Hepatic LRP-1 plays an important role in amyloidosis in Alzheimer's disease mice: Potential role in chronic heavy alcohol feeding.

BACKGROUND: Hepatic lipoprotein receptor-related protein 1 (LRP-1) plays a central role in peripheral amyloid beta (Aß) clearance, but its importance in Alzheimer's disease (AD) pathology is understudied. Our previous work showed that intragastric alcohol feeding to C57BL/6 J mice reduced hepatic LRP-1 expression which correlated with significant AD-relevant brain changes. Herein, we examined the role of hepatic LRP-1 in AD pathogenesis in APP/PS1 AD mice using two approaches to modulate hepatic LRP-1, intragastric alcohol feeding to model chronic heavy drinking shown by us to reduce hepatic LRP-1, and hepato-specific LRP-1 silencing. METHODS: Eight-month-old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7-11/group). Brain and liver Aß were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP-1 (major peripheral Aß regulator), blood-brain barrier (BBB) function (vascular Aß regulator), and microglia (major brain Aß regulator) using immunoassays. Spatial LRP-1 gene expression in the periportal versus pericentral hepatic regions was confirmed using NanoString GeoMx Digital Spatial Profiler. Further, hepatic LRP-1 was silenced by injecting LRP-1 microRNA delivered by the adeno-associated virus 8 (AAV8) and the hepato-specific thyroxine-binding globulin (TBG) promoter to 4-month-old male APP/PS1 mice (n = 6). Control male APP/PS1 mice received control AAV8 (n = 6). Spatial memory and locomotion were assessed 12 weeks after LRP-1 silencing using Y-maze and open-field test, respectively, and brain and liver Aß were measured. RESULTS: Alcohol feeding reduced plaque-associated microglia in APP/PS1 mice brains and increased aggregated Aß (p < 0.05) by ELISA and 6E10-positive Aß load by immunostaining (p < 0.05). Increased brain Aß corresponded with a significant downregulation of hepatic LRP-1 (p < 0.01) at the protein and transcript level, primarily in pericentral hepatocytes (zone 3) where alcohol-induced injury occurs. Hepato-specific LRP-1 silencing significantly increased brain Aß and locomotion hyperactivity (p < 0.05) in APP/PS1 mice. CONCLUSION: Chronic heavy alcohol intake reduced hepatic LRP-1 expression and increased brain Aß. The hepato-specific LRP-1 silencing similarly increased brain Aß which was associated with behavioral deficits in APP/PS1 mice. Collectively, our results suggest that hepatic LRP-1 is a key regulator of brain amyloidosis in alcohol-dependent AD.

Comparison of intraocular pressure and anterior segment parameters in subjects with asymmetrical primary angle closure disease.

BACKGROUND: To compare intraocular pressure (IOP) and anterior segment parameters between eyes with unilateral primary angle closure glaucoma (PACG) and their fellow eyes with primary angle closure (PAC) or primary angle closure suspect (PACS). METHODS: Subjects underwent anterior segment imaging using 360-degree swept-source optical coherence tomography (SS-OCT, CASIA Tomey, Nagoya, Japan) and ocular investigations including gonioscopy and IOP measurement. Each SS-OCT scan (divided into 8 frames, 22.5 degrees apart) was analysed and an average was obtained for the following anterior segment parameters: iridotrabecular contact (ITC), angle opening distance (AOD750), iris thickness and curvature, anterior chamber width, depth and area (ACW, ACD and ACA) and lens vault (LV). RESULTS: Among 132 unilateral PACG subjects (mean age: 62.91 ± 7.2 years; 59.1% male), eyes with PACG had significantly higher presenting IOP (24.81 ± 0.94 vs. 18.43 ± 0.57 mmHg, p < 0.001), smaller gonioscopic Shaffer grade (2.07 ± 0.07 vs. 2.31 ± 0.07, p < 0.001) and a greater extent of peripheral anterior synechiae (PAS, 1.21 ± 0.21 vs. 0.54 ± 0.16 clock hours, p = 0.001). PACG eyes also exhibited increased ITC, ITC area, greater LV and smaller AOD750, ACD and ACA (all p < 0.05). Using the forward stepwise regression model, an increase in 1 mmHg in presenting IOP before laser peripheral iridotomy (LPI) increases the odds of having PACG by 9% (95% confidence interval 5%-14%). CONCLUSIONS: PACG eyes have higher presenting IOP, smaller anterior segment parameters, greater extent of PAS, and larger LV compared to their fellow eyes with angle closure. Narrower anterior chamber dimensions and higher presenting IOP before LPI may increase risk of chronic elevated IOP and glaucomatous optic neuropathy after LPI.

Differing Associations between Optic Nerve Head Strains and Visual Field Loss in Patients with Normal- and High-Tension Glaucoma.

PURPOSE: To study the associations between optic nerve head (ONH) strains under intraocular pressure (IOP) elevation with retinal sensitivity in patients with glaucoma. DESIGN: Clinic-based cross-sectional study. PARTICIPANTS: Two hundred twenty-nine patients with primary open-angle glaucoma (subdivided into 115 patients with high-tension glaucoma [HTG] and 114 patients with normal-tension glaucoma [NTG]). METHODS: For 1 eye of each patient, we imaged the ONH using spectral-domain OCT under the following conditions: (1) primary gaze and (2) primary gaze with acute IOP elevation (to approximately 35 mmHg) achieved through ophthalmodynamometry. A 3-dimensional strain-mapping algorithm was applied to quantify IOP-induced ONH tissue strain (i.e., deformation) in each ONH. Strains in the prelaminar tissue (PLT), the retina, the choroid, the sclera, and the lamina cribrosa (LC) were associated (using linear regression) with measures of retinal sensitivity from the 24-2 Humphrey visual field test (Carl Zeiss Meditec). This was performed globally, then locally according to a previously published regionalization scheme. MAIN OUTCOME MEASURES: Associations between ONH strains and values of retinal sensitivity from visual field testing. RESULTS: For patients with HTG, we found (1) significant negative linear associations between ONH strains and retinal sensitivity (P < 0.001; on average, a 1% increase in ONH strains corresponded to a decrease in retinal sensitivity of 1.1 decibels [dB]), (2) that high-strain regions colocalized with anatomically mapped regions of high visual field loss, and (3) that the strongest negative associations were observed in the superior region and in the PLT. In contrast, for patients with NTG, no significant associations between strains and retinal sensitivity were observed except in the superotemporal region of the LC. CONCLUSIONS: We found significant negative associations between IOP-induced ONH strains and retinal sensitivity in a relatively large glaucoma cohort. Specifically, patients with HTG who experienced higher ONH strains were more likely to exhibit lower retinal sensitivities. Interestingly, this trend in general was less pronounced in patients with NTG, which could suggest a distinct pathophysiologic relationship between the two glaucoma subtypes.

Hepatic Mitochondrial SAB Deletion or Knockdown Alleviates Diet-Induced Metabolic Syndrome, Steatohepatitis, and Hepatic Fibrosis.

BACKGROUND AND AIMS: The hepatic mitogen-activated protein kinase (MAPK) cascade leading to c-Jun N-terminal kinase (JNK) activation has been implicated in the pathogenesis of nonalcoholic fatty liver (NAFL)/NASH. In acute hepatotoxicity, we previously identified a pivotal role for mitochondrial SH3BP5 (SAB; SH3 homology associated BTK binding protein) as a target of JNK, which sustains its activation through promotion of reactive oxygen species production. Therefore, we assessed the role of hepatic SAB in experimental NASH and metabolic syndrome. APPROACH AND RESULTS: In mice fed high-fat, high-calorie, high-fructose (HFHC) diet, SAB expression progressively increased through a sustained JNK/activating transcription factor 2 (ATF2) activation loop. Inducible deletion of hepatic SAB markedly decreased sustained JNK activation and improved systemic energy expenditure at 8 weeks followed by decreased body fat at 16 weeks of HFHC diet. After 30 weeks, mice treated with control-antisense oligonucleotide (control-ASO) developed steatohepatitis and fibrosis, which was prevented by Sab-ASO treatment. Phosphorylated JNK (p-JNK) and phosphorylated ATF2 (p-ATF2) were markedly attenuated by Sab-ASO treatment. After 52 weeks of HFHC feeding, control N-acetylgalactosamine antisense oligonucleotide (GalNAc-Ctl-ASO) treated mice fed the HFHC diet exhibited progression of steatohepatitis and fibrosis, but GalNAc-Sab-ASO treatment from weeks 40 to 52 reversed these findings while decreasing hepatic SAB, p-ATF2, and p-JNK to chow-fed levels. CONCLUSIONS: Hepatic SAB expression increases in HFHC diet-fed mice. Deletion or knockdown of SAB inhibited sustained JNK activation and steatohepatitis, fibrosis, and systemic metabolic effects, suggesting that induction of hepatocyte Sab is an important driver of the interplay between the liver and the systemic metabolic consequences of overfeeding. In established NASH, hepatocyte-targeted GalNAc-Sab-ASO treatment reversed steatohepatitis and fibrosis.

Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. PATIENTS AND METHODS: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. RESULTS: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). CONCLUSIONS: Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Selecting Patients with Favorable Risk, Grade Group 2 Prostate Cancer for Active Surveillance-Does Magnetic Resonance Imaging Have a Role?

PURPOSE: The National Comprehensive Cancer Network® recommends that selected men with grade group 2 prostate cancer be considered for active surveillance. However, selecting which patients with grade group 2 disease can be safely managed by active surveillance remains controversial. The aim of this study was to evaluate the association of multiparametric magnetic resonance imaging with adverse pathology in the radical prostatectomy specimen of men with favorable risk grade group 2 prostate cancer, which could help select patients for active surveillance. MATERIALS AND METHODS: We retrospectively analyzed a cohort of patients with favorable grade group 2 disease who underwent radical prostatectomy between 2010 and 2019. Preoperative multiparametric magnetic resonance imaging was scored as negative (no identifiable lesion), positive (identifiable lesion) or equivocal. We defined a multivariable logistic regression model with multiparametric magnetic resonance imaging score as the predictor and adverse pathology (up staging to T3a/b disease, upgrading to ≥grade group 3 or lymph node invasion) as the outcome, adjusting for preoperative prostate specific antigen, biopsy Gleason grade, clinical stage, and number of negative and positive prostate biopsy cores. Secondary outcomes of biochemical recurrence, grade group upgrading alone and the added value of incorporating multiparametric magnetic resonance imaging data into the nomogram were also investigated. RESULTS: We identified 1,117 patients with favorable risk grade group 2 disease who underwent radical prostatectomy. Positive multiparametric magnetic resonance imaging was associated with higher rates of adverse pathology (OR 2.55, 95% CI 1.75-3.40, p <0.0001) and upgrading (OR 3.89, 95% CI 2.00-7.56, p <0.0001). However, as our study included only grade group 2 patients who underwent radical prostatectomy, our cohort may represent a higher risk group than grade group 2 patients as a whole. Adding multiparametric magnetic resonance imaging results to a standard prediction model led to higher net benefit on decision curve analysis. An identifiable lesion on multiparametric magnetic resonance imaging was associated with an increased risk of aggressive pathological features in the radical prostatectomy specimen of patients with favorable risk grade group 2 prostate cancer who were potential active surveillance candidates. This information could be used to inform biopsy strategy, counsel patients on treatment options and guide strategies for those on active surveillance. CONCLUSIONS: Combining multiple magnetic resonance imaging modalities (multiparametric magnetic resonance imaging) provides a more accurate prediction of the risk presented by prostate cancer than current prediction methods. In this study, positive magnetic resonance imaging results approximately doubled the chances that a patient with favorable risk prostate cancer would be found to have adverse pathology when their prostate was removed. Thus, multiparametric magnetic resonance imaging could help select patients with favorable risk cancer who may be good candidates for active surveillance, and help guide biopsy and surveillance strategies for such patients.

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. METHODS: Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah-/-/Rag2-/-/Il2rg-/-/NOD (FRGN) mice to create mice with humanized livers. RESULTS: Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. CONCLUSIONS: In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.

Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps.

Despite tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex differences in NAFLD remains insufficient. This review summarizes the current knowledge on sex differences in NAFLD, identifies gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women, suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate the sex differences observed in patients, with more severe steatosis and steatohepatitis, more proinflammatory/profibrotic cytokines, and a higher incidence of hepatic tumors in male than female subjects. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex-specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause), and synthetic hormone use. Conclusion: Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD, suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines; adequate consideration of sex differences, sex hormones/menopausal status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD.

Gut Microbiota and Liver Injury (I)-Acute Liver Injury.

Over the last few decades, intestinal microbial communities have been considered to play a vital role in host liver health. Acute liver injury (ALI) is the manifestation of sudden hepatic injury and arises from a variety of causes. The studies of dysbiosis in gut microbiota provide new insight into the pathogenesis of ALI. However, the relationship of gut microbiota and ALI is not well understood, and the contribution of gut microbiota to ALI has not been well characterized. In this chapter, we integrate several major pathogenic factors in ALI with the role of gut microbiota to stress the significance of gut microbiota in prevention and treatment of ALI.

Investigation of the variability of anterior chamber scan protocol with Cirrus high definition optical coherence tomography.

IMPORTANCE: The evaluation of anterior chamber scan of Cirrus optical coherence tomography for routine clinical use. BACKGROUND: To assess the variability of anterior chamber angle measurements. DESIGN: This was a cross-sectional study. PARTICIPANTS: Forty subjects aged 40-80 years were included. METHODS: One randomly selected eye from 40 subjects was imaged with Cirrus optical coherence tomography (Carl Zeiss Meditec, Dublin, CA) by two different operators (expert vs. non-expert) with a 15-min interval for inter-observer and intra-observer variability of image acquisition. For image grading, the angle opening distance (AOD750) and the trabecular iris space area (TISA750) of nasal and temporal quadrants were measured with a customized algorithm (ImageJ, NIH, Bethesda, MD) by two different graders in a masked and random fashion. Bland Altman analysis and intraclass correlation coefficient (ICC) were calculated. MAIN OUTCOME MEASURES: ICC and limit of agreements (LOA). RESULTS: There were 15 (37.5%) eyes with closed angles. For inter-observer variability, the mean difference (95% LOA) of AOD750 for image acquisition and grading were -0.0039 mm (-0.0486, 0.0408) and 0.0011 mm (-0.0228, 0.025), respectively. The mean difference (95% LOA) of AOD750 for intra-observer variability for image acquisition and grading were 0.0013 mm (-0.0362, 0.0389) and -0.0013 mm (-0.0482, 0.0457), respectively. The ICCs were all ≥0.9. There was no significant difference in measurement variability between open and closed angles (P > 0.05). CONCLUSIONS AND RELEVANCE: Anterior chamber scan had low inter-observer and intra-observer variability in quantitative evaluation that was not affected by the angle status or the experience of an operator.

Iris Crypts Influence Dynamic Changes of Iris Volume.

PURPOSE: To determine the association of iris surface features with iris volume change after physiologic pupil dilation in adults. DESIGN: Cross-sectional observational study. PARTICIPANTS: Chinese adults aged ≥ 50 years without ocular diseases. METHODS: Digital iris photographs were taken from eyes of each participant and graded for crypts (by number and size) and furrows (by number and circumferential extent) following a standardized grading scheme. Iris color was measured objectively, using the Commission Internationale de l'Eclairage (CIE) L* color parameter (higher value denoting lighter iris). The anterior segment was imaged by swept-source optical coherence tomography (SS-OCT) (Casia; Tomey, Nagoya, Japan) under bright light and dark room conditions. Iris volumes in light and dark conditions were measured with custom semiautomated software, and the change in iris volume was quantified. Associations of the change in iris volume after pupil dilation with underlying iris surface features in right eyes were assessed using linear regression analysis. MAIN OUTCOME MEASURES: Iris volume change after physiologic pupil dilation from light to dark condition. RESULTS: A total of 65 Chinese participants (mean age, 59.8±5.7 years) had gradable data for iris surface features. In light condition, higher iris crypt grade was associated independently with smaller iris volume (ß [change in iris volume in millimeters per crypt grade increment] = -1.43, 95% confidence interval [CI], -2.26 to -0.59; P = 0.001) and greater reduction of iris volume on pupil dilation (ß [change in iris volume in millimeters per crypt grade increment] = 0.23, 95% CI, 0.06-0.40; P = 0.010), adjusting for age, gender, presence of corneal arcus, and change in pupil size. Iris furrows and iris color were not associated with iris volume in light condition or change in iris volume (all P > 0.05). CONCLUSIONS: Although few Chinese persons have multiple crypts on their irides, irides with more crypts were significantly thinner and lost more volume on pupil dilation. In view that the latter feature is known to be protective for acute angle-closure attack, it is likely that the macroscopic and microscopic composition of the iris is a contributing feature to angle-closure disease.

Argon Laser Peripheral Iridoplasty for Primary Angle-Closure Glaucoma: A Randomized Controlled Trial.

PURPOSE: To determine the effectiveness of argon laser peripheral iridoplasty (ALPI) in primary angle closure (PAC) and primary angle-closure glaucoma (PACG). DESIGN: Randomized controlled trial. PARTICIPANTS: Eighty PAC or PACG subjects who underwent laser iridotomy (LI) and had at least 180° of persistent appositional angle closure and intraocular pressure (IOP) of more than 21 mmHg were enrolled. METHODS: Subjects were randomized to receive either 360° ALPI (Visulas 532s; Carl Zeiss Meditec, Jena, Germany) or medical therapy (Travoprost 0.004%; Alcon-Couvreur, Puurs, Antwerp, Belgium). Repeat ALPI was performed if the IOP reduction was less than 20% from baseline along with inadequate angle widening at the month 1 or month 3 visit. Intraocular pressure was controlled with systematic addition of medications when required. MAIN OUTCOME MEASURES: The primary outcome measure was success rates after ALPI at 1 year. Complete success was defined as an IOP of 21 mmHg or less without medication, and qualified success was defined as an IOP of 21 mmHg or less with medication. Failure was defined as an IOP more than 21 mmHg despite additional medications or requiring glaucoma surgery. RESULTS: Forty subjects (51 eyes) were randomized to ALPI and 40 subjects (55 eyes) were randomized to medical therapy. Complete success (IOP ≤21 mmHg without medication) was achieved in 35.0% eyes of the ALPI group compared with 85.0% of eyes in the prostaglandin analog (PGA) group (P < 0.001), and qualified success (IOP ≤21 mmHg with medication) was achieved in 35.0% and 7.5%, respectively (P = 0.003). The IOP decreased by 4.9 mmHg (95% confidence interval [CI], 3.5-6.3 mmHg) in the ALPI group (P < 0.001) and by 6.1 mmHg (95% CI, 5.1-7.1 mmHg) in the medication group (P < 0.001). A failure rate of 30.0% was noted in the ALPI group compared with 7.5% in the medication group (P = 0.01). No treatment-related complications were recorded in either group. CONCLUSIONS: After 1 year, ALPI was associated with higher failure rates and lower IOP reduction compared with PGA therapy in eyes with persistent appositional angle closure and raised IOP after LI.

GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study.

AIM: To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes. METHODS: We conducted a genome-wide association study of log-transformed plasma lactate levels in 6901 European-American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects. RESULTS: The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele ß=0.08; P=1.8×10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele ß=0.06; P=1.6×10(-9) ). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01). CONCLUSIONS: We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes-related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism.

Sectoral variations of iridocorneal angle width and iris volume in Chinese Singaporeans: a swept-source optical coherence tomography study.

PURPOSE: To assess variations in the iridocorneal angle width and iris volume in Chinese subjects using swept-source optical coherence tomography (SS-OCT). METHODS: Consecutive subjects, aged 40-80 years, with no previous ophthalmic problems were recruited from a population-based study of Chinese Singaporeans. All subjects underwent 360° SS-OCT (SS-1000 CASIA, Tomey Corporation, Nagoya, Japan) angle imaging and gonioscopy in one randomly selected eye in the dark. For each eye, 16 frames (11.25° apart) were selected for analysis from 128 cross-sectional images, and measurements of the trabecular iris space area 750 µm from the scleral spur (TISA750) and iris volume were made for each image. The measurements from four consecutive frames were further averaged as a sector of 45°. Sector-wise angle width and quadrant-wise iris volume were analyzed. RESULTS: Two hundred and twelve subjects (90 with closed-angles) were examined. The majority of the subjects were female (70.7 %) with mean age 61 (±8.9) years. The TISA750 (mm(2)) of superior [0.101 (0.09)], inferior [0.105 (0.09)], superior-nasal [0.111 (0.09)] and superior-temporal [0.117 (0.09)] sectors were smaller compared with other sectors (P < 0.05). The nasal iris volume (mm(3)) was the smallest compared with other quadrants for the entire cohort [nasal 8.18 (1.2) < inferior 9.13 (1.3) < temporal 9.16 (1.2) < superior 9.33 (1.3), P < 0.001], as well as for open- and closed-angle groups. CONCLUSIONS: The irido-corneal angle was narrower in the superior, inferior, superior-nasal and superior-temporal sectors compared with other sectors. Iris volume in the nasal quadrant was the smallest compared with the other quadrants.

Optical Coherence Tomography Angiography Assessment of Optic Nerve Head and Macula across the Primary Angle Closure Disease Spectrum.

PRCIS: The microvasculature of the optic disc and macula in eyes with acute primary angle closure and primary angle closure glaucoma was lower across the disease spectrum, but the significant difference was only observed in primary angle closure glaucoma. PURPOSE: To assess the microvasculature in the optic nerve head (ONH) and macula across primary angle-closure disease (PACD) spectrum using optical coherence tomography angiography (OCTA). METHODS: OCTA (AngioVue, Fremont, CA) imaging was performed on 122 PACD subjects. Flow area (FA) and vessel density (VD) in the ONH, radial peripapillary capillary (RPC) network, and superficial and deep capillary plexuses of the macula were calculated and compared across the PACD spectrum using linear regression models with generalized estimating equations adjusted for inter-eye correlation. RESULTS: A total of 234 eyes including 44 primary angle-closure suspects (PACS), 93 primary angle-closure (PAC), 79 primary angle-closure glaucoma (PACG) and 18 PAC with history of previous acute primary angle-closure (APAC) were included in the analysis. Compared to other groups, PACG eyes showed smaller FA in the ONH (1.35±0.02 mm2), RPC (0.78±0.03 mm2), and the superficial retinal layer (1.08±0.03 mm2) (all P<0.05). Lower VD was also observed in the "whole image", "inside disc", and "peripapillary" regions of the ONH and RPC, and the "whole image" and "parafoveal" regions of the retinal layer in the PACG group when compared with other groups (all P<0.05). No significant differences were found for the other groups (all P>0.05). Lower VD in the ONH, RPC, and superficial retinal layer significantly correlated with worse visual field loss in PACG eyes (all P<0.05). CONCLUSIONS: Significant reduction in the microvasculature of the optic disc and macula in PACG suggests that glaucoma development may contribute to lower VD in these regions.

AI-based clinical assessment of optic nerve head robustness superseding biomechanical testing.

BACKGROUND/AIMS: To use artificial intelligence (AI) to: (1) exploit biomechanical knowledge of the optic nerve head (ONH) from a relatively large population; (2) assess ONH robustness (ie, sensitivity of the ONH to changes in intraocular pressure (IOP)) from a single optical coherence tomography (OCT) volume scan of the ONH without the need for biomechanical testing and (3) identify what critical three-dimensional (3D) structural features dictate ONH robustness. METHODS: 316 subjects had their ONHs imaged with OCT before and after acute IOP elevation through ophthalmo-dynamometry. IOP-induced lamina cribrosa (LC) deformations were then mapped in 3D and used to classify ONHs. Those with an average effective LC strain superior to 4% were considered fragile, while those with a strain inferior to 4% robust. Learning from these data, we compared three AI algorithms to predict ONH robustness strictly from a baseline (undeformed) OCT volume: (1) a random forest classifier; (2) an autoencoder and (3) a dynamic graph convolutional neural network (DGCNN). The latter algorithm also allowed us to identify what critical 3D structural features make a given ONH robust. RESULTS: All three methods were able to predict ONH robustness from a single OCT volume scan alone and without the need to perform biomechanical testing. The DGCNN (area under the curve (AUC): 0.76±0.08) outperformed the autoencoder (AUC: 0.72±0.09) and the random forest classifier (AUC: 0.69±0.05). Interestingly, to assess ONH robustness, the DGCNN mainly used information from the scleral canal and the LC insertion sites. CONCLUSIONS: We propose an AI-driven approach that can assess the robustness of a given ONH solely from a single OCT volume scan of the ONH, and without the need to perform biomechanical testing. Longitudinal studies should establish whether ONH robustness could help us identify fast visual field loss progressors. PRECIS: Using geometric deep learning, we can assess optic nerve head robustness (ie, sensitivity to a change in IOP) from a standard OCT scan that might help to identify fast visual field loss progressors.

Iris Morphological and Biomechanical Factors Influencing Angle Closure During Pupil Dilation.

Purpose: To use finite element (FE) analysis to assess what morphologic and biomechanical factors of the iris and anterior chamber are more likely to influence angle narrowing during pupil dilation. Methods: The study consisted of 1344 FE models comprising the cornea, sclera, lens, and iris to simulate pupil dilation. For each model, we varied the following parameters: anterior chamber depth (ACD = 2-4 mm) and anterior chamber width (ACW = 10-12 mm), iris convexity (IC = 0-0.3 mm), iris thickness (IT = 0.3-0.5 mm), stiffness (E = 4-24 kPa), and Poisson's ratio (v = 0-0.3). We evaluated the change in (△∠) and the final dilated angles (∠f) from baseline to dilation for each parameter. Results: The final dilated angles decreased with a smaller ACD (∠f = 53.4° ± 12.3° to 21.3° ± 14.9°), smaller ACW (∠f = 48.2° ± 13.5° to 26.2° ± 18.2°), larger IT (∠f = 52.6° ± 12.3° to 24.4° ± 15.1°), larger IC (∠f = 45.0° ± 19.2° to 33.9° ± 16.5°), larger E (∠f = 40.3° ± 17.3° to 37.4° ± 19.2°), and larger v (∠f = 42.7° ± 17.7° to 34.2° ± 18.1°). The change in angles increased with larger ACD (△∠ = 9.37° ± 11.1° to 15.4° ± 9.3°), smaller ACW (△∠ = 7.4° ± 6.8° to 16.4° ± 11.5°), larger IT (△∠ = 5.3° ± 7.1° to 19.3° ± 10.2°), smaller IC (△∠ = 5.4° ± 8.2° to 19.5° ± 10.2°), larger E (△∠ = 10.9° ± 12.2° to 13.1° ± 8.8°), and larger v (△∠ = 8.1° ± 9.4° to 16.6° ± 10.4°). Conclusions: The morphology of the iris (IT and IC) and its innate biomechanical behavior (E and v) were crucial in influencing the way the iris deformed during dilation, and angle closure was further exacerbated by decreased anterior chamber biometry (ACD and ACW).

Deep Learning Classification of Angle Closure based on Anterior Segment OCT.

PURPOSE: To assess the performance and generalizability of a convolutional neural network (CNN) model for objective and high-throughput identification of primary angle-closure disease (PACD) as well as PACD stage differentiation on anterior segment swept-source OCT (AS-OCT). DESIGN: Cross-sectional. PARTICIPANTS: Patients from 3 different eye centers across China and Singapore were recruited for this study. Eight hundred forty-one eyes from the 2 Chinese centers were divided into 170 control eyes, 488 PACS, and 183 PAC + PACG eyes. An additional 300 eyes were recruited from Singapore National Eye Center as a testing data set, divided into 100 control eyes, 100 PACS, and 100 PAC + PACG eyes. METHODS: Each participant underwent standardized ophthalmic examination and was classified by the presiding physician as either control, primary angle-closure suspect (PACS), primary angle closure (PAC), or primary angle-closure glaucoma (PACG). Deep Learning model was used to train 3 different CNN classifiers: classifier 1 aimed to separate control versus PACS versus PAC + PACG; classifier 2 aimed to separate control versus PACD; and classifier 3 aimed to separate PACS versus PAC + PACG. All classifiers were evaluated on independent validation sets from the same region, China and further tested using data from a different country, Singapore. MAIN OUTCOME MEASURES: Area under receiver operator characteristic curve (AUC), precision, and recall. RESULTS: Classifier 1 achieved an AUC of 0.96 on validation set from the same region, but dropped to an AUC of 0.84 on test set from a different country. Classifier 2 achieved the most generalizable performance with an AUC of 0.96 on validation set and AUC of 0.95 on test set. Classifier 3 showed the poorest performance, with an AUC of 0.83 and 0.64 on test and validation data sets, respectively. CONCLUSIONS: Convolutional neural network classifiers can effectively distinguish PACD from controls on AS-OCT with good generalizability across different patient cohorts. However, their performance is moderate when trying to distinguish PACS versus PAC + PACG. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.

Adduction induces large optic nerve head deformations in subjects with normal-tension glaucoma.

PURPOSE: To assess intraocular pressure (IOP)-induced and gaze-induced optic nerve head (ONH) strains in subjects with high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). DESIGN: Clinic-based cross-sectional study. METHODS: The ONH from one eye of 228 subjects (114 subjects with HTG (pre-treatment IOP≥21 mm Hg) and 114 with NTG (pre-treatment IOP<21 mm Hg)) was imaged with optical coherence tomography (OCT) under the following conditions: (1) OCT primary gaze, (2) 20° adduction from OCT primary gaze, (3) 20° abduction from OCT primary gaze and (4) OCT primary gaze with acute IOP elevation (to approximately 33 mm Hg). We then performed digital volume correlation analysis to quantify IOP-induced and gaze-induced ONH tissue deformations and strains. RESULTS: Across all subjects, adduction generated high effective strain (4.4%±2.3%) in the LC tissue with no significant difference (p>0.05) with those induced by IOP elevation (4.5%±2.4%); while abduction generated significantly lower (p=0.01) effective strain (3.1%±1.9%). The lamina cribrosa (LC) of HTG subjects exhibited significantly higher effective strain than those of NTG subjects under IOP elevation (HTG: 4.6%±1.7% vs NTG: 4.1%±1.5%, p<0.05). Conversely, the LC of NTG subjects exhibited significantly higher effective strain than those of HTG subjects under adduction (NTG: 4.9%±1.9% vs HTG: 4.0%±1.4%, p<0.05). CONCLUSION: We found that NTG subjects experienced higher strains due to adduction than HTG subjects, while HTG subjects experienced higher strain due to IOP elevation than NTG subjects-and that these differences were most pronounced in the LC tissue.

Novel hyperparallel optical coherence tomography for angle closure assessment: comparison with swept-source OCT and gonioscopy.

AIM: To evaluate reproducibility and agreement of angle closure assessment by a novel hyperparallel optical coherence tomography (OCT) system (HP-OCT, Cylite Optics, Melbourne, Australia), in comparison with swept-source OCT (SS-OCT, CASIA SS-1000, Tomey Corporation, Nagoya, Japan) and gonioscopy. METHODS: Cross-sectional study. Phakic subjects >40 years, with no relevant ophthalmic history were consecutively recruited from the glaucoma clinic. Subjects underwent same-day evaluation with HP-OCT, SS-OCT and gonioscopy. The primary outcome was the presence of angle closure, defined as iridotrabecular contact in HP-OCT and SS-OCT images at 0°-180° meridional and as non-visibility of the posterior trabecular meshwork (TM) by gonioscopy. Visibility of TM was also assessed (secondary outcome). Intra and interdevice agreement analysis (Gwet AC1) and logistic regression analysis were performed for primary and secondary outcomes, respectively. RESULTS: 154 sectors from horizontal scans of 77 subjects were analysed. The reproducibility of angle closure assessment by HP-OCT was excellent (AC1 of 0.95 for temporal angle and 1.00 for nasal). Agreement for angle closure detection was very good between HP-OCT and SS-OCT (AC1 of 0.88 for temporal and 0.81 for nasal angle) and good between HP-OCT and gonioscopy (AC1 of 0.71 for temporal and 0.78 for nasal angle). TM was identifiable in 64.4% (94/146) of unprocessed HP-OCT images (both open and closed angles), however not visible in any of the SS-OCT unprocessed images. CONCLUSIONS: HP-OCT showed excellent reproducibility for angle closure assessment and good agreement with SS-OCT and gonioscopy. HP-OCT technology also provides a unique capability to visualise regions around TM and Schlemm's canal, opening new avenues for clinical research of distal outflow pathways.