Plasma proteomic profile of abdominal obesity in older adults.

OBJECTIVE: This study examines the plasma proteomic profile of abdominal obesity in older adults. METHODS: The association of abdominal obesity (waist circumference [WC]) with 4265 plasma proteins identified using the SomaScan Assay was examined in 969 Ashkenazi Jewish participants (LonGenity cohort), aged 65 years and older (mean [SD] age 75.7 [6.7] years, 55.4% women), using regression models. Pathway analysis, as well as weighted correlation network analysis, was performed. WC was determined from the proteome using elastic net regression. RESULTS: A total of 480 out of 4265 proteins were associated with WC in the linear regression model. Leptin (ß [SE] = 12.363 [0.490]), inhibin ß C chain (INHBC; ß [SE] = 24.324 [1.448]), insulin-like growth factor-binding protein 2 (IGFBP-2; ß [SE] = -12.782 [0.841]), heparan-sulfate 6-O-sulfotransferase 3 (H6ST3; ß [SE] = -39.995 [2.729]), and matrix-remodeling-associated protein 8 (MXRA8; ß [SE] = -27.101 [1.850]) were the top proteins associated with WC. Cell adhesion, extracellular matrix remodeling, and IGF transport pathways were the top enriched pathways associated with WC. WC signature determined from plasma proteins was highly correlated with measured WC (r = 0.80) and was associated with various metabolic and physical traits. CONCLUSIONS: The study unveiled a multifaceted plasma proteomic profile of abdominal obesity in older adults, offering insights into its wide-ranging impact on the proteome. It also elucidated novel proteins, clusters of correlated proteins, and pathways that are intricately associated with abdominal obesity.

Frailty Resilience Score: A Novel Measure of Frailty Resilience Associated With Protection From Frailty and Survival.

Frailty is characterized by increased vulnerability to disability and high risk for mortality in older adults. Identification of factors that contribute to frailty resilience is an important step in the development of effective therapies that protect against frailty. First, a reliable quantification of frailty resilience is needed. We developed a novel measure of frailty resilience, the Frailty Resilience Score (FRS), that integrates frailty genetic risk, age, and sex. Application of FRS to the LonGenity cohort (n = 467, mean age 74.4) demonstrated its validity compared to phenotypic frailty and its utility as a reliable predictor of overall survival. In a multivariable-adjusted analysis, 1-standard deviation increase in FRS predicted a 38% reduction in the hazard of mortality, independent of baseline frailty (p < .001). Additionally, FRS was used to identify a proteomic profile of frailty resilience. FRS was shown to be a reliable measure of frailty resilience that can be applied to biological studies of resilience.

Biological Age Acceleration and Motoric Cognitive Risk Syndrome.

OBJECTIVE: Motoric cognitive risk (MCR) syndrome, a predementia syndrome characterized by slow gait and subjective cognitive concerns, is associated with multiple age-related risk factors. We hypothesized that MCR is associated with biological age acceleration. We examined the associations of biological age acceleration with MCR, and mortality risk in MCR cases. METHODS: Biological age was determined using proteomic and epigenetic clocks in participants aged 65 years and older in the LonGenity study (N = 700, females = 57.9%) and Health and Retirement Study (HRS; N = 1,043, females = 57.1%) cohorts. Age acceleration (AgeAccel) was operationally defined as the residual from regressing predicted biological age (from both clocks separately) on chronological age. Association of AgeAccel with incident MCR in the overall sample as well as with mortality risk in MCR cases was examined using Cox models and reported as hazard ratios (HRs). RESULTS: AgeAccel scores derived from a proteomic clock were associated with prevalent MCR (odds ratio adjusted for age, gender, education years, and chronic illnesses [aOR] = 1.36, 95% confidence interval [CI] = 1.09-1.71) as well as predicted incident MCR (HR = 1.19, 95% CI = 1.00-1.41) in the LonGenity cohort. In HRS, the association of AgeAccel using an epigenetic clock with prevalent MCR was confirmed (aOR = 1.47, 95% CI = 1.16-1.85). Participants with MCR and accelerated aging (positive AgeAccel score) were at the highest risk for mortality in both LonGenity (HR = 3.38, 95% CI = 2.01-5.69) and HRS (HR = 2.47, 95% CI = 1.20-5.10). INTERPRETATION: Accelerated aging predicts risk for MCR, and is associated with higher mortality in MCR patients. ANN NEUROL 2023;93:1187-1197.

Objective estimation of fusional reserves using infrared eye tracking: the digital fusion-range test.

CLINICAL RELEVANCE: Horizontal fusional reserves are used in the diagnosis and monitoring of common vergence disorders, such as convergence insufficiency, which can cause asthenopia and impact near work. Infrared eyetracking technology shows promise for obtaining automated and objective measurements of fusional reserves, expanding options for screening, clinical testing, and at-home monitoring/vision training. BACKGROUND: Current clinical tests for fusional reserves rely on subjective judgements made by patients (for diplopia) and clinicians (for eye movements). This paper describes an objective and automated "digital fusion-range test" pilot-tested in adults without current eye disease or binocular vision anomalies. This test combines a consumer-grade infrared eyetracker, a dichoptic display, and custom analyses programs to measure convergence and divergence reserves. METHODS: Twenty-nine adult participants completed the study. Horizontal fusional reserves at 55 cm were measured using prism bars and with our computer-based digital fusion-range test. For the digital test, observers viewed dichoptic targets whose binocular disparity modulated over time (at speeds of 0.5, 1.0, or 2.0 Δ/s) while their eye movements were continuously recorded. Subjective reports of break and recovery (by keyboard button press) were compared to objective estimates extracted from eyetracking recordings (via automated analyses). RESULTS: Objective and subjective measures of break and recovery agreed closely. Clinically small (0.3-2Δ) but statistically significant (p < 0.012) differences were found between measurement types for divergence breaks/recoveries and convergence recoveries. No significant differences were found for convergence breaks (p = 0.11). Such differences are consistent with an average 0.91 (SD 1.66) seconds delay between objective break/recovery and subjective responses. The digital test produced comparable results to the standard clinical prism bar method. CONCLUSION: The digital fusion-range test supports an automated, reliable assessment of horizontal fusional reserves, which do not depend on subjective responses. This technology may prove useful in a variety of clinical and community-based settings.

Polygenic prediction of human longevity on the supposition of pervasive pleiotropy.

The highly polygenic nature of human longevity renders cross-trait pleiotropy an indispensable feature of its genetic architecture. Leveraging the genetic correlation between the aging-related traits (ARTs), we sought to model the additive variance in lifespan as a function of cumulative liability from pleiotropic segregating variants. We tracked allele frequency changes as a function of viability across different age bins and prioritized 34 variants with an immediate implication on lipid metabolism, body mass index (BMI), and cognitive performance, among other traits, revealed by PheWAS analysis in the UK Biobank. Given the highly complex and non-linear interactions between the genetic determinants of longevity, we reasoned that a composite polygenic score would approximate a substantial portion of the variance in lifespan and developed the integrated longevity genetic scores (iLGSs) for distinguishing exceptional survival. We showed that coefficients derived from our ensemble model could potentially reveal an interesting pattern of genomic pleiotropy specific to lifespan. We assessed the predictive performance of our model for distinguishing the enrichment of exceptional longevity among long-lived individuals in two replication cohorts and showed that the median lifespan in the highest decile of our composite prognostic index is up to 4.8 years longer. Finally, using the proteomic correlates of iLGS, we identified protein markers associated with exceptional longevity irrespective of chronological age and prioritized drugs with repurposing potentials for gerotherapeutics. Together, our approach demonstrates a promising framework for polygenic modeling of additive liability conferred by ARTs in defining exceptional longevity and assisting the identification of individuals at higher risk of mortality for targeted lifestyle modifications earlier in life. Furthermore, the proteomic signature associated with iLGS highlights the functional pathway upstream of the PI3K-Akt that can be effectively targeted to slow down aging and extend lifespan.

Integrity of hypothalamic-pituitary-testicular axis in exceptional longevity.

Hypothalamic integrity increasingly is being recognized as a marker of healthy longevity in rodent models. Insight into hypothalamic function in humans with exceptional longevity can be gained via investigation of the hypothalamic-pituitary-testicular (HPT) axis in men with exceptional longevity. This study aimed to characterize the HPT axis function, defined by levels of testosterone (T) and luteinizing hormone (LH), in 84 Ashkenazi Jewish men aged 90-106 years. We found that 94% of men exhibited preserved hypothalamic-pituitary function, as evidenced by either normal testosterone and LH levels (25%) or an appropriate rise in LH in response to aging-related primary testicular dysfunction (69%), a hormone pattern mirroring female menopause. Total T level was not associated with metabolic parameters or survival. These results demonstrate a high prevalence of testicular dysfunction with preserved hypothalamic-pituitary function in men with exceptional longevity. Thus, the role of hypothalamic integrity and HPT axis in healthy aging warrants further investigation.

Measuring aniseikonia and investigating neuroplasticity and image factors in amblyopia (MAGNIFY): study protocol for a randomised clinical trial.

BACKGROUND: Aniseikonia represents a potential barrier to neuroplasticity which may limit visual outcomes in children with anisometropic amblyopia. Full correction of refractive error is the first step in standard amblyopia treatment, which corrects for image focus but neglects image size differences. METHODS: The MAGNIFY study is a double-masked, randomised clinical trial investigating the effectiveness of aniseikonia correcting lenses in children at first diagnosis of significant anisometropia. We hypothesis that aniseikonia correction lenses will improve image clarity and reduce the retinal size differences producing better visual acuity and stereoacuity improvements after 15 weeks of optical treatment for children with anisometropia. Eligible children will be randomly allocated to the treatment group (aniseikonia-correcting spectacle lenses) or control group (standard spectacle lenses). Visual acuity and binocular functions will be assessed every 5 weeks during the 15-week optical treatment phase according to standard amblyopia treatment protocol. DISCUSSION: It is possible that correcting aniseikonia along with anisometropia at first diagnosis will promote binocularity as well as increase spectacle adherence by reducing visual discomfort, improving optical treatment outcomes. This could then reduce the need for additional amblyopia treatment such as patching or atropine, reducing the burden on hospital eye departments and potentially improving visual outcomes for children with amblyopia. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000061932 . Registered on 24 January 2020. Protocol 15th November 2019, version one.

Analysis of in-hospital mortality among people with and without diabetes in South Western Sydney public hospitals (2014-2017).

BACKGROUND: Diabetes is a major public health problem affecting about 1.4 million Australians, especially in South Western Sydney, a hotspot of diabetes with higher than average rates for hospitalisations. The current understanding of the international burden of diabetes and related complications is poor and data on hospital outcomes and/or what common factors influence mortality rate in people with and without diabetes in Australia using a representative sample is lacking. This study determined in-hospital mortality rate and the factors associated among people with and without diabetes. METHODS: Retrospective data for 554,421 adult inpatients was extracted from the population-based New South Wales (NSW) Admitted Patient Data over 3 financial years (from 1 July 2014-30 June 2015 to 1 July 2016-30 June 2017). The in-hospital mortality per 1000 admitted persons, standardised mortality ratios (SMR) were calculated. Binary logistic regression was performed, adjusting for potential covariates and co-morbidities for people with and without diabetes over three years. RESULTS: Over three years, 8.7% (48,038 people) of admissions involved people with diabetes. This increased from 8.4% in 2014-15 to 8.9% in 2016-17 (p = 0.007). Across all age groups, in-hospital mortality rate was significantly greater in people with diabetes (20.6, 95% Confidence intervals CI 19.3-21.9 per 1000 persons) than those without diabetes (11.8, 95%CI 11.5-12.1) and more in men than women (23.1, 95%CI 21.2-25.0 vs 17.9, 95%CI 16.2-19.8) with diabetes. The SMR for those with and without diabetes were 3.13 (95%CI 1.78-4.48) and 1.79 (95%CI 0.77-2.82), respectively. There were similarities in the factors associated with in hospital mortality in both groups including: older age (> 54 years), male sex, marital status (divorced/widowed), length of stay in hospital (staying longer than 4 days), receiving intensive care in admission and being admitted due to primary respiratory and cardiovascular diagnoses. The odds of death in admission was increased in polymorbid patients without diabetes (28.68, 95%CI 23.49-35.02) but not in those with diabetes. CONCLUSIONS: In-patients with diabetes continue to have higher mortality rates than those without diabetes and the Australian population. Overall, similar factors influenced mortality rate in people with and without diabetes, but significantly more people with diabetes had two or more co-morbidities, suggesting that hospital mortality may be driven by those with pre-existing health/comorbidities. Urgent measures in primary care to prevent admissions among people with multiple co-morbidities are needed.

Development of a Spectacle Wear Monitor System: SpecsOn Monitor.

Purpose: This study aimed to custom design, build, and test a removable device that accurately and objectively monitors adherence to spectacle wear in preschool children participating in clinical trials. This work will provide researchers with the tools to investigate the effect of adherence to optical treatment in conditions relating to refractive error, such as anisometropia, amblyopia, myopia, and accommodative esotropia, where spectacle wearing behaviors are of interest. Methods: Several sensors were considered in the design of the SpecsOn monitor. The final version included two temperature sensors, one that measures skin temperature through an infrared sensor directed at the wearer's temple on the spectacle arm and the other measuring device temperature. The difference between the two temperature readings is used to determine if the spectacles were worn. The SpecsOn monitor was tested in two phases in adult participants (laboratory n = 10 and real world n = 5). Results: Results from both phases showed good agreement between the objective measurement of wear based on skin and device temperature differences and participants' manually logged wear times. The custom built SpecsOn monitor was 99% successful in accurately detecting spectacle wear in our adult cohort. Conclusions: The SpecsOn monitor offers a convenient, accurate, and reliable system to monitor spectacle adherence. The devices were comfortable, secure, and unobtrusive to wear, and fitted easily to a variety of frame styles. Translational Relevance: Easy access to spectacle compliance information from the SpecsOn monitor during the optical treatment phase will optimize visual outcomes and provide detailed clinical data to support decision making on the need and timing of additional therapies, improving treatment efficiency.

GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis.

Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.

Adherence to home-based videogame treatment for amblyopia in children and adults.

Clinical relevance: Home-based videogame treatments are increasingly popular for amblyopia treatment. However, at-home treatments tend to be done in short sessions and with frequent disruptions, which may reduce the effectiveness of binocular visual stimulation. These treatment adherence patterns need to be accounted for when considering dose-response relationships and treatment effectiveness.Background: Home-based videogame treatments are increasingly being used for various sensory conditions, including amblyopia ('lazy eye'), but treatment adherence continues to limit success. To examine detailed behavioural patterns associated with home-based videogame treatment, we analysed in detail the videogame adherence data from the Binocular tReatment of Amblyopia with VideOgames (BRAVO) clinical trial (ACTRN12613001004752).Methods: Children (7-12 years), teenagers (13-17 years) and adults (≥ 18 years) with unilateral amblyopia were loaned iPod Touch devices with either an active treatment or placebo videogame and instructed to play for a total of 1-2 hours/day for six weeks at home. Objectively-recorded adherence data from device software were used to analyse adherence patterns such as session length, daily distribution of gameplay, use of the pause function, and differences between age groups. Objectively-recorded adherence was also compared to subjectively-reported adherence from paper-based diaries.Results: One hundred and five of the 115 randomised participants completed six weeks of videogame training. Average adherence was 65% (SD 37%) of the minimum hours prescribed. Game training was generally performed in short sessions (mean 21.5, SD 11.2 minutes), mostly in the evening, with frequent pauses (median every 4.1 minutes, IQR 6.1). Children played in significantly shorter sessions and paused more frequently than older age groups (p < 0.0001). Participants tended to over-report adherence in subjective diaries compared to objectively-recorded gameplay time.Conclusion: Adherence to home-based videogame treatment was characterised by short sessions interspersed with frequent pauses, suggesting regular disengagement. This complicates dose-response calculations and may interfere with the effectiveness of treatments like binocular treatments for amblyopia, which require sustained visual stimulation.

Rare genetic coding variants associated with human longevity and protection against age-related diseases.

Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on individuals harboring the known common risk allele APOE4. The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms.

Plasma proteomic profile of age, health span, and all-cause mortality in older adults.

Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan® proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65-95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; ß[SE] = 0.0262 [0.0012]; p = 3.21 × 10-86 ), WNT1-inducible-signaling pathway protein 2 (WISP-2; ß[SE] = 0.0189 [0.0009]; p = 4.60 × 10-82 ), chordin-like protein 1 (CRDL1; ß[SE] = 0.0203[0.0010]; p = 1.45 × 10-77 ), transgelin (TAGL; ß[SE] = 0.0215 [0.0011]; p = 9.70 × 10-71 ), and R-spondin-1(RSPO1; ß[SE] = 0.0208 [0.0011]; p = 1.09 × 10-70 ), were the proteins most significantly associated with age. Weighted gene co-expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age-associated diseases and other age-related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E-16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity.

Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity.

Centenarians (exceptionally long-lived individuals-ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease-associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews. The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss-of-function (LoF) variants in ELLI and offspring compared to the control group. Case-control pathogenic variants enrichment analyses conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer's disease-associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested. The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.

Plasma proteomic profile of frailty.

Frailty is a state of decreased physiological reserve and increased vulnerability to adverse outcomes in aging, and is characterized by dysregulation across various biological pathways. Frailty may manifest biologically as alteration in protein expression, possibly regulated at genetic, transcriptional and epigenetic levels. In this study, we examined the proteomic profile associated with frailty defined by an established cumulative frailty index (FI). Using the SomaScan® assay, 4265 proteins were measured in plasma, of which 55 were positively associated and 88 were negatively associated with the FI. The proteins most strongly associated with frailty were fatty acid-binding proteins, including fatty acid-binding protein (FABP) (p = 1.96 × 10-19 ) and FABPA (p = 8.10 × 10-16 ), leptin (p = 1.43 × 10-14 ), and ANTR2 (p = 7.95 × 10-20 ). Pathway analysis with the top 143 frailty-associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell-to-cell signaling and interaction, cellular assembly, and organization. Frailty prediction model constructed with elastic net regression utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty (r = 0.57, p < 2.2 × 10-16 ). Predicted frailty was also more strongly correlated with chronological age (r = 0.54, p < 2.2 × 10-16 ) than observed frailty (r = 0.37, p = 1.2 × 10-15 ). This study identified novel proteins and pathways related to frailty that may offer improved frailty phenotyping and prediction.

Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults.

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05-1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680-0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08-2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004-1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29-0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

Local Defects in Colloidal Quantum Dot Thin Films Measured via Spatially Resolved Multi-Modal Optoelectronic Spectroscopy.

The morphology, chemical composition, and electronic uniformity of thin-film solution-processed optoelectronics are believed to greatly affect device performance. Although scanning probe microscopies can address variations on the micrometer scale, the field of view is still limited to well under the typical device area, as well as the size of extrinsic defects introduced during fabrication. Herein, a micrometer-resolution 2D characterization method with millimeter-scale field of view is demonstrated, which simultaneously collects photoluminescence spectra, photocurrent transients, and photovoltage transients. This high-resolution morphology mapping is used to quantify the distribution and strength of the local optoelectronic property variations in colloidal quantum dot solar cells due to film defects, physical damage, and contaminants across nearly the entire test device area, and the extent to which these variations account for overall performance losses. It is found that macroscopic defects have effects that are confined to their localized areas, rarely prove fatal for device performance, and are largely not responsible for device shunting. Moreover, quantitative analysis based on statistical partitioning methods of such data is used to show how defect identification can be automated while identifying variations in underlying properties such as mobilities and recombination strengths and the mechanisms by which they govern device behavior.

Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy.

BACKGROUND: Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. METHODS: We utilized a doxycycline-inducible shRNA-mediated strategy to knockdown GOT1 in PDA and colorectal cancer (CRC) cell lines and tumor models of similar genotype. These cells were analyzed for the ability to form colonies and tumors to test if tissue type impacted GOT1 dependence. Additionally, the ability of GOT1 to impact the response to chemo- and radiotherapy was assessed. Mechanistically, the associated specimens were examined using a combination of steady-state and stable isotope tracing metabolomics strategies and computational modeling. Statistics were calculated using GraphPad Prism 7. One-way ANOVA was performed for experiments comparing multiple groups with one changing variable. Student's t test (unpaired, two-tailed) was performed when comparing two groups to each other. Metabolomics data comparing three PDA and three CRC cell lines were analyzed by performing Student's t test (unpaired, two-tailed) between all PDA metabolites and CRC metabolites. RESULTS: While PDA exhibits profound growth inhibition upon GOT1 knockdown, we found CRC to be insensitive. In PDA, but not CRC, GOT1 inhibition disrupted glycolysis, nucleotide metabolism, and redox homeostasis. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. CONCLUSIONS: Taken together, these results illustrate the role of tissue type in dictating metabolic dependencies and provide new insights for targeting metabolism to treat PDA.

Clinical Aniseikonia in Anisometropia and Amblyopia.

PURPOSE: Clinically, aniseikonia (a perceived difference in shape and image size between the eyes) is often neglected in anisometropic amblyopia due to assumed measurement difficulties. Therefore, we currently lack evidence on whether correction of aniseikonia is beneficial. This study aimed to determine whether subjective aniseikonia is measurable in anisometropia with or without amblyopia. METHODS: Participants (15-52 years) with Anisometropic Amblyopia (n = 7), Anisometropia without amblyopia (n = 6) and Isometropic Controls (n = 6) were recruited. Subjective aniseikonia was measured using three clinical techniques: Robertson Technique (RT) (penlight and Maddox rod), Aniseikonia Inspector Version 3 (AI3), and the New Aniseikonia Test booklet (NAT), and a psychophysical adaptive method, the Contrast-balanced Aniseikonia Test (CAT), where dichoptic contrast adjustments compensate for any suppression. RESULTS: Eighteen participants completed all tests, one Anisometropic Amblyopia participant could only complete the CAT and NAT due to fusion loss. The Anisometropic Amblyopia group exhibited the most aniseikonia (range -1.50-+10.50%) followed by Anisometropic Controls (range -3.30-+4.50%) and Isometropic Controls (range -1.50-+3.28%). There was a significant trend of more subjective aniseikonia with increasing amounts of anisometropia across all four tests (AI3 r = 0.630, p = 0.005; NAT r = 0.542, p = 0.017; RT r = 0.499, p = 0.035; CAT r = 0.440, p = 0.059. Bland Altman analysis demonstrated clinically significant levels of variability between the tests. CONCLUSIONS: Subjective aniseikonia can be reliably measured in patients with anisometropia and suppression. Subjective aniseikonia measurement is recommended as four of the most commonly used clinical tests did not support the 1% per dioptre rule of thumb.