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Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

The susceptibility of surface soil to drying when rainfall is scarce has prompted evaluation of deeper placement (20 cm) of fertilizers within the profile to where soil moisture is more likely to be stored. However, concerns arise regarding potential chemical challenges to P availability in the subsurface. This study examined differences in chemical conditions between the soil surface (0–10 cm) and subsurface (15–25 cm), and investigated the effect on the diffusion and extractability of banded P. Analysis of surface and subsurface samples from 15 sites revealed substantial differences in characteristics that influence P behavior between depths. The phosphorus buffering index (PBI) was largely explained by concentrations of amorphous Al and Fe (hydr)oxides and CaCO3. The measured diffusion distance of P from monoammonium phosphate (MAP) granules was found to be inversely related to PBI. Consequently, significant differences in diffusion distances were typically observed between soil layers characterized by marked PBI variations. The measured diffusion radii were used to calculate the mean P concentrations of surface-banded and deep-banded MAP in a field scenario, which were replicated in a 4-week laboratory incubation. The resulting lability of applied P was determined through isotopic exchange, and although significantly higher P recoveries were measured from the subsurface at two sites where large pH differences existed between depths, no significant differences were measured between depths at all other sites. Hence, the subsurface is not a more hostile zone for deep-placed P. [ABSTRACT FROM AUTHOR]

Background: Equinus contractures can commonly be due to contractures of gastrocnemius muscle or combined contractures of the gastrocnemius-soleus Achilles tendon complex. The decision to release part or all of the gastrocnemius-soleus Achilles tendon complex is often assessed intraoperatively while the patient is under anesthesia. It remains unknown whether the administration of general anesthesia affects the measurement of passive ankle dorsiflexion. Methods: The unaffected, nonoperative limb on 46 foot and ankle patients underwent a Silfverskiold test measuring passive ankle dorsiflexion preoperatively and intraoperatively after administration of general anesthesia using an instrumented force-angular displacement goniometer. To determine clinical significance, we surveyed experienced surgeons to estimate the perceived minimally detectable clinical accuracy for measuring passive ankle dorsiflexion. Results: Forty-six subjects were included with mean age of 42 ± 14.8 years, mean body mass index of 26.2 ± 4.9, and 52% female. The mean change in dorsiflexion values from before anesthesia to after the administration of general anesthesia was 1.9 degrees with 10 lb of pressure with knee extended (E10), 2.3 degrees with 20 lb of pressure with knee extended (E20), 2.8 degrees with 10 lb of pressure with knee flexed (F10), and 2.3 degrees with 20 lb of pressure with knee flexed (F20) (all P <.001). Thirty-three of 45 (73%) surgeons responded to the survey; all thought their minimally detectable clinical accuracy was 5 degrees or greater. Conclusion: After the administration of general anesthesia, a small but likely not clinically detectable increase in passive ankle dorsiflexion occurs. The common clinical practice of making intraoperative treatment decisions regarding the presence of a gastrocnemius-soleus driven equinus contractures after general anesthesia without use of paralytic agents appears reasonable given the magnitude of the changes identified in this study. [ABSTRACT FROM AUTHOR]

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Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G>A mutation.Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo.Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals.Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G>A Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials.