GA and the genetics and basic science of complement in AMD. RESULTS: The approval of pegcetacoplan and avacincaptad was based on an anatomic endpoint of a reduction in the rate of GA expansion over time. However, functional data from 2 phase 3 clinical trials for each drug demonstrated no visual benefit to patients in the treatment groups. Review of the genetics of AMD and the basic science of the role for complement in AMD provides only modest support for targeting complement as treatment for GA expansion, and alternative molecular targets for GA treatment are therefore discussed. Reasons for the disconnect between anatomic and functional outcomes in the clinical trials of anti-complement therapies are discussed, providing insight to guide the configuration of future clinical studies for GA. CONCLUSION: Although avacincaptad and pegcetacoplan are our first FDA-approved treatments for GA, results from the clinical trials failed to show any functional improvement after 1 and 2 years, respectively, calling into question whether the drugs represent a "clinically relevant outcome." To improve the chances of more impactful therapies in the future, we provide basic-science rationale for pursuing non-complement targets; emphasize the importance of ongoing clinical research that more closely pins anatomic features of GA to functional outcomes; and provide suggestions for clinical endpoints for future clinical trials on GA.

Intraocular Pressure Lowering Associated With Worsening Optic Pit-Like Retinoschisis.

In this article, we present a case of optic pit-like macular retinoschisis in the absence of advanced glaucomatous cupping. Intraocular pressure (IOP)-lowering therapy, which was started due to an early concern for glaucoma, caused a worsening of the retinoschisis, which subsequently resolved on discontinuation of the IOP-lowering therapy. Lower IOP likely triggered intraretinal fluid accumulation by facilitating a translaminar gradient from the subarachnoid to intraretinal space. [Ophthalmic Surg Lasers Imaging Retina 2024;55:100-102.].

Multi-symptom Relief with Propylene Glycol-Hydroxypropyl-Guar Nanoemulsion Lubricant Eye Drops in Subjects with Dry Eye Disease: A Post-Marketing Prospective Study.

INTRODUCTION: The study aimed to evaluate multi-symptom relief of dry eye manifestations with the use of propylene glycol-hydroxypropyl-guar (PG-HPG) nanoemulsion lubricant eye drops, among subjects with dry eye disease (DED). METHODS: This was a post-marketing, prospective, single-arm study conducted in the USA. Subjects aged ≥ 18 years, with tear breakup time (TBUT) ≤ 10 s for both eyes, dry eye questionnaire-5 (DEQ-5) "watery eyes" symptom score 1-4, symptoms of burning/stinging, sore and tired eyes as determined by impact of dry eye on everyday living-symptom bother (IDEEL-SB) questionnaire, and IDEEL-SB score 16-65 were included. Subjects were required to complete IDEEL-SB and DEQ-5 at days 0, 14 ± 2, and 28 ± 2, and self-administer one drop of PG-HPG four times daily for 28 ± 2 days. Primary endpoints were change from baseline at day 28 in symptoms of sore, stinging/burning, and tired eyes on IDEEL-SB; and symptom of watery eyes on DEQ-5. Other endpoints evaluated were corneal staining and TBUT at baseline and day 28 ± 2; symptom relief (5-point Likert scale) at day 28 ± 2, and safety. RESULTS: Of 119 subjects enrolled, 95 completed the study (mean ± SD age 61.2 ± 13.0 years; female 69.5%). Mean IDEEL-SB scores reduced significantly from baseline at day 28 for symptoms of aching/sore eyes (change from baseline - 1.0 ± 1.1), burning/stinging eyes (change from baseline - 1.1 ± 0.9), and tired eyes (change from baseline - 1.1 ± 1.0) (all p < 0.0001). Mean DEQ-5 score for watery eye symptoms significantly reduced from baseline at day 28 (change from baseline - 0.9 ± 1.0, p < 0.0001). Corneal staining at day 28 was comparable to baseline. TBUT improved from baseline to day 28. On a Likert scale, more than 50% of subjects reported relief from symptoms of sore, stinging, and burning eyes. Three (3.1%) subjects reported treatment-emergent adverse events (non-ocular). CONCLUSIONS: PG-HPG nanoemulsion lubricant eye drops significantly improved multiple dry eye symptoms in subjects with DED over 28 days, with no new safety concerns. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT05056155.

Race, Ethnicity, and Ancestry in Clinical Pathways: A Framework for Evaluation.

Clinical algorithms, or "pathways," promote the delivery of medical care that is consistent and equitable. Race, ethnicity, and/or ancestry terms are sometimes included in these types of guidelines, but it is unclear if this is appropriate for clinical decision-making. At our institution, we developed and applied a structured framework to determine whether race, ethnicity, or ancestry terms identified in our clinical pathways library should be retained, modified, or removed. First, we reviewed all text and associated reference documents for 132 institutionally-developed clinical pathways and identified 8 pathways that included race, ethnicity, or ancestry terms. Five pathways had clear evidence or a change in institutional policy that supported removal of the term. Multispecialty teams conducted additional in-depth evaluation of the 3 remaining pathways (Acute Viral Illness, Hyperbilirubinemia, and Weight Management) by applying the framework. In total, based on these reviews, race, ethnicity, or ancestry terms were removed (n = 6) or modified (n = 2) in all 8 pathways. Application of the framework established several recommended practices, including: (1) define race, ethnicity, and ancestry rigorously; (2) assess the most likely mechanisms underlying epidemiologic associations; (3) consider whether inclusion of the term is likely to mitigate or exacerbate existing inequities; and (4) exercise caution when applying population-level data to individual patient encounters. This process and framework may be useful to other institutional programs and national organizations in evaluating the inclusion of race, ethnicity, and ancestry in clinical guidelines.

Medium Depth Influences O2 Availability and Metabolism in Human RPE Cultures.

Purpose: Retinal pigment epithelium (RPE) oxidative metabolism is critical for normal retinal function and is often studied in cell culture systems. Here, we show that conventional culture media volumes dramatically impact O2 availability, limiting oxidative metabolism. We suggest optimal conditions to ensure cultured RPE is in a normoxic environment permissive to oxidative metabolism. Methods: We altered the availability of O2 to human primary and induced pluripotent stem cell-derived RPE cultures directly via a hypoxia chamber or indirectly via the amount of medium over cells. We measured oxygen consumption rates (OCRs), glucose consumption, lactate production, 13C6-glucose and 13C5-glutamine flux, hypoxia inducible factor 1α (HIF-1α) stability, intracellular lipid droplets after a lipid challenge, transepithelial electrical resistance, cell morphology, and pigmentation. Results: Medium volumes commonly employed during RPE culture limit diffusion of O2 to cells, triggering hypoxia, activating HIF-1α, limiting OCR, and dramatically altering cell metabolism, with only minor effects on typical markers of RPE health. Media volume effects on O2 availability decrease acetyl-CoA utilization, increase glycolysis and reductive carboxylation, and alter the size and number of intracellular lipid droplets under lipid-rich conditions. Conclusions: Despite having little impact on visible and typical markers of RPE culture health, media volume dramatically affects RPE physiology "under the hood." As RPE-centric diseases like age-related macular degeneration involve oxidative metabolism, RPE cultures need to be optimized to study such diseases. We provide guidelines for optimal RPE culture volumes that balance ample nutrient availability from larger media volumes with adequate O2 availability seen with smaller media volumes.

Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux.

Purpose: In age-related macular degeneration (AMD) and Sorsby's fundus dystrophy (SFD), lipid-rich deposits known as drusen accumulate under the retinal pigment epithelium (RPE). Drusen may contribute to photoreceptor and RPE degeneration in AMD and SFD. We hypothesize that stimulating ß-oxidation in RPE will reduce drusen accumulation. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate ß-oxidation and diminish lipid accumulation in fatty liver disease. In this report we test the hypothesis that an ACC inhibitor, Firsocostat, limits the accumulation of lipid deposits in cultured RPE cells. Methods: We probed metabolism and cellular function in mouse RPE-choroid, human fetal- derived RPE cells, and induced pluripotent stem cell-derived RPE cells. We used 13 C6-glucose and 13 C16-palmitate to determine the effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism. 13 C labeling of metabolites in these pathways were analyzed using gas chromatography-linked mass spectrometry. We quantified ApoE and VEGF release using enzyme-linked immunosorbent assays. Immunostaining of sectioned RPE was used to visualize ApoE deposits. RPE function was assessed by measuring the trans-epithelial electrical resistance (TEER). Results: ACC inhibition with Firsocostat increases fatty acid oxidation and remodels lipid composition, glycolytic metabolism, lipoprotein release, and enhances TEER. When human serum is used to induce sub-RPE lipoprotein accumulation, fewer lipoproteins accumulate with Firsocostat. In a culture model of Sorsby's fundus dystrophy, Firsocostat also stimulates fatty acid oxidation, improves morphology, and increases TEER. Conclusions: Firsocostat remodels intracellular metabolism and improves RPE resilience to serum-induced lipid deposition. This effect of ACC inhibition suggests that it could be an effective strategy for diminishing drusen accumulation in the eyes of patients with AMD.

Treatment of mild to severe acne with 1726 nm laser: A safe alternative to traditional acne therapies.

INTRODUCTION: Acne is the most common reason for dermatology consultation in adolescents and young adults. Consultation is often delayed despite unsuccessful self-treatment. Postponing effective treatment places acne sufferers at higher risk for permanent acne scars and post-inflammatory pigment changes. AIM: This review discusses clinical challenges with present therapeutic options for acne treatment and the role of a 1726 nm laser for acne. METHODS: Current acne treatment guidelines were reviewed. A literature review was conducted for trials of light-based acne therapy. The selectivity of previous light-based therapies was reviewed. RESULTS: Available acne therapy is effective, but treatment-related side effects are common. Acne treatment guidelines do not include recommendations for light-based treatments. Different types of light-based treatments have been tried but until now no wavelength specifically targeted sebaceous glands. CONCLUSION: The 1726 nm laser is safe and effective for treating mild to severe acne in all Fitzpatrick skin types. Acne resolution is apparent within the first month and improves for up to 2 years beyond treatment.

Structural evidence for MADS-box type I family expansion seen in new assemblies of Arabidopsis arenosa and A. lyrata.

Arabidopsis thaliana diverged from A. arenosa and A. lyrata at least 6 million years ago. The three species differ by genome-wide polymorphisms and morphological traits. The species are to a high degree reproductively isolated, but hybridization barriers are incomplete. A special type of hybridization barrier is based on the triploid endosperm of the seed, where embryo lethality is caused by endosperm failure to support the developing embryo. The MADS-box type I family of transcription factors is specifically expressed in the endosperm and has been proposed to play a role in endosperm-based hybridization barriers. The gene family is well known for its high evolutionary duplication rate, as well as being regulated by genomic imprinting. Here we address MADS-box type I gene family evolution and the role of type I genes in the context of hybridization. Using two de-novo assembled and annotated chromosome-level genomes of A. arenosa and A. lyrata ssp. petraea we analyzed the MADS-box type I gene family in Arabidopsis to predict orthologs, copy number, and structural genomic variation related to the type I loci. Our findings were compared to gene expression profiles sampled before and after the transition to endosperm cellularization in order to investigate the involvement of MADS-box type I loci in endosperm-based hybridization barriers. We observed substantial differences in type-I expression in the endosperm of A. arenosa and A. lyrata ssp. petraea, suggesting a genetic cause for the endosperm-based hybridization barrier between A. arenosa and A. lyrata ssp. petraea.

Improved Lipofuscin Models and Quantification of Outer Segment Phagocytosis Capacity in Highly Polarized Human Retinal Pigment Epithelial Cultures.

The daily phagocytosis of photoreceptor outer segments by the retinal pigment epithelium (RPE) contributes to the accumulation of an intracellular aging pigment termed lipofuscin. The toxicity of lipofuscin is well established in Stargardt's disease, the most common inherited retinal degeneration, but is more controversial in age-related macular degeneration (AMD), the leading cause of irreversible blindness in the developed world. Determining lipofuscin toxicity in humans has been difficult, and animal models of Stargardt's have limited toxicity. Thus, in vitro models that mimic human RPE in vivo are needed to better understand lipofuscin generation, clearance, and toxicity. The majority of cell culture lipofuscin models to date have been in cell lines or have involved feeding RPE a single component of the complex lipofuscin mixture rather than fragments/tips of the entire photoreceptor outer segment, which generates a more complete and physiologic lipofuscin model. Described here is a method to induce the accumulation of lipofuscin-like material (termed undigestible autofluorescence material, or UAM) in highly differentiated primary human pre-natal RPE (hfRPE) and induced pluripotent stem cell (iPSC) derived RPE. UAM accumulated in cultures by repeated feedings of ultraviolet light-treated OS fragments taken up by the RPE via phagocytosis. The key ways that UAM approximates and differs from lipofuscin in vivo are also discussed. Accompanying this model of lipofuscin-like accumulation, imaging methods to distinguish the broad autofluorescence spectrum of UAM granules from concurrent antibody staining are introduced. Finally, to assess the impact of UAM on RPE phagocytosis capacity, a new method for quantifying outer segment fragment/tips uptake and breakdown has been introduced. Termed "Total Consumptive Capacity", this method overcomes potential misinterpretations of RPE phagocytosis capacity inherent in classic outer segment "pulse-chase" assays. The models and techniques introduced here can be used to study lipofuscin generation and clearance pathways and putative toxicity.

Specific Deoxyceramide Species Correlate with Expression of Macular Telangiectasia Type 2 (MacTel2) in a SPTLC2 Carrier HSAN1 Family.

Hereditary sensory and autonomic neuropathy type 1 (HSAN1/HSN1) is a peripheral neuropathy most commonly associated with pathogenic variants in the serine palmitoyltransferase complex (SPTLC1, SPTLC2) genes, which are responsible for sphingolipid biosynthesis. Recent reports have shown that some HSAN1 patients also develop macular telangiectasia type 2 (MacTel2), a retinal neurodegeneration with an enigmatic pathogenesis and complex heritability. Here, we report a novel association of a SPTLC2 c.529A>G p.(Asn177Asp) variant with MacTel2 in a single member of a family that otherwise has multiple members afflicted with HSAN1. We provide correlative data to suggest that the variable penetrance of the HSAN1/MacTel2-overlap phenotype in the proband may be explained by levels of certain deoxyceramide species, which are aberrant intermediates of sphingolipid metabolism. We provide detailed retinal imaging of the proband and his HSAN1+/MacTel2- brothers and suggest mechanisms by which deoxyceramide levels may induce retinal degeneration. This is the first report of HSAN1 vs. HSAN1/MacTel2 overlap patients to comprehensively profile sphingolipid intermediates. The biochemical data here may help shed light on the pathoetiology and molecular mechanisms of MacTel2.

Medium depth influences O 2 availability and metabolism in cultured RPE cells.

PURPOSE: RPE oxidative metabolism is critical for normal retinal function and is often studied in cell culture systems. Here, we show that conventional culture media volumes dramatically impact O 2 availability, limiting oxidative metabolism. We suggest optimal conditions to ensure cultured RPE is in a normoxic environment permissive to oxidative metabolism. METHODS: We altered the availability of O 2 to human primary RPE cultures directly via a hypoxia chamber or indirectly via the amount of medium over cells. We measured oxygen consumption rates (OCR), glucose consumption, lactate production, 13 C-glucose flux, hypoxia inducible factor (HIF-1α) stability, intracellular lipid droplets after a lipid challenge, trans-epithelial electrical resistance, cell morphology, and pigmentation. RESULTS: Medium volumes commonly employed during RPE culture limit diffusion of O 2 to cells, triggering hypoxia, activating HIF-1α, limiting OCR, and dramatically altering cell metabolism, with only minor effects on typical markers of RPE health. Media volume effects on O 2 availability decrease acetyl-CoA utilization, increase glycolysis, and alter the size and number of intracellular lipid droplets under lipid-rich conditions. CONCLUSIONS: Despite having little impact on visible and typical markers of RPE culture health, media volume dramatically affects RPE physiology ″under the hood″. As RPE-centric diseases like age-related macular degeneration (AMD) involve oxidative metabolism, RPE cultures need to be optimized to study such diseases. We provide guidelines for optimal RPE culture volumes that balance ample nutrient availability from larger media volumes with adequate O 2 availability seen with smaller media volumes.

Approach to the Ankle in Adult Acquired Flatfoot Deformity.

Adult acquired flatfoot is a progressive deformity of the foot and ankle, which frequently becomes increasingly symptomatic. The posterior tibial tendon is most commonly associated with the deformity. A targeted physical examination with plain film radiographs is the recommended initial assessment, which will further guide a physician toward procuring more advanced imaging or toward surgical intervention. In this chapter the authors review the current literature of their approach to the treatment of the ankle in end stage of adult acquired flatfoot deformity.

A Telephone Triage System for Patients Calling with Symptoms of a Posterior Vitreous Detachment.

PURPOSE: The purpose of the study was to develop a simple telephone questionnaire, without physical examination input, that predicts which patients calling with symptoms of a posterior vitreous detachment (PVD) have a retinal tear (RT) or rhegmatogenous retinal detachment (RD). DESIGN: Prospective cohort (quality improvement) study. PARTICIPANTS: All patients with symptoms consistent with a PVD calling a major academic ophthalmology department over a 4-month period in 2020 and who were seen on follow-up within 1.5 months (211 screened and 193 included). METHODS: A comprehensive telephone questionnaire assessing for RT/RD risk factors was administered by telephone triage staff to all patients calling with symptoms of flashes, floaters, or curtain/veil in their vision. Multivariable logistic regression was used to determine risk factors most predictive of having an RT/RD during the add-on visit. Risk factor odds ratios were used to develop an RT/RD risk score. MAIN OUTCOMES MEASURES: Development of a clinical risk score for having an RT/RD at the add-on visit after telephone triage. RESULTS: Approximately 55% of patients were previously established in the retina clinic, 26% were new to the department, 19% were previously established in the comprehensive clinic, and 7% had an RT/RD at the add-on visit. Out of 23 questions and 70 prespecified possible answers from the telephone questionnaire, the final clinical risk score for RT/RDs was derived from 7 questions and 15 possible answers. The simplified questionnaire can be administered quickly by telephone operators without any reference to physical examination or the patient's chart. The receive-operator curve for our final multivariable logistic regression and clinical risk score models have an area under the curve of > 0.90. Using a conservative clinical risk score, approximately 50% of all patients without an RT/RD can be safely seen nonurgently. Progressively higher scores can be used to determine relative urgency of an appointment. CONCLUSIONS: To our knowledge, this is the first study to predict risk of an RT/RD in a patient calling with symptoms consistent with a PVD without reference to the patient's physical examination or chart. Our clinical risk scoring system can be used to determine urgency of an add-on appointment and increase the number of low-risk patients with symptomatic PVDs who are scheduled routinely. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.