Sidewall depletion in nano-patterned LAO/STO heterostructures

We report the fabrication of nanostructures from the quasi-two-dimensional electron gas (q2DEG) formed at the LaAlO$_{3}$/ SrTiO$_{3}$ (LAO/STO) interface. The process uses electron beam lithography in combination with reactive ion etching. This technique allows to pattern high-quality structures down to lateral dimensions as small as $100$nm while maintaining the conducting properties without inducing conductivity in the STO substrate. Temperature dependent transport properties of patterned Hall bars of various widths show only a small size dependence of conductivity at low temperature as well as at room temperature. The deviation can be explained by a narrow lateral depletion region. All steps of the patterning process are fully industry compatible.Comment: 5 pages, 4 figure

Controlling magnetic anisotropy in La_0.7Sr_0.3MnO₃ nanostructures

We have developed a chlorine based dry etching process for nanopatterning the ferromagnetic oxide La<sub>0.7</sub>Sr<sub>0.3</sub>MnO<sub>3</sub> (LSMO). Large arrays of millions of identical structures have been fabricated from thin LSMO films by electron-beam lithography and reactive ion etching. SQUID magnetometry demonstrates that patterned nanostructures with lateral dimensions down to 100 nm retain their full magnetization and the Curie temperature of the bulk layer. In addition, their shape anisotropy is sufficient to overcome the crystalline anisotropy of the bulk. High resolution scanning transmission electron microscopy shows that crystallinity is preserved even at the edges of the nanostructures

Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial

Background: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. Methods: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. Findings: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0–30·9; range 9·5–49·7) in the lower dose cohort, 31·1 months (16·0–64·7; 6·8–72·7) in the higher dose cohort, and 18·7 months (10·1–31·5; 5·9–39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0–49·5; range 2·1–54·7) for lower dose participants, 27·6 months (24·6–29·1; 3·4–41·0) for higher dose participants, and 28·3 months (9·7–46·9; 5·7–32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). Interpretation: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. Funding: Astellas Gene Therapies

INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy

Supplementary Material: The supplementary material is available in the electronic version of this article: https://doi.org/10.3233/JND-210871.Copyright © 2022 The authors. Background X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. Objective We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. Methods Thirty-four participants 16 hours/day); 20% required non-invasive support (6–16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19–52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. Conclusions INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.The INCEPTUS and ASPIRO studies are sponsored by Astellas Gene Therapies

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder

Holocene Cyclic Records of Ice-Rafted Debris and Sea Ice Variations on the East Greenland and Northwest Iceland Margins

The dynamics of the Greenland Ice Sheet and drift of sea ice from the Arctic Ocean reaching Denmark Strait are poorly constrained. We present data on the provenance of Fe oxide detrital grains from two cores in the Denmark Strait area and compare the Fe grain source data with other environmental proxies in order to document the variations and potential periodicities in ice-rafted debris delivery during the Holocene. Based on their Fe grain geochemistry, the sediments can be traced to East Greenland sources and to more distal sites around the Arctic Basin. On the Holocene time scales of the two cores, sea ice biomarker (IP25) data, and quartz weight percent reveal positive associations with T°C and inverse associations with biogenic carbonate wt%. Trends in the data were obtained from Singular Spectrum Analysis (SSA), and residuals were tested for cyclicity. Trends on the environmental proxies explained between 15 and 90% of the variance. At both sites the primary Fe grain sources were from Greenland, but significant contributions were also noted from Banks Island and Svalbard. There is a prominent cyclicity of 800 yrs as well as other less prominent cycles for both Greenland and arctic sources. The Fe grain sources from Greenland and the circum-Arctic Ocean are in synchronization, suggesting that the forcings for these cycles are regional and not local ice sheet instabilities