A Fast Transient Response Capacitor-Less LDO with Transient Enhancement Technology.

This paper proposes a fast transient load response capacitor-less low-dropout regulator (CL-LDO) for digital analog hybrid circuits in the 180 nm process, capable of converting input voltages from 1.2 V to 1.8 V into an output voltage of 1 V. The design incorporates a rail-to-rail input and push-pull output (RIPO) amplifier to enhance the gain while satisfying the requirement for low power consumption. A super source follower buffer (SSFB) with internal stability is introduced to ensure loop stability. The proposed structure ensures the steady-state performance of the LDO without an on-chip capacitor. The auxiliary circuit, or transient enhancement circuit, does not compromise the steady-state stability and effectively enhances the transient performance during sudden load current steps. The proposed LDO consumes a quiescent current of 47 µA and achieves 25 µV/mA load regulation with a load current ranging from 0 to 20 mA. The simulation results demonstrate that a settling time of 0.2 µs is achieved for load steps ranging from 0 mA to 20 mA, while a settling time of 0.5 µs is attained for load steps ranging from 20 mA to 0 mA, with an edge time of 0.1 µs.

Progress of stimulus responsive nanosystems for targeting treatment of bacterial infectious diseases.

In recent decades, due to insufficient concentration at the lesion site, low bioavailability and increasingly serious resistance, antibiotics have become less and less dominant in the treatment of bacterial infectious diseases. It promotes the development of efficient drug delivery systems, and is expected to achieve high absorption, targeted drug release and satisfactory therapy effects. A variety of endogenous stimulation-responsive nanosystems have been constructed by using special infection microenvironments (pH, enzymes, temperature, etc.). In this review, we firstly provide an extensive review of the current research progress in antibiotic treatment dilemmas and drug delivery systems. Then, the mechanism of microenvironment characteristics of bacterial infected lesions was elucidated to provide a strong theoretical basis for bacteria-targeting nanosystems design. In particular, the discussion focuses on the design principles of single-stimulus and dual-stimulus responsive nanosystems, as well as the use of endogenous stimulus-responsive nanosystems to deliver antimicrobial agents to target locations for combating bacterial infectious diseases. Finally, the challenges and prospects of endogenous stimulus-responsive nanosystems were summarized.

METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Automated localization of mandibular landmarks in the construction of mandibular median sagittal plane.

OBJECTIVE: To use deep learning to segment the mandible and identify three-dimensional (3D) anatomical landmarks from cone-beam computed tomography (CBCT) images, the planes constructed from the mandibular midline landmarks were compared and analyzed to find the best mandibular midsagittal plane (MMSP). METHODS: A total of 400 participants were randomly divided into a training group (n = 360) and a validation group (n = 40). Normal individuals were used as the test group (n = 50). The PointRend deep learning mechanism segmented the mandible from CBCT images and accurately identified 27 anatomic landmarks via PoseNet. 3D coordinates of 5 central landmarks and 2 pairs of side landmarks were obtained for the test group. Every 35 combinations of 3 midline landmarks were screened using the template mapping technique. The asymmetry index (AI) was calculated for each of the 35 mirror planes. The template mapping technique plane was used as the reference plane; the top four planes with the smallest AIs were compared through distance, volume difference, and similarity index to find the plane with the fewest errors. RESULTS: The mandible was segmented automatically in 10 ± 1.5 s with a 0.98 Dice similarity coefficient. The mean landmark localization error for the 27 landmarks was 1.04 ± 0.28 mm. MMSP should use the plane made by B (supramentale), Gn (gnathion), and F (mandibular foramen). The average AI grade was 1.6 (min-max: 0.59-3.61). There was no significant difference in distance or volume (P > 0.05); however, the similarity index was significantly different (P < 0.01). CONCLUSION: Deep learning can automatically segment the mandible, identify anatomic landmarks, and address medicinal demands in people without mandibular deformities. The most accurate MMSP was the B-Gn-F plane.

Integration of mRNA and miRNA analysis reveals the molecular mechanisms of sugar beet (Beta vulgaris L.) response to salt stress.

The continuous increase of saline-alkali areas worldwide has led to the emergence of saline-alkali conditions, which are the primary abiotic stress or hindering the growth of plants. Beet is among the main sources of sugar, and its yield and sugar content are notably affected by saline-alkali stress. Despite sugar beet being known as a salt-tolerant crop, there are few studies on the mechanisms underlying its salt tolerance, and previous studies have mainly delineated the crop's response to stress induced by NaCl. Recently, advancements in miRNA-mRNA network analysis have led to an increased understanding of how plants, including sugar beet, respond to stress. In this study, seedlings of beet variety "N98122" were grown in the laboratory using hydroponics culture and were exposed to salt stress at 40 days of growth. According to the phenotypic adaptation of the seedlings' leaves from a state of turgidity to wilting and then back to turgidity before and after exposure, 18 different time points were selected to collect samples for analysis. Subsequently, based on the data of real-time quantitative PCR (qRT-PCR) of salt-responsive genes, the samples collected at the 0, 2.5, 7.5, and 16 h time points were subjected to further analysis with experimental materials. Next, mRNA-seq data led to the identification of 8455 differentially expressed mRNAs (DEMs) under exposure to salt stress. In addition, miRNA-seq based investigation retrieved 3558 miRNAs under exposure to salt stress, encompassing 887 known miRNAs belonging to 783 families and 2,671 novel miRNAs. With the integrated analysis of miRNA-mRNA network, 57 miRNA-target gene pairs were obtained, consisting of 55 DEMIs and 57 DEMs. Afterwards, we determined the pivotal involvement of aldh2b7, thic, and δ-oat genes in the response of sugar beet to the effect of salt stress. Subsequently, we identified the miRNAs novel-m035-5p and novel-m0365-5p regulating the aldh gene and miRNA novel-m0979-3p regulating the thic gene. The findings of miRNA and mRNA expression were validated by qRT-PCR.

A Fast Transient Adaptive On-Time Controlled BUCK Converter with Dual Modulation.

This paper proposed a fully integrated adaptive on-time (AOT) controlled buck converter with fast load transient. An adaptive on-time generator is presented to stabilize the output frequency. To enhance the light load efficiency, the converter could transfer from the pulse width modulation (PWM) to pulse skip modulation (PSM) as the load current decreases. The buck converter can switch between these two modulation modes adaptively with the assistance of a zero current detection circuit. Implemented in the TSMC 0.18 µm BCD (BiCMOS/DMOS) process, the proposed buck converter works with an input voltage ranging from 5.5 to 15 V, an output voltage ranging from 0.5 to 5 V, and an output load ranging up to 5 A. The experimental results show that based on the dual modulation adaptive on-time controlled mode, the transient recovery time from light to heavy load and from heavy load to light load is 13 µs and 15 µs, respectively. An overshot voltage of 57 mV and an undershot voltage of 53 mV are also achieved.

Identification and Expression Analysis of DFR Gene Family in Brassica napus L.

Dihydroflavonol 4-reductase (DFR) is a key enzyme in the flavonoid biosynthetic pathway and is essential for the formation of plants' color. In this study, 26 BnDFR genes were identified using 6 Arabidopsis DFR genes as reference. The physicochemical properties, subcellular localization, and conserved structure of BnDFR proteins were analyzed; the evolutionary relationship, collinearity analysis, and expression characteristics of BnDFR genes were studied; and the correlation between the expression level of BnDFR genes and anthocyanin content in rape petals were analyzed. The results showed that the 26 BnDFRs were located in chloroplasts, cytoplasm, nuclei, and mitochondria, distributed on 17 chromosomes, and divided into 4 groups; members of the same group have a similar function, which may be related to the environmental response elements and plant hormone response elements. Intraspecific collinearity analysis showed 51 pairs of collinear genes, and interspecific collinearity analysis showed 30 pairs of collinear genes. Analysis of the expression levels of BnDFRs and anthocyanin content in different color rape petals showed that BnDFR6 and BnDFR26 might play an important role in the synthesis of anthocyanins in rape petals. This provides theoretical guidance for further analysis of the anthocyanin anabolism mechanism involved in the DFR gene in Brassica napus.

Improving Performance of Al2O3/AlN/GaN MIS HEMTs via In Situ N2 Plasma Annealing.

A novel monocrystalline AlN interfacial layer formation method is proposed to improve the device performance of the fully recessed-gate Al2O3/AlN/GaN Metal-Insulator-Semiconductor High Electron Mobility Transistors (MIS-HEMTs), which is achieved by plasma-enhanced atomic layer deposition (PEALD) and in situ N2 plasma annealing (NPA). Compared with the traditional RTA method, the NPA process not only avoids the device damage caused by high temperatures but also obtains a high-quality AlN monocrystalline film that avoids natural oxidation by in situ growth. As a contrast with the conventional PELAD amorphous AlN, C-V results indicated a significantly lower interface density of states (Dit) in a MIS C-V characterization, which could be attributed to the polarization effect induced by the AlN crystal from the X-ray Diffraction (XRD) and Transmission Electron Microscope (TEM) characterizations. The proposed method could reduce the subthreshold swing, and the Al2O3/AlN/GaN MIS-HEMTs were significantly enhanced with ~38% lower on-resistance at Vg = 10 V. What is more, in situ NPA provides a more stable threshold voltage (Vth) after a long gate stress time, and ΔVth is inhibited by about 40 mV under Vg,stress = 10 V for 1000 s, showing great potential for improving Al2O3/AlN/GaN MIS-HEMT gate reliability.

Blending controlled-release urea and urea under ridge-furrow with plastic film mulching improves yield while mitigating carbon footprint in rainfed potato.

Ridge-furrow with plastic film mulching and various urea types have been applied in rainfed agriculture, but their interactive effects on potato (Solanum tuberosum L.) yield and especially environments remain poorly understood. A three-year experiment was conducted to explore the responses of tuber yield, methane (CH4) and nitrous oxide (N2O) emissions, net global warming potential (NGWP), carbon footprint (CF), and net ecosystem economic budget (NEEB) of rainfed potato to two mulching practices [plastic film mulching (RM) and no plastic film mulching (NM)] and three urea types [conventional urea (U), controlled-release urea (C), and a mixture of equal amounts of conventional urea and controlled-release urea at a ratio of 1:1 (CU)] and their interactions. The results showed that RM significantly decreased cumulative N2O emissions and CH4 uptake by 4.9% and 28.4%, but significantly increased NGWP by 8.9% relative to NM. Compared with U, the C and CU produced much lower cumulative N2O emissions and NGWP and higher CH4 uptake. The interaction of mulching methods and urea type had significant influence on tuber yield and NEEB. Considering both environment and production, RMCU could not only achieve a high tuber yield and NEEB (by up to 26.5% and 42.9%, respectively), but also reduce the CF (by up to 13.7%), and therefore should be considered an effective strategy for dryland potato.

ABC Transporters and CYP3A4 Mediate Drug Interactions between Enrofloxacin and Salinomycin Leading to Increased Risk of Drug Residues and Resistance.

Enrofloxacin (ENR) is one of the most common drugs used in poultry production to treat bacterial diseases, and there is a high risk of drug interactions (DDIs) between polyether anticoccidial drugs added to poultry feed over time. This may affect the efficacy of antibiotics or lead to toxicity, posing a potential risk to the environment and food safety. This study aimed to investigate the DDI of ENR and salinomycin (SAL) in broilers and the mechanism of their DDI. We found that SAL increased the area under the curve and elimination half-life of ENR and ciprofloxacin (CIP) by 1.3 and 2.4 times, 1.2 and 2.5 times, respectively. Cytochrome 3A4 (CYP3A4), p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) were important factors for the DDI between ENR and SAL in broilers. ENR and SAL are substrates of CYP3A4, P-gp and BCRP in broilers; ENR and SAL inhibited the expression of CYP3A4 activity in a time- and concentration-dependent. Meanwhile, ENR downregulated the expression of P-gp and BCRP in a time- and concentration-dependent manner. A single oral administration of SAL inhibited CYP3A4, P-gp, and BCRP, but long-term mixed feeding upregulated the expression of CYP3A4, P-gp, and BCRP. Molecular docking revealed that ENR and SAL compete with each other for CYP3A4 to affect hepatic metabolism, and compete with ATP for P-gp and BCRP binding sites to inhibit efflux. ENR and SAL in broilers can lead to severe DDI. Drug residues and resistance following co-administration of ENR and SAL and other SAL-based drug-feed interactions warrant further study.

Associations of systemic health and medication use with the enlargement rate of geographic atrophy in age-related macular degeneration.

BACKGROUND: The associations of geographic atrophy (GA) progression with systemic health status and medication use are unclear. METHODS: We manually delineated GA in 318 eyes in the Age-Related Eye Disease Study. We calculated GA perimeter-adjusted growth rate as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye (mean follow-up=5.3 years). Patients' history of systemic health and medications was collected through questionnaires administered at study enrolment. We evaluated the associations between GA perimeter-adjusted growth rate and 27 systemic health factors using univariable and multivariable linear mixed-effects regression models. RESULTS: In the univariable model, GA perimeter-adjusted growth rate was associated with GA in the fellow eye at any visit (p=0.002), hypertension history (p=0.03), cholesterol-lowering medication use (p<0.001), beta-blocker use (p=0.02), diuretic use (p<0.001) and thyroid hormone use (p=0.03). Among the six factors, GA in the fellow eye at any visit (p=0.008), cholesterol-lowering medication use (p=0.002), and diuretic use (p<0.001) were independently associated with higher GA perimeter-adjusted growth rate in the multivariable model. GA perimeter-adjusted growth rate was 51.1% higher in patients with versus without cholesterol-lowering medication use history and was 37.8% higher in patients with versus without diuretic use history. CONCLUSIONS: GA growth rate may be associated with the fellow eye status, cholesterol-lowering medication use, and diuretic use. These possible associations do not infer causal relationships, and future prospective studies are required to investigate the relationships further.

The influence of the topographic location of geographic atrophy on vision-related quality of life in nonexudative age-related macular degeneration.

PURPOSE: To examine associations between the topographic distribution of geographic atrophy (GA) and vision-related quality of life (VRQoL). METHODS: This study included 237 eyes from 161 participants in the Age-Related Eye Disease Study (AREDS). GA lesions were manually delineated with color fundus photographs obtained by the AREDS Research Group and atrophic area was measured in an Early Treatment Diabetic Retinopathy Study (ETDRS) grid. VRQoL was measured using the National Eye Institute Visual Function Questionnaire (NEI-VFQ). Area of atrophy in the ETDRS grid subfields was correlated with VRQoL by linear regression modeling. RESULTS: The average area of atrophy in the better and worse eye was 3.43mm2 and 7.15mm2 respectively. In multivariable analysis, VRQoL was not associated with total area of atrophy in the better eye (ß, - 0.53; 95% confidence interval [CI], - 1.11 to 0.05; P = 0.07) or worse eye (ß, 0.12; 95% CI, - 0.32 to 0.55; P = 0.59). However, area of atrophy in the central 1-mm-diameter zone of the better eye was significantly associated with VRQoL when the ETDRS subfields were examined individually (ß, - 14.57; 95% CI, - 27.12 to - 2.02; P = 0.023), grouped into quadrants (ß, - 18.35; 95% CI, - 30.03 to - 6.67; P = 0.002), inner and outer zones (ß, - 17.26; 95% CI, - 29.38 to - 5.14; P = 0.006), or vertical and horizontal zones (ß, - 18.97; 95% CI, - 30.18 to - 7.77; P = 0.001). CONCLUSION: In patients with GA, greater area of atrophy in the central 1-mm-diameter zone of the better eye was independently associated with lower VRQoL, while total area of atrophy in the better or worse eye was not.

Relationship between gut microbiota and lymphocyte subsets in Chinese Han patients with spinal cord injury.

This study is to investigate the changes of lymphocyte subsets and the gut microbiota in Chinese Han patients with spinal cord injury (SCI). We enrolled 23 patients with SCI and 21 healthy controls. Blood and fecal samples were collected. The proportion of lymphocyte subsets was detected by flow cytometry. 16S rDNA sequencing of the V4 region was used to analyze the gut microbiota. The changes of the gut microbiota were analyzed by bioinformatics. Correlation analysis between gut microbiota and lymphocyte subsets was performed. CD4 + cells, CD4 + /CD8 + ratio and CD4 + CD8 + cells in peripheral blood of SCI patients were significantly lower than those of the control group (P < 0.05). There was no significant difference in B cells and CIK cells between the SCI group and the control group. The gut microbiota community diversity index of SCI patients was significantly higher than that of healthy controls. In SCI patients, the relative abundance of Lachnospiraceae (related to lymphocyte subset regulation), Ruminococcaceae (closely related to central nervous system diseases), and Escherichia-Shigella (closely related to intestinal infections) increased significantly, while the butyrate producing bacteria (Fusobacterium) that were beneficial to the gut were dramatically decreased. Correlation analysis showed that the five bacterial genera of SCI patients, including Lachnospiraceae UCG-008, Lachnoclostridium 12, Tyzzerella 3, Eubacterium eligens group, and Rumencocciucg-002, were correlated with T lymphocyte subsets and NK cells. In the SCI group, the flora Prevotella 9, Lachnospiraceae NC2004 group, Veillonella, and Sutterella were positively correlated with B cells. However, Fusobacterium and Akkermansia were negatively correlated with B cells. Moreover, Roseburia and Ruminococcaceae UCG-003 were positively correlated with CIK cells. Our results suggest that the gut microbiota of patients with SCI is associated with lymphocyte subsets. Therefore, it is possible to improve immune dysregulation in SCI patients by modulating gut microbiota, which may serve as a new therapeutic method for SCI.

Natural history of central sparing in geographic atrophy secondary to non-exudative age-related macular degeneration.

BACKGROUND: The macular central 1 mm diameter zone is crucial to patients' visual acuity, but the long-term natural history of central sparing in eyes with geographic atrophy (GA) is unknown. METHODS: We manually segmented GA in 210 eyes with GA involving central 1 mm diameter zone (mean follow-up=3.8 years) in the Age-Related Eye Disease Study. We measured the residual area in central 1 mm diameter zone and calculated central residual effective radius (CRER) as square root of (residual area/π). A linear mixed-effects model was used to model residual size over time. We added a horizontal translation factor to each data set to account for different durations of GA involving the central zone. RESULTS: The decline rate of central residual area was associated with baseline residual area (p=0.008), but a transformation from central residual area to CRER eliminated this relationship (p=0.51). After the introduction of horizontal translation factors to each data set, CRER declined linearly over approximately 13 years (r2=0.80). The growth rate of total GA effective radius was 0.14 mm/year (95% CI 0.12 to 0.15), 3.7-fold higher than the decline rate of CRER (0.038 mm/year, 95% CI 0.034 to 0.042). The decline rate of CRER was 53.3% higher in eyes with than without advanced age-related macular degeneration in the fellow eyes at any visit (p=0.007). CONCLUSIONS: CRER in eyes with GA declined linearly over approximately 13 years and may serve as an anatomic endpoint in future clinical trials aiming to preserve the central zone.

Local Progression Kinetics of Geographic Atrophy Depends Upon the Border Location.

Purpose: To assess the influence of lesion morphology and location on geographic atrophy (GA) growth rate. Methods: We manually delineated GA on color fundus photographs of 237 eyes in the Age-Related Eye Disease Study. We calculated local border expansion rate (BER) as the linear distance that a point on the GA border traveled over 1 year based on a Euclidean distance map. Eye-specific BER was defined as the mean local BER of all points on the GA border in an eye. The percentage area affected by GA was defined as the GA area divided by the total retinal area in the region. Results: GA enlarged 1.51 ± 1.96 mm2 in area and 0.13 ± 0.11 mm in distance over 1 year. The GA area growth rate (mm2/y) was associated with the baseline GA area (P < 0.001), perimeter (P < 0.001), lesion number (P < 0.001), and circularity index (P < 0.001); in contrast, eye-specific BER (mm/y) was not significantly associated with any of these factors. As the retinal eccentricity increased from 0 to 3.5 mm, the local BER increased from 0.10 to 0.24 mm/y (P < 0.001); in contrast, the percentage of area affected by GA decreased from 49.3% to 2.3%. Conclusions: Using distance-based measurements allows GA progression evaluation without significant confounding effects from baseline GA morphology. Local GA progression rates increased as a function of retinal eccentricity within the macula which is opposite of the trend for GA distribution, suggesting that GA initiation and enlargement may be mediated by different biological processes.

The roles of cadmium on growth of seedlings by analysing the composition of metabolites in pumpkin tissues.

Changes in the types and contents of metabolites in plants can occur in response to environmental stress. In this study, pumpkin seeds were cultivated in a cadmium ion solution (cadmium sulfate) for 7 days, and growth parameters, antioxidant enzyme activities, and metabolites in the root, stem, and leaf were analyzed. The results showed that cadmium accumulation characteristics were in the order of root > stem > leaf. Cadmium restrained root growth and promoted superoxide dismutase, peroxidase, catalase activities in the root, but inhibited their activities in the leaf. Cadmium did not change the total biomass of pumpkin seedlings. Orthogonal partial least squares (OPLS) analyses were conducted to detect the relationships between fresh weight and metabolites. These analyses revealed that maltose had significantly positive relationships with the fresh weight of the root, stem, and leaf. Cadmium influenced glyoxylate and dicarboxylate metabolism, aminoacyl-tRNA biosynthesis, sulfur metabolism, butanoate metabolism, alanine, aspartate and glutamate metabolism, glutathione metabolism, glycine, serine and threonine metabolism in the root; glycolysis/gluconeogenesis in the stem; and biosynthesis of unsaturated fatty acids, galactose metabolism, cutin, suberine and wax biosynthesis in the leaf. It is important that cadmium inhibited root growth by inhibiting carbohydrate transport from the leaf to the root and promoted leaf growth by the accumulation of carbohydrates in the leaf. Furthermore, cadmium also restrained amino acid metabolism in the root of pumpkin seedlings. These results provide new information about how pumpkin seedlings respond to cadmium stress.

Geographic atrophy severity and mortality in age-related macular degeneration.

PURPOSE: To examine the association between geographic atrophy (GA) disease characteristics and mortality risk. METHODS: We manually delineated color fundus photographs of 209 Age-Related Eye Disease Study (AREDS) participants with GA secondary to age-related macular degeneration to identify total area of atrophy, GA effective radius growth rate, disease laterality, and the presence of foveal center involvement. Associations between GA characteristics and mortality were assessed with Cox proportional hazards models adjusted for health status indicators. RESULTS: During a median follow-up of 6.8 years, 48 (23.0%) participants with GA died. In adjusted models, accounting for age, sex, and health status, participants with total GA area in the highest quartile had a significantly increased risk of all-cause mortality compared to those with total GA area in the lowest quartile (hazard ratio [HR], 3.42; 95% confidence interval [CI], 1.32-8.86; P = 0.011). GA effective radius growth rate, bilateral disease, and the presence of foveal center involvement were not significantly associated with mortality. In a multivariable model, including health status indicators and all GA characteristics, total area of atrophy in the highest quartile remained significantly associated with mortality (HR, 4.65; 95% CI, 1.29-16.70; P = 0.019). CONCLUSIONS: More extensive GA, as indicated by a greater total area of atrophy, was associated with an increased risk of all-cause mortality in our cohort. The extent of GA may reflect the extent of underlying disease processes that contribute to greater mortality risk, further suggesting that GA may be part of a systemic rather than purely ocular disease process.

Long-term natural history of visual acuity in eyes with choroideremia: a systematic review and meta-analysis of data from 1004 individual eyes.

BACKGROUND/AIMS: Best-corrected visual acuity (BCVA) is the most common primary endpoint in treatment trials for choroideremia (CHM) but the long-term natural history of BCVA is unclear. METHODS: We searched in seven databases to identify studies that reported BCVA of untreated eyes with CHM. We sought individual-level data and performed segmented regression between BCVA and age. For eyes followed longitudinally, we introduced a horizontal translation factor to each dataset to account for different ages at onset of a rapid BCVA decline. RESULTS: We included 1004 eyes from 23 studies. BCVA of the right and left eyes was moderately correlated (r=0.60). BCVA as a function of age followed a 2-phase decline (slow followed by rapid decline), with an estimated transition age of 39.1 years (95% CI 33.5 to 44.7). After the introduction of horizontal translation factors to longitudinal datasets, BCVA followed a 2-phase decline until it reached 0 letters (r2=0.90). The BCVA decline rate was 0.33 letters/year (95% CI -0.38 to 1.05) before 39 years, and 1.23 letters/year (95% CI 0.55 to 1.92) after 39 years (p=0.004). CONCLUSION: BCVA in eyes with CHM follows a 2-phase linear decline with a transition age of approximately 39 years. Future trials enrolling young patients may not be able to use BCVA as a primary or sole endpoint, but rather, may need to employ additional disease biomarkers that change before age 39. BCVA may still have utility as a primary endpoint for patients older than 39 years who have measurable BCVA decline rates.

Geographic Atrophy Growth Is Strongly Related to Lesion Perimeter: Unifying Effects of Lesion Area, Number, and Circularity on Growth.

PURPOSE: To investigate the underlying reason for the previously observed impact of baseline lesion size, number, and circularity on geographic atrophy (GA) growth rate. DESIGN: Retrospective analysis of a multicenter, prospective, randomized controlled trial. PARTICIPANTS: Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. METHODS: We manually delineated atrophic lesions on color fundus photographs of 318 eyes with GA followed up over at least 2 visits (mean follow-up duration, 5.1 ± 3.0 years). We calculated GA area growth rate for each eye based on the first and last visit. GA perimeter-adjusted growth rate was defined as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye. MAIN OUTCOME MEASURES: GA area growth rate, growth rate of the square root of GA area, and GA perimeter-adjusted growth rate. RESULTS: GA area growth rate was correlated strongly with mean GA perimeter (r2 = 0.66). GA area growth rate was associated with baseline GA area (r2 = 0.39; P < 0.001), lesion number (r2 = 0.10; P < 0.001), and circularity index (r2 = 0.28; P < 0.001). The use of the square root of GA area reduced the influence of baseline GA area (but not lesion number or circularity) on GA growth rate. In comparison, GA perimeter-adjusted growth rate (0.098 ± 0.062 mm/year) was not correlated with baseline GA area (r2 = 0.005; P = 0.20), lesion number (r2 = 0.00009; P = 0.86), or circularity index (r2 = 0.007; P = 0.14). GA perimeter-adjusted growth rate was 50.0% higher in eyes whose fellow eyes showed GA at any visit (0.102 ± 0.062 mm/year) than in eyes whose fellow eyes never demonstrated GA during follow-up (0.068 ± 0.049 mm/year). CONCLUSIONS: The growth rate of GA area is associated strongly with lesion perimeter. This relationship explains the previously observed influences of baseline GA size, lesion number, and circularity on GA growth rate. GA perimeter-adjusted growth rate is uncorrelated with the 3 morphologic factors and may serve as a surrogate outcome measure to monitor GA progression in future studies.

Relationship of Topographic Distribution of Geographic Atrophy to Visual Acuity in Nonexudative Age-Related Macular Degeneration.

PURPOSE: To investigate the topographic distribution of geographic atrophy (GA) and to identify an anatomic endpoint that correlates with visual acuity (VA) in eyes with GA. DESIGN: Retrospective analysis of a multicenter, prospective, randomized controlled trial. PARTICIPANTS: The Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. METHODS: We manually delineated GA on 1654 fundus photographs of 365 eyes. We measured GA areas in 9 subfields on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid and correlated them with VA via a mixed-effects model. We determined the optimal diameter for the central zone by varying the diameter from 0 to 10 mm until the highest r2 between GA area in the central zone and VA was achieved. We estimated the VA decline rate over 8 years using a linear mixed model. MAIN OUTCOME MEASURES: Geographic atrophy area in macular subfields and VA. RESULTS: The percentage of area affected by GA declined as a function of retinal eccentricity. GA area was higher in the temporal than the nasal region (1.30 ± 1.75 mm2 vs. 1.10 ± 1.62 mm2; P = 0.005) and in the superior than the inferior region (1.26 ± 1.73 mm2 vs. 1.03 ± 1.53 mm2; P < 0.001). Total GA area correlated poorly with VA (r2 = 0.07). Among GA areas in 9 subfields, only GA area in the central zone was associated independently with VA (P < 0.001). We determined 1 mm as the optimal diameter for the central zone in which GA area correlated best with VA (r2 = 0.45). On average, full GA coverage of the central 1-mm diameter zone corresponded to 34.8 letters' decline in VA. The VA decline rate was comparable between eyes with initial noncentral and central GA before GA covered the entire central 1-mm diameter zone (2.7 letters/year vs. 2.8 letters/year; P = 0.94). CONCLUSIONS: The prevalence of GA varies significantly across different macular regions. Although total GA area was associated poorly with VA, GA area in the central 1-mm diameter zone was correlated significantly with VA and may serve as a surrogate endpoint in clinical trials.