MAROON-X is a state-of-the-art extreme-precision radial velocity spectrograph deployed on the 8.1 m Gemini-N telescope on Maunakea, Hawai’i. Using a stabilized Fabry–Pérot etalon for wavelength and drift calibration, MAROON-X has achieved a short-term precision of ∼30 cm s ^−1 . However, due to a long-term drift in the etalon (2.2 cm s ^−1 per day) and various interruptions of the instrument baseline over the first few years of operation, MAROON-X experiences radial velocity (RV) offsets between observing runs several times larger than the short-term precision during any individual run, which hinders the detection of longer-period signals. In this study, we analyze RV measurements of 11 targets that either exhibit small RV scatter or have signals that can be precisely constrained using Keplerian or Gaussian process models. Leveraging this ensemble, we calibrate MAROON-X’s run offsets for data collected between 2020 September and early 2024 January to a precision of ∼0.5 m s ^−1 . When applying these calibrated offsets to HD 3651, a quiet star, we obtain residual velocities with an rms of <70 cm s ^−1 in both the red and blue channels of MAROON-X over a baseline of 29 months. We also demonstrate the sensitivity of MAROON-X data calibrated with these offsets through a series of injection-recovery tests. Based on our findings, MAROON-X is capable of detecting sub m s ^−1 signals out to periods of more than 1000 days.

In a pilot program in which 109,259 newborns were screened for metachromatic leukodystrophy, blood-spot samples were obtained for analysis and three newborns with MLD were identified, which made presymptomatic treatment possible.

Pompe disease (PD) is a rare autosomal recessive lysosomal disorder caused by loss-of-function of the α-glucosidase (GAA) gene. The deficient GAA enzyme activity may result in potential life-threatening muscle weakness, thus requiring a rapid diagnosis to initiate therapeutic interventions. In this large retrospective study, we analyzed 30.836 PD suspect samples from 57 countries using a two-step approach utilizing dried blood spots (DBSs): biochemical testing of GAA activity followed by complementary genetic sequencing of GAA in biochemically conspicuous cases. Of these 30.836 samples, 2% (n = 639) were excluded; accordingly, this study consisted of 30.193 cases. Biochemical testing of GAA enzyme activity showed normal values in 28.354 (93.90%) and enzyme activity below the cut-off in 1843 (6.10%) cases. These biochemically suspicious cases were genetically analyzed. We identified 723 Pompe cases with 283 different GAA alterations, and 98 variants have been unpublished so far. The most common variant was the splice variant c.-32-13T>G (IVS1). Looking at the IVS1-genotype, the majority was compound heterozygous (n = 169) and identified in late-onset cases (n = 162). Comparison of early- versus late-onset cases to evaluate whether certain genotypes correlate with the age of onset revealed that homozygosity was predominantly found in infantile (85.65%) and compound heterozygosity in late-onset (76.9%) cases. Analysis of homozygous cases revealed 61% nonsense variants in the early stages and 87% missense variants in the late stages. Mapping of disease-associated (homozygous) missense variants to functional GAA protein domains showed that missense variants were found throughout GAA, but we identified enrichment in the catalytic domain. A strict genotype-phenotype correlation cannot be established; nevertheless, a phenotypic implication of some GAA variants could be drawn (e.g., c.896T>C/p.L299P, c.2015G>A/p.R672Q, and c.-32-13T>G). The combined enzyme activity and genetic testing from DBS cards can reliably identify PD and significantly accelerate diagnosis. We identified new genetic variants that contribute to the spectrum of pathogenic variants of the GAA gene.

Newborn screening (NBS) for metachromatic leukodystrophy (MLD) is based on first-tier measurement of sulfatides in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A in the same DBS. This approach is very precise with 0 -1 false positives per similar to 30,000 newborns tested. Recent data reported here shows that the sulfatide molecular species with an alpha-hydroxyl, 16-carbon, mono-unsaturated fatty acyl group (16:1-OHsulfatide) is superior to the original biomarker 16:0-sulfatide in reducing the number of first-tier false positives. This result is consistent across 4 MLD NBS centers. By measuring 16:1-OH-sulfatide alone or together with 16:0sulfatide, the estimated false positive rate is 0.048% and is reduced essentially to zero with second-tier arylsulfatase A activity assay. The false negative rate is predicted to be extremely low based on the demonstration that 40 out of 40 newborn DBS from clinically-confirmed MLD patients are detected with these methods. The work shows that NBS for MLD is extremely precise and ready for deployment. Furthermore, it can be multiplexed with several other inborn errors of metabolism already tested in NBS centers worldwide.

OBJECTIVE:To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment. METHODS:From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed. RESULTS:1935 patients were screened (94.7% sporadic ALS). 48.8% (n = 928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n = 34), variants of unknown significance (class 3) 0.8% (n = 16), FUS (class 4/5) 0.9% (n = 17), TARDBP (class 4/5) 1.3% (n = 25), C9orf72 hexanucleotide repeat expansion 7.0% (n = 135). In SOD1-ALS (encompassing class 3-5 variants, n = 50), 68.0% (n = 34) reported a negative family history. 74.0% (n = 37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy. CONCLUSION:The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.

Although investigation of the potential role of lysosomal storage disorders in Parkinson's disease (PD) has been ongoing since reports highlighted that Gaucher disease can be accompanied by parkinsonism,1for Fabry disease (FD), an X-linked recessive multisystem disorder caused by Galactosidase gene (GLA) mutations, the potential relationship to PD has not been studied until more recently2 and literature cited therein. Here, we report the frequency of GLA variants in 252 PD patients retrospectively selected from our database (mean age, 68.6 years; range, 33–93 years; 59.9% male). With the systematic sequence strategy applied, we found a mean α-galactosidase-A (GAL)-activity of 3.4 μM/h ± 1.44 μM/h (cutoff, <2,8 μM/h) and mean Lyso-globotriaosylsphingosine (Lyso-Gb3) levels of 3.6 ng/mL ±1.30 ng/mL (cutoff, >3.5 ng/mL). By bidirectional Sanger sequencing of all seven exons and flanking 5´untranslated region with at least 20 base pairs of flanking intronic sequences, we detected a total of 96 GLA variants in 57 individuals. None of these variants were classified as pathogenic/likely pathogenic for FD according to the American College of Medical Genetics and Genomics, inasmuch as most variants were intronic or in non-coding part of the gene.3 Most had similar mean allele frequencies (MAF), as reported in major genetic databases gnomAD.4 Nevertheless, two variants predicted to alter the GLA protein were detected in four patients (p.Asp182Asn and p.Asp313Tyr, both of uncertain significance). Of these, p.Asp313Tyr (MAF, 0.85%; MAF in general world population [GWP], 0.30%; P = 0.094; MAF in European Non-Finnish Population [ENFP], 0.45%; P = 0.209) drew our attention (Table 1). All three patients displayed clinical FD features predominantly involving the central nervous system and heart (Table 1), showing a lower mean GAL-activity of 2.3 μM/h ± 0.19 μM/h than cutoff (P = 0.001) and normal mean Lyso-Gb3 level of 3.0 ng/mL ±0.33 ng/mL (P = 0.197). Because p.Asp313Tyr formerly was considered to result in a “pseudodeficient allele” with a pH-dependent enzyme activity, it failed to be classified as clinically relevant or pathogenetic for FD. In recent literature, however, this opinion has shifted, as p.Asp313Tyr may cause predominantly FD nervous system manifestations associated with a milder phenotype and later disease onset—a hypothesis that our data support.5, 6 We performed a meta-analysis with a similarly-sized previous study,7 which screened 236 PD patients in a multistep approach, including GLA next generation sequencing in females and all males with abnormal GAL levels, thereby identifying four women with a p.Asp313Tyr variant. By merging the data, MAF of the GLA p.Asp313Tyr variant in PD patients clearly reached statistical significance (P = 0.006 compared to MAF of the GWP/alone P = 0.021; and P = 0.038 to ENFP/alone P = 0.068).7 In closing, ours is the first biochemically and genetically systematic study of FD in patients with PD. The limited sample size and the lack of a control group make it challenging to draw firm conclusions; nevertheless, we believe our study is meaningful because it highlights anew the possible link between the GLA p.Asp313Tyr variant and PD. Further studies involving larger cohorts are required because the possible pathogenetic role might influence monitoring of p.Asp313Tyr variant carriers and decisions involving potential enzyme replacement therapy. Open Access funding enabled and organized by Projekt DEAL. (1) Research project: A. Conception: Albert C. Ludolph, Kelly del Tredici, Jan Kassubek, Susanne Müller, B. Organization: Susanne Müller, C. Execution: Susanne Müller, Stephan T. Hold, Kathrin Müller; (2) Statistical Analysis: A. Design: Susanne Müller, Stephan T. Hold, Kathrin Müller, Axel Freischmidt, B. Execution: Susanne Müller, Stephan T. Hold, Kathrin Müller, Axel Freischmidt, C. Review and Critique: Susanne Müller, Stephan T. Hold, David C. Kasper, Kathrin Müller, Axel Freischmidt, Reiner Siebert, Benjamin Mayer; (3) Manuscript: A. Writing of the First Draft: Susanne Müller, Stephan T. Hold, Kathrin Müller, B. Review and Critique: Susanne Müller, Jan Kassubek, Benjamin Mayer, Kelly Del Tredici, Heiko Braak, Reiner Siebert, Albert C. Ludolph. Study design: Albert C. Ludolph, Kelly del Tredici, Jan Kassubek, Susanne Müller; execution: Susanne Müller; statistical analysis: Susanne Müller, Stephan T. Hold, David C. Kasper, Kathrin Müller, Axel Freischmidt, Reiner Siebert, Benjamin Mayer; writing: Susanne Müller, Stephan T. Hold, Kathrin Müller; editing of final manuscript version: Susanne Müller, Jan Kassubek, Benjamin Mayer, Kelly Del Tredici, Heiko Braak, Reiner Siebert, Albert C. Ludolph. S.T.H. is an employee of Archimedlife Science since February 2021. D.C.K. is an employee of ARCHIMED Life Science and is a stockholder in ARCHIMED Life Science. J.K. has received honoraria or consultation fees from AbbVie, Bial, Biogen, Desitin, Esteve, Licher MT, Medtronic, NeuroDerm, Novartis, STADA, UCB Pharma, and Zambon; in addition, he is Specialty Chief Editor in Frontiers in Neurology (section Applied Neuroimaging) and Associate Editor (Neurology) in Therapeutic Advances in Chronic Disease. A.C.L. is a member of Advisory Boards of Roche Pharma AG, Biogen, Alector, and Amylyx. He received compensation for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx, and the company Streamed Up! He is involved in trials that are sponsored by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, the European Union, BMBF, Biogen, and Orphazyme. The remaining authors declare no competing interests. Data are available from the corresponding author upon individual request. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

M-dwarf s +/- tars provide us with an ideal opportunity to study nearby small planets. The HUnting for M Dwarf Rocky planets Using MAROON-X (HUMDRUM) survey uses the MAROON-X spectrograph, which is ideally suited to studying these stars, to measure precise masses of a volume-limited (<30 pc) sample of transiting M-dwarf planets. TOI-1450 is a nearby (22.5 pc) binary system containing a M3 dwarf with a roughly 3000 K companion. Its primary star, TOI-1450A, was identified by the Transiting Exoplanet Survey Satellite (TESS) to have a 2.04 days transit signal, and is included in the HUMDRUM sample. In this paper, we present MAROON-X radial velocities (RVs) which confirm the planetary nature of this signal and measure its mass at nearly 10% precision. The 2.04 days planet, TOI-1450A b, has R-b = 1.13 +/- 0.04 R-circle plus and M-b = 1.26 +/- 0.13 M-circle plus. It is the second-lowest-mass transiting planet with a high-precision RV mass measurement. With this mass and radius, the planet's mean density is compatible with an Earth-like composition. Given its short orbital period and slightly sub-Earth density, it may be amenable to JWST follow-up to test whether the planet has retained an atmosphere despite extreme heating from the nearby star. We also discover a nontransiting planet in the system with a period of 5.07 days and a Msin i(c)1.53 +/- 0.18 M-circle plus. We also find a 2.01 days signal present in the systems's TESS photometry that likely corresponds to the rotation period of TOI-1450A's binary companion, TOI-1450B. TOI-1450A, meanwhile, appears to have a rotation period of approximately 40 days, which is in line with our expectations for a mid-M dwarf.

We present an updated characterization of the TOI-1685 planetary system, which consists of a P b = 0.69 day ultra-short-period super-Earth planet orbiting a nearby (d = 37.6 pc) M2.5V star (TIC 28900646, 2MASS J04342248+4302148). This planet was previously featured in two contemporaneous discovery papers, but the best-fit planet mass, radius, and bulk density values were discrepant, allowing it to be interpreted either as a hot, bare rock or a 50% H2O/50% MgSiO3 water world. TOI-1685 b will be observed in three independent JWST Cycle 2 programs, two of which assume the planet is a water world, while the third assumes that it is a hot rocky planet. Here we include a refined stellar classification with a focus on addressing the host star's metallicity, an updated planet radius measurement that includes two sectors of TESS data and multicolor photometry from a variety of ground-based facilities, and a more accurate dynamical mass measurement from a combined CARMENES, InfraRed Doppler, and MAROON-X radial velocity data set. We find that the star is very metal-rich ([Fe/H] similar or equal to +0.3) and that the planet is systematically smaller, lower mass, and higher density than initially reported, with new best-fit parameters of R pl = 1.468 -0.051+0.050 R circle plus and M pl = 3.03-0.32+0.33 M circle plus. These results fall in between the previously derived values and suggest that TOI-1685 b is a hot rocky planet with an Earth-like density (rho pl = 5.3 +/- 0.8 g cm-3, or 0.96 rho circle plus), high equilibrium temperature (T eq = 1062 +/- 27 K), and negligible volatiles, rather than a water world.

TOI-561 is a galactic thick-disk star hosting an ultra-short-period (0.45-day-orbit) planet with a radius of 1.37 R ⊕, making it one of the most metal-poor ([Fe/H] = −0.41) and oldest (≈10 Gyr) sites where an Earth-sized planet has been found. We present new simultaneous radial velocity (RV) measurements from Gemini-N/MAROON-X and Keck/HIRES, which we combined with literature RVs to derive a mass of M b = 2.24 ± 0.20 M ⊕. We also used two new sectors of TESS photometry to improve the radius determination, finding R b = 1.37 ± 0.04 R ⊕ and confirming that TOI-561 b is one of the lowest-density super-Earths measured to date (ρ b = 4.8 ± 0.5 g cm−3). This density is consistent with an iron-poor rocky composition reflective of the host star’s iron and rock-building element abundances; however, it is also consistent with a low-density planet with a volatile envelope. The equilibrium temperature of the planet (∼2300 K) suggests that this envelope would likely be composed of high mean molecular weight species, such as water vapor, carbon dioxide, or silicate vapor, and is likely not primordial. We also demonstrate that the composition determination is sensitive to the choice of stellar parameters and that further measurements are needed to determine whether TOI-561 b is a bare rocky planet, a rocky planet with an optically thin atmosphere, or a rare example of a nonprimordial envelope on a planet with a radius smaller than 1.5 R ⊕.

Context: Chronic myeloid leukemia (CML) is characterized by a relapsing evolution, increased disease burden and poor prognosis in the advanced phases. Objective: The assessment of diagnosis and management options of CML in the Republic of Moldova. Design: We performed the case-control study of 134 CML patients, who were treated and followed up at the comprehensive cancer center – Institute of Oncology between 2007–2022. The real-time PCR was used with the aim to determine the expression of BCR-ABL p210 and p190 transcripts while proceeding CML diagnosis. Setting: The study was related to the outpatient and hospitalized care. Participants: The patients' age ranged between 14-81 years. The median age was 51.4 ± 2.13 years. There were 78 (58.2%) males and 56 (41.8%) females. Interventions: Tyrosine kinase inhibitors (TKIs) were supplied by The Max Foundation via Max Access Solutions (MAS). Imatinib, nilotinib, and ponatinib were used as a front-line therapy in newly diagnosed CML patients and in the cases of resistance to non-TKIs treatment. Main Outcome Measures: Complete response (CR) rate estimated the short-term results of chemotherapy, and the overall survival (OS) –long-term results. Results: CML was diagnosed in chronic phase in 122 (91,04 ± 2.32%) patients. The rate of Ph-positive bone marrow (BM) cells ranged between 20 – 100%. In 72.7% of cases Ph-chromosome was detected in over 70% of the BM cells. BCR-ABL p210 transcript range was 21.84–100%. In 69.8% of cases BCR-ABL transcripts were identified in over 65% of the peripheral blood cells. Under the TKIs therapy the hematologic CR was achieved in 92.8% of cases, and the molecular CR – in 28.5%. One- and 5-year OS of patients treated with TKIs was 98.5% and 91%. IFN a-2b was used with partial response in cases of resistance to conventional chemotherapy (CC) and TKIs. In 79% of patients treated initially with CC, only the minor cytogenetic response was obtained. Conclusions: MAS program may be considered an efficient and transparent management option to ensure CML patients with potentially curable TKIs medication in the emerging regions regardless the age, gender, and social categories. The Max Foundation delivers TKIs medication to CML patients on a regular basis, accelerating health equity in low-and middle-income countries.

A star's obliquity with respect to its planetary system can provide us with insight into the system's formation and evolution, as well as hinting at the presence of additional objects in the system. However, M dwarfs, which are the most promising targets for atmospheric follow-up, are underrepresented in terms of obliquity characterization surveys due to the challenges associated with making precise measurements. In this paper, we use the extreme-precision radial velocity spectrograph MAROON-X to measure the obliquity of the late M dwarf TRAPPIST-1. With the Rossiter-McLaughlin effect, we measure a system obliquity of $-2^{+17}_{-19}$ degrees and a stellar rotational velocity of 2.1 $\pm$ 0.3 km s$^{-1}$. We were unable to detect stellar surface differential rotation, and we found that a model in which all planets share the same obliquity was favored by our current data. We were unable to make a detection of the signatures of the planets using Doppler tomography, which is likely a result of the both the slow rotation of the star and the low SNR of the data. Overall, TRAPPIST-1 appears to have a low obliquity, which could imply that the system has a low primordial obliquity. It also appears to be a slow rotator, which is consistent with past characterizations of the system and estimates of the star's rotation period. The MAROON-X data allow for a precise measurement of the stellar obliquity through the Rossiter-McLaughlin effect, highlighting the capabilities of MAROON-X and its ability to make high-precision RV measurements around late, dim stars.

To treat anxiety disorders in children and adolescents, cognitive-behavioral therapy (CBT) is often used as an effective psychosocial treatment. However, disseminating CBT to underrepresented cultures, such as those in Asia, remains inadequate. This chapter discusses culturally adapted CBT for children with anxiety disorders in Japan. The Japanese Anxiety Children/Adolescents Cognitive Behavior Therapy program (JACA-CBT) was developed for children and adolescents with anxiety disorders based on bidirectional cultural adaptation from top-down and bottom-up approaches. The JACA-CBT achieved 50% and 66.67% remissions among participants from their principal diagnoses at a post- and 6-month follow-up, respectively, which were comparable with the results of previous trials in Western countries. A cross-cultural comparison between the JACA-CBT and a representative Western-model program revealed cultural differences in how soon therapists should ask questions about children’s anxiety, how much therapists should lead conversations, and the amount of parental involvement in the programs. The clinical implications of culturally sensitive case management for clients from Asian cultural backgrounds are discussed from the perspective of expressive cultural adaptation.

A quantitative proteomics and metabolomics analysis was performed using iTRAQ, HPLC and GC–MS in the filamentous cyanobacterium Nostoc punctiforme ATCC 29133 to understand the effect of short and long term UV-A exposure. Changes in the proteome were measured for short-term stress (4–24 h) using iTRAQ. Changes in the photosynthetic pigments and intracellular metabolites were observed at exposures of up to 7 days (pigments) and up to 11 days (intracellular metabolites). To assess iTRAQ measurement quality, pseudo selected reaction monitoring (pSRM) was used, with this confirming underestimation of protein abundance levels by iTRAQ. Our results suggest that short term UV-A radiation lowers the abundance of PS-I and PS-II proteins. We also observed an increase in abundance of intracellular redox homeostasis proteins and plastocyanin. Additionally, we observed statistically significant changes in scytonemin, Chlorophyll A, astaxanthin, zeaxanthin, and β-carotene. Assessment of intracellular metabolites showed significant changes in several, suggesting their potential role in the Nostoc's stress mitigation strategy. Cyanobacteria under UV-A radiation have reduced growth due to intensive damage to essential functions, but the organism shows a defense response by remodeling bioenergetics pathway, induction of the UV protection compound scytonemin and increased levels of proline and tyrosine as a mitigation response.The effect of UV-A radiation on the proteome and intracellular metabolites of N. punctiforme ATCC 29133 including photosynthetic pigments has been described. We also verify the expression of 13 iTRAQ quantified protein using LC-pSRM. Overall we observed that UV-A radiation has a drastic effect on the photosynthetic machinery, photosynthetic pigments and intracellular amino acids. As a mitigation strategy against UV-A radiation, proline, glycine, and tyrosine were accumulated.