Zinc-containing Mohs' paste affects blood flow and angiogenesis suppression.

PURPOSE: Mohs' paste, which is composed of zinc chloride and zinc oxide starch, is used for hemostasis of superficial malignancy in the clinical setting. We investigated the concentration of intramuscular zinc in mice after Mohs' paste application and evaluated its relationship with angiogenesis from the perspective of blood flow levels within 24 h. METHODS: Male C57BL/6JJmsSlc mice were administered single dose of Mohs' paste at 25%, 50%, and 75% after unilateral hind limb surgery, and glycerin, a viscosity modifier, was administered to the control group (0%). Hind limb blood flow levels were measured with a laser Doppler perfusion imaging system (n = 6). The amounts of intramuscular zinc and vascular endothelial growth factor-A (VEGF-A) expression were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) and western blotting, respectively (n = 5 or 3). RESULTS: Blood flow levels were significantly decreased in the 50% group after 8 h, and significantly decreased in the 25% and 50% groups after 24 h. Intramuscular zinc was significantly increased in the 50% and 75% groups after 8 h. Western blotting showed that VEGF-A levels were significantly increased in the 25% and 50% groups after 8 h. Based on analytical experiments and biological investigation, we predicated the pharmacological effect of Mohs' paste and found over 50% of it is critical in the blood flow and angiogenesis suppression after more than 8 h of its application. CONCLUSIONS: The results suggest that the mechanism of blood flow suppression is independent of VEGF-A levels and might suppress future angiogenesis. Our findings support that of previous studies, in which Mohs' paste was expected to induce hemostasis and suppress angiogenesis. It is an excellent ointment that facilitates hemostasis by suppressing blood flow regardless of angiogenesis, and may be apt for situations where hemostasis is required in the clinical setting.

Dual Encapsulated Dacarbazine and Zinc Phthalocyanine Polymeric Nanoparticle for Photodynamic Therapy of Melanoma.

PURPOSE: Melanoma is an invasive and very aggressive skin cancer due to its multi-drug resistance that results in poor patient survival. There is a need to test new treatment approaches to improve therapeutic efficacy and reduce side effects of conventional treatments. METHODS: PLA/PVA nanoparticles carrying both Dacarbazine and zinc phthalocyanine was produced by double emulsion technique. The characterization was performed by dynamic light scattering and atomic force microscopy. In vitro photodynamic therapy test assay using MV3 melanoma cells as a model has been performed. In vitro cell viability (MTT) was performed to measure cell toxicity of of nanoparticles with and without drugs using human endothelial cells as a model. The in vivo assay (biodistribution/tissue deposition) has been performed using radiolabeled PLA/PVA NPs. RESULTS: The nanoparticles produced showed a mean diameter of about 259 nm with a spherical shape. The in-vitro photodynamic therapy tests demonstrated that the combination is critical to enhance the therapeutic efficacy and it is dose dependent. The in vitro cell toxicity assay using endothelial cells demonstrated that the drug encapsulated into nanoparticles had no significant toxicity compared to control samples. In-vivo results demonstrated that the drug loading affects the biodistribution of the nanoparticle formulations (NPs). Low accumulation of the NPs into the stomach, heart, brain, and kidneys suggested that common side effects of Dacarbazine could be reduced. CONCLUSION: This work reports a robust nanoparticle formulation with the objective to leveraging the synergistic effects of chemo and photodynamic therapies to potentially suppressing the drug resistance and reducing side effects associated with Dacarbazine. The data corroborates that the dual encapsulated NPs showed better in-vitro efficacy when compared with the both compounds alone. The results support the need to have a dual modality NP formulation for melanoma therapy by combining chemotherapy and photodynamic therapy.

Co-administration of zinc phthalocyanine and quercetin via hybrid nanoparticles for augmented photodynamic therapy.

The photodynamic anticancer activity of a photosensitizer can be further increased by co-administration of a flavonoid. However, this requires that both molecules must be effectively accumulated at the tumor site. Hence, in order to enhance the activity of zinc phthalocyanine (ZnPc, photosensitizer), it was co-encapsulated with quercetin (QC, flavonoid) in lipid polymer hybrid nanoparticles (LPNs) developed using biodegradable & biocompatible materials and prepared using a single-step nanoprecipitation technique. High stability and cellular uptake, sustained release, inherent fluorescence, of ZnPC were observed after encapsulation in the LPNs, which also showed a higher cytotoxic effect in breast carcinoma cells (MCF-7) compared to photodynamic therapy (PDT) alone. In vivo studies in tumor-bearing Sprague Dawley rats demonstrated that the LPNs were able to deliver ZnPc and QC to the tumor site with minimal systemic toxicity and increased antitumor effect. Overall, the photodynamic effect of ZnPc was synergized by QC. This strategy could be highly beneficial for cancer management in the future while nullifying the side effects of chemotherapy.

Polaprezinc for prevention of oral mucositis in patients receiving chemotherapy followed by hematopoietic stem cell transplantation: A multi-institutional randomized controlled trial.

Oral mucositis is a common and distressing complication in patients receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). We reported previously in a single-center retrospective analysis that zinc-L-carnosine (polaprezinc [PZ]) reduced the incidence of oral mucositis associated with HSCT. To verify the accuracy of the prophylactic effect of PZ against oral mucositis, we carried out a multi-institutional prospective randomized controlled study. Patients were randomly allocated to either the prevention group, in which PZ lozenge treatment was started before chemotherapy, or the control group, in which administration of PZ lozenges was initiated immediately after the onset of Grade 2 oral mucositis. Oral mucositis was evaluated daily from the start of chemotherapy to 35 days after transplantation. A total of 91 patients were enrolled, and 88 patients (47 in the control group and 41 in the prevention group) were eligible for data analysis. The incidence of Grade ≥2 but not Grade ≥3 oral mucositis was significantly reduced in the prevention group compared to the control group (44.7% in control group vs 22.0% in the prevention group, P = .025). There were no significant differences in the incidence rates of other adverse events or the rate of engraftment (95.6% vs 97.2%, P = .693) between the two groups. These findings suggest that PZ lozenge is effective for prophylaxis against Grade ≥2 oral mucositis associated with chemotherapy in patients undergoing HSCT without any influence on the HSCT outcome.

Time-dependent changes in proliferation, DNA damage and clock gene expression in hepatocellular carcinoma and healthy liver of a transgenic mouse model.

Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time-of-day dependent changes of proliferation and DNA damage in HCC. Using transgenic c-myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ-H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev-erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ-H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time-of-day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.

A Kidney Transplant Recipient with Recurrent Henoch-Schönlein Purpura Nephritis Successfully Treated with Steroid Pulse Therapy and Epipharyngeal Abrasive Therapy.

There is no specific treatment for recurrent Henoch-Schönlein purpura nephritis (HSPN) in a transplanted kidney. We herein report a case of a kidney transplant recipient with recurrent HSPN that was successfully treated with steroid pulse therapy and epipharyngeal abrasive therapy (EAT). A 39-year-old Japanese man developed HSPN 4 years ago and had to start hemodialysis after 2 months despite receiving steroid pulse therapy followed by oral prednisolone, plasma exchange therapy, and cyclophosphamide pulse therapy. He had undergone tonsillectomy 3 years earlier in the hopes of achieving a better outcome of a planned kidney transplantation and received a living-donor kidney transplantation from his mother 1 year earlier. Although there were no abnormalities in the renal function or urinalysis 2 months after transplantation, a routine kidney allograft biopsy revealed evidence of mesangial proliferation and cellular crescent formation. Mesangial deposition for IgA and C3 was noted, and he was diagnosed with recurrent HSPN histologically. Since the renal function and urinalysis findings deteriorated 5 months after transplantation, 2 courses of steroid pulse therapy were performed but were ineffective. EAT using 0.5% zinc chloride solution once per day was combined with the third course of steroid pulse therapy, as there were signs of chronic epipharyngitis. His renal function recovered 3 months after daily EAT and has been stable for 1.5 years since transplantation. Daily EAT continued for >3 months might be a suitable strategy for treating recurrent HSPN in cases of kidney transplantation.

Prognostic factors of recovery with medication in patients with taste disorders.

OBJECTIVES: We aimed to elucidate the prognostic factors of the patients with taste disorders who were treated with popular and common medication in Japan. MATERIALS AND METHODS: A retrospective study on the medical charts of a total of 255 patients with taste disorders who were treated primarily with oral medication including a zinc agent. RESULTS: The factors below were significantly linked with poor prognosis: 1) male gender, 2) taste disorders that began 3 months before starting treatment and 3) a severe taste disorder grade at the initial visit. CONCLUSIONS: We have concluded that the prognosis for the patients with taste disorders who were treated by popular and standard medication therapy in Japan recently was significantly linked to gender, the period of 3 months before starting the treatment and the severity of the disorder at the time of diagnosis. In addition, we recognized some limitations we should resolve in further research including a method of measuring "umami" and so on. CLINICAL RELEVANCE: Better awareness of these factors should be clinically useful when we manage patients with taste disorders. Earlier treatment should be started to cure the symptoms.

Nephrotoxicity Evaluation of Indium Phosphide Quantum Dots with Different Surface Modifications in BALB/c Mice.

InP QDs have shown a great potential as cadmium-free QDs alternatives in biomedical applications. It is essential to understand the biological fate and toxicity of InP QDs. In this study, we investigated the in vivo renal toxicity of InP/ZnS QDs terminated with different functional groups-hydroxyl (hQDs), amino (aQDs) and carboxyl (cQDs). After a single intravenous injection into BALB/c mice, blood biochemistry, QDs distribution, histopathology, inflammatory response, oxidative stress and apoptosis genes were evaluated at different predetermined times. The results showed fluorescent signals from QDs could be detected in kidneys during the observation period. No obvious changes were observed in histopathological detection or biochemistry parameters. Inflammatory response and oxidative stress were found in the renal tissues of mice exposed to the three kinds of QDs. A significant increase of KIM-1 expression was observed in hQDs and aQDs groups, suggesting hQDs and aQDs could cause renal involvement. Apoptosis-related genes (Bax, Caspase 3, 7 and 9) were up-regulated in hQDs and aQDs groups. The above results suggested InP/ZnS QDs with different surface chemical properties would cause different biological behaviors and molecular actions in vivo. The surface chemical properties of QDs should be fully considered in the design of InP/ZnS QDs for biomedical applications.

In vitro hyperthermic effect of magnetic fluid on cervical and breast cancer cells.

Self-regulating temperature-controlled nanoparticles such as Mn-Zn ferrite nanoparticles based magnetic fluid can be a better choice for magnetic fluid hyperthermia because of its controlled regulation of hyperthermia temperature window of 43-45 °C. To test this hypothesis magnetic fluid with said properties was synthesized, and its effect on cervical and breast cancer cell death was studied. We found that the hyperthermia window of 43-45 °C was maintained for one hour at the smallest possible concentration of 0.35 mg/mL without altering the magnetic field applicator parameters. Their hyperthermic effect on HeLa and MCF7 was investigated at the magnetic field of 15.3 kA/m and frequency 330 kHz, which is close to the upper safety limit of 5 * 109 A/m s. We have tested the cytotoxicity of synthesized Mn-Zn ferrite fluid using MTT assay and the results were validated by trypan blue dye exclusion assay that provides the naked eye microscopic view of actual cell death. Since cancer cells tend to resist treatment and show re-growth, we also looked into the effect of multiple sessions hyperthermia using a 24 h window till 72 h using trypan blue assay. The multiple sessions of hyperthermia showed promising results, and it indicated that a minimum of 3 sessions, each of one-hour duration, is required for the complete killing of cancer cells. Moreover, to simulate an in vivo cellular environment, a phantom consisting of magnetic nanoparticles dispersed in 1 and 5% agarose gel was constituted and studied. These results will help to decide the magnetic fluid based hyperthermic therapeutic strategies using temperature-sensitive magnetic fluid.

Pre-dialysis serum creatinine as an independent predictor of responsiveness to zinc supplementation among patients on hemodialysis.

BACKGROUND: To investigate whether pre-dialysis level of serum creatinine (SCre) could indicate the responsiveness to zinc supplementation of patients on maintenance hemodialysis (MHD). METHODS: We retrospectively reviewed the results of our previous randomized study of 91 patients who had been on MHD and received zinc supplementation with either zinc acetate hydrate (ZAH; zinc, 50 mg/day) or polaprezinc (PPZ; zinc, 34 mg/day). A late response to zinc supplementation was defined as a serum zinc level of < 80 µg/dL three months after the study began. Patients were divided into two groups: late response (serum zinc level < 80 µg/dL) and early response (serum zinc level ≥ 80 µg/dL). Factors independently associated with a late response to zinc supplementation were determined using inverse probability of treatment weighting (IPTW) multivariate logistic analysis. RESULTS: Of 91 patients, 86 continued to receive zinc supplementation after three months. The mean pre-dialysis SCre level was 10.0 mg/dL. The number of patients with a late response and response to zinc supplementation was 32 and 54, respectively. There was a significant negative correlation between the pre-dialysis SCre and the Δserum zinc change for 3 months. (r = - 0.284, P = 0.008). IPTW multivariate analysis showed that a pre-dialysis SCre level ≥ 10.0 mg/dL (odds ratio, 3.71; 95% confidence interval; 1.24-11.1, P = 0.022) was an independent factor associated with a late response to zinc supplementation. CONCLUSIONS: Pre-dialysis SCre level was independently associated with responsiveness to zinc supplementation after three months in patients on MHD.

Zinc Iodide in combination with Dimethyl Sulfoxide for treatment of SARS-CoV-2 and other viral infections.

Zinc Iodide and Dimethyl Sulfoxide compositions are proposed as therapeutic agents to treat and prevent chronic and acute viral infections including SARS-CoV-2 infected patients. The therapeutic combinations have a wide range of virucidal effects on DNA and RNA containing viruses. The combinations also exhibit anti-inflammatory, immunomodulating, antifibrotic, antibacterial, antifungal and antioxidative effects. Given the fact that Zinc Iodide has been used as an oral antiseptic agent and DMSO has been already proven as a safe pharmaceutical solvent and therapeutic agent, we hypothesize that the combination of these two agents can be applied as an effective, safe and inexpensive treatment for SARS-CoV-2 and other viral infection. The therapeutic compound can be applied as both etiological and pathogenesis therapy and used as an effective and safe antiseptic (disinfectant) for human and animals as well.

A versatile cholera toxin conjugate for neuronal targeting and tracing.

Tracing of neurons plays an essential role in elucidating neural networks in the brain and spinal cord. Cholera toxin B subunit (CTB) is already widely used as a tracer although its use is limited by the need for immunohistochemical detection. A new construct incorporating non-canonical azido amino acids (azido-CTB) offers a novel way to expand the range and flexibility of this neuronal tracer. Azido-CTB can be detected rapidly in vivo following intramuscular tongue injection by 'click' chemistry, eliminating the need for antibodies. Cadmium selenide/zinc sulfide (CdSe/ZnS) core/shell nanoparticles were attached to azido-CTB by strain-promoted alkyne-azide cycloaddition to make a nano-conjugate. Following tongue injections the complex was detected in vivo in the brainstem by light microscopy and electron microscopy via silver enhancement. This method does not require membrane permeabilization and so ultrastructure is maintained. Azido-CTB offers new possibilities to enhance the utility of CTB as a neuronal tracer and delivery vehicle by modification using 'click' chemistry.

Efficacy and Safety of Polaprezinc (Zinc Compound) on Zinc Deficiency: A Systematic Review and Dose-Response Meta-Analysis of Randomized Clinical Trials Using Individual Patient Data.

Zinc intake is recommended for zinc deficiency. In clinical practice, polaprezinc has been used as a zinc replacement therapy for zinc deficiency. However, the efficacy of polaprezinc has not been established. To confirm the efficacy on zinc deficiency of polaprezinc and provide additional information on an appropriate regimen, we conducted a systematic review using individual patient data (IPD). We searched PubMed, the Japanese database Ichushi, and the database owned by the marketing authorization holder of polaprezinc. Randomized placebo-controlled trials that reported the serum zinc concentration were eligible. The mean difference of the change from baseline in serum zinc concentration was estimated using a fixed-effects model. The linear dose-response relationship and the subgroup effects were also assessed. Out of 54 unique randomized clinical trials (RCTs), four studies met the eligibility criteria, and we could access IPD for all of them. All three doses of polaprezinc (75 mg, 150 mg, and 300 mg) and the placebo group were examined. The dose-combined overall polaprezinc increased the change from baseline by a mean of 9.08 µg/dL (95% confidence interval: 5.46, 12.70; heterogeneity: I2 = 0.61%) compared to the placebo. A significant dose-response relationship was confirmed (p < 0.001). Baseline serum zinc concentration was considered an effect modifier in polaprezinc 300 mg. All doses of polaprezinc were tolerable, but a dose-response relationship with adverse events (AEs) was observed in gastrointestinal disorders. The dose of 300 mg may be useful among patients with baseline serum zinc concentration of less than 70 µg/dL, and 150 mg for 70 µg/dL or more.

A Review of Zinc-L-Carnosine and Its Positive Effects on Oral Mucositis, Taste Disorders, and Gastrointestinal Disorders.

Zinc-L-carnosine (ZnC), also called polaprezinc known as PepZin GI™, is a chelated compound that contains L-carnosine and zinc. It is a relatively new molecule and has been associated with multiple health benefits. There are several studies that support ZnC's benefits in restoring the gastric lining, healing other parts of the gastrointestinal (GI) tract, improving taste disorders, improving GI disorders, and enhancing skin and liver. Oral mucositis is a common complication of cytotoxic radiotherapy and/or chemotherapy. It occurs in almost every person with head and neck cancer who receive radiotherapy. It is often overlooked because it is not considered life threatening. However, mucositis often leads to a decreased quality of life and cessation of treatment, ultimately decreasing positive outcomes. Therefore, solutions to address it should be considered. The primary mechanisms of action are thought to be localized and related to ZnC's anti-inflammatory and antioxidant functions. Therefore, the purpose of this review is to discuss the research related to ZnC and to explore its benefits, especially in the management of conditions related to damaged epithelial cells, such as oral mucositis. Evidence supports the safety and efficacy of ZnC for the maintenance, prevention, and treatment of the mucosal lining and other epithelial tissues. The research supports its use for gastric ulcers (approved in Japan) and conditions of the upper GI and suggests other applications, particularly for oral mucositis.

Supplementation of various zinc sources modify sexual development and testicular IGF family gene expression in pre-pubertal male Japanese quail.

Zinc plays an important role in the regulation of insulin-like growth factor-I (IGF-I). IGF system, in turn, has a key role in the development and functions of the reproductive organs. This research was performed to investigate the effects of different sources of zinc on IGF-I gene expression and testicular development in pre-pubertal male Japanese quail. A total of 512 unsexed day-old Japanese quail chicks were randomly divided into 16 groups (4 dietary treatments × 4 replicates) and kept for 35 days. The control group diet was not supplemented with zinc whereas the diets of three groups were supplemented with 25 mg kg-1 zinc oxide (ZnO), zinc oxide nanoparticle (ZnON), and zinc-methionine (Zn-Met). On days 28 and 35, one birds from each subgroup were weighed, bled, and euthanized to evaluate gonado-somatic index (GSI), testicular histology, serum testosterone concentration, cloacal gland index (CGI), and the testicular IGF family gene expression. The results showed that GSI was higher in ZnON (2.307) than control (1.619) on day 35 (P < .05). Germinal epithelium thickness was higher in ZnON (78.88 µm) and Zn-Met (79.73 µm) than control (67.73 µm) on day 35 (P < .05). On day 35, the testosterone concentration was lowest in the control (5.830 ng/ml, P < .05). The CGI of 35-day-old birds was higher in Zn-Met (411.28) than the control (307.59, P < .05). IGF-IR mRNA expression was highest in Zn-Met group on day 28. Therefore, supplementation of diet with Zn-methionine is superior to other sources of zinc for diet supplementation in immature Japanese quail.

[Transepidermal Water Loss (TEWL)-decreasing Effect by Administration of Zinc in the Elderly People].

In recent years, it has become clear that zinc deficiency is closely related in several skin disorders. In elderly people, chronic itch and dry skin are common. In addition, the zinc concentrations are known to decrease with age. Therefore, we examined the beneficial effects of oral zinc supplementation on dry skin and itch in elderly people. Patients 65 years of age or older who visited the Jose Clinic (Odai-town, Mie Pref.) with serum zinc concentrations below 80 µg/dL were enrolled in the study (low zinc group). The participants were administered zinc acetate hydrate for 12 weeks from the start of the study, and transepidermal water loss (TEWL) and stratum corneum moisture content measurements, blood collection, and itch evaluation were performed every 4 weeks. Patients in the control group had serum zinc concentrations of ≥80 µg/dL (the normal zinc group). Results showed that TEWL was significantly higher in the low zinc group than in the normal zinc group, indicating that skin barrier function is impaired in the low zinc group. Serum zinc concentrations increased and TEWL decreased significantly over the 12 weeks of treatment. In addition, a negative correlation was observed between serum zinc concentrations and TEWL. Our results indicate that zinc supplementation is effective to improve the skin barrier function in elderly people.

Successful pre-operative local control of skin exposure by sarcoma using combination of systemic chemotherapy and Mohs' chemosurgery.

BACKGROUND: Sarcomas sometimes invade the skin and become exposed, producing malignant wounds characterized by bleeding, exudate, odor, and infection. Malignant cutaneous sarcomas are generally incurable and ultimately impair patients' quality of life. Mohs' chemosurgery is a previously published technique for chemical fixation of a cutaneous tumor and subsequent excision. CASE PRESENTATION: We present the case of a 44-year-old man with an undifferentiated pleomorphic sarcoma arising in the right chest wall and rupturing through the skin. The tumor manifested as a malignant wound with ulceration, bleeding, exudate, and a strong odor. Treatment with systemic chemotherapy and Mohs' chemosurgery was initiated. After repeated courses, the tumor demonstrated significant shrinkage. We were then able to perform wide resection and reconstruction with a rectus abdominis musculocutaneous flap. Pathologic examination of the resected specimen confirmed negative margins. CONCLUSIONS: Mohs' chemosurgery with concurrent systemic chemotherapy is an effective and reliable treatment option for achieving pre-operative local control of sarcomas that rupture through the skin.

Incidence of Macular Atrophy after Untreated Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study Report 40.

PURPOSE: To report the natural history of untreated neovascular age-related macular degeneration (nAMD) regarding subsequent macular atrophy. DESIGN: Prospective cohort within a randomized, controlled trial of oral micronutrient supplements. PARTICIPANTS: Age-Related Eye Disease Study (AREDS) participants (55-80 years) who demonstrated nAMD during follow-up (1992-2005), prior to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Color fundus photographs were collected at annual study visits and graded centrally for late age-related macular degeneration (AMD). Incident macular atrophy after nAMD was examined by Kaplan-Meier analysis and proportional hazards regression. MAIN OUTCOME MEASURES: Incident macular atrophy after nAMD. RESULTS: Of the 4757 AREDS participants, 708 eyes (627 participants) demonstrated nAMD during follow-up and were eligible. The cumulative risks of incident macular atrophy after untreated nAMD were 9.6% (standard error, 1.2%), 31.4% (standard error, 2.2%), 43.1% (standard error, 2.6%), and 61.5% (standard error, 4.3%) at 2, 5, 7, and 10 years, respectively. This corresponded to a linear risk of 6.5% per year. The cumulative risk of central involvement was 30.4% (standard error, 3.2%), 43.4% (standard error, 3.8%), and 57.0% (standard error, 4.8%) at first appearance of atrophy, 2 years, and 5 years, respectively. Geographic atrophy (GA) in the fellow eye was associated with increased risk of macular atrophy (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.17-2.49; P = 0.006). However, higher 52-single nucleotide polymorphism AMD genetic risk score was not associated with increased risk of macular atrophy (HR, 1.03; 95% CI, 0.90-1.17; P = 0.67). Similarly, no significant differences were observed according to SNPs at CFH, ARMS2, or C3. CONCLUSIONS: The rate of incident macular atrophy after untreated nAMD is relatively high, increasing linearly over time and affecting half of eyes by 8 years. Hence, factors other than anti-VEGF therapy are involved in atrophy development, including natural progression to GA. Comparison with studies of treated nAMD suggests it may not be necessary to invoke a large effect of anti-VEGF therapy on inciting macular atrophy, although a contribution remains possible. Central involvement is present in one third of eyes at the outset (similar to pure GA) and increases linearly to half at 3 years.