Corrigendum to "Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency".

[This corrects the article DOI: 10.1016/j.ymgmr.2023.101001.].

Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency.

Background: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aß40, Aß42 and total tau are abnormal in Alzheimer disease (AD), a common neurodegenerative disorder pathologically characterized by Aß peptide containing amyloid plaques and tau neurofibrillary tangles. Although CTD results in neuronal energy deficiency, the pathological processes underlying the CTD phenotype are not fully characterized. Methods: Cerebral spinal fluid (CSF) was collected as an optional part of a natural history study of CTD. Aß40, Aß42 and total tau levels were quantified in CSF from individuals with CTD and from age-appropriate comparison samples. Neuro3-Plex enzyme-linked immunoassay was performed on a Quanterix SR-X instrument. The Vineland Adaptive Behavior Scale, 3rd Edition was used to determine an overall Adaptive Behavior Composite (ABC) standard score. Results: CSF from 12 individuals with CTD and 23 age appropriate non-CTD comparison samples were analyzed. We found that levels of total tau [t(32) = 4.05, p = 0.0003], Aß40 [t(31) = 6.11, p < 0.0001], and Aß42 [t(32) = 3.20, p = 0.003] were elevated in the participants with CTD relative to the comparison group. Additionally, except for one individual that we considered an outlier, all three biomarkers correlated inversely with the adaptive behavior score (total tau: ρ = -0.60 [-0.88, 0.005]; Aß40: ρ = -0.67 [-0.91, -0.12]; Aß42: ρ = -0.62 [-0.89, -0.02]). Conclusion: We describe here the novel finding of elevated protein biomarkers in the CSF of individuals with CTD. Aß40, Aß42 and total tau are markedly elevated in individuals with CTD compared to comparison samples, and increased levels of these biomarkers inversely correlated with ABC scores. We hypothesize that elevated CSF levels of Aß40 and Aß42 are due to cellular energy deficiency. Elevated CSF total tau levels may indicate ongoing neuronal damage. The observed inverse correlation of Vineland ABC scores with increased biomarker levels needs to be confirmed in a larger CTD cohort; however, our observation of increased Aß40, Aß42 and total tau levels in CSF from individuals with CTD may provide insight into pathological mechanisms contributing to the CTD phenotype and may prove useful as supportive data in future therapeutic trials.

Simultaneous multimodal fNIRS-EEG recordings reveal new insights in neural activity during motor execution, observation, and imagery.

Motor execution, observation, and imagery are important skills used in motor learning and rehabilitation. The neural mechanisms underlying these cognitive-motor processes are still poorly understood. We used a simultaneous recording of functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG) to elucidate the differences in neural activity across three conditions requiring these processes. Additionally, we used a new method called structured sparse multiset Canonical Correlation Analysis (ssmCCA) to fuse the fNIRS and EEG data and determine the brain regions of neural activity consistently detected by both modalities. Unimodal analyses revealed differentiated activation between conditions; however, the activated regions did not fully overlap across the two modalities (fNIRS: left angular gyrus, right supramarginal gyrus, as well as right superior and inferior parietal lobes; EEG: bilateral central, right frontal, and parietal). These discrepancies might be because fNIRS and EEG detect different signals. Using fused fNIRS-EEG data, we consistently found activation over the left inferior parietal lobe, superior marginal gyrus, and post-central gyrus during all three conditions, suggesting that our multimodal approach identifies a shared neural region associated with the Action Observation Network (AON). This study highlights the strengths of using the multimodal fNIRS-EEG fusion technique for studying AON. Neural researchers should consider using the multimodal approach to validate their findings.

Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3ß,5α,6ß-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study.

PURPOSE: To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. METHODS: We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. RESULTS: Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. CONCLUSION: ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model.

PURPOSE: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). CTD features include developmental delay, seizures, and autism spectrum disorder. This study was designed to investigate CTD cardiac phenotype and sudden death risk. METHODS: We performed a cross-sectional analysis of CTD males between 2017 and 2020. Subjects underwent evaluation with electrocardiogram (ECG), echocardiography, and ambulatory ECG with comparable analysis in creatine transporter deficient mice (Slc6a8-/y) using ECG, echocardiography, exercise testing, and indirect calorimetry. RESULTS: Eighteen subjects with CTD (18 males, age 7.4 [3.8] years) were evaluated: seven subjects (39%) had QTc ≥ 470 milliseconds: 510.3 ± 29.0 vs. 448.3 ± 15.9, P < 0.0001. The QTc ≥ 470 milliseconds cohort had increased left ventricular internal dimension (diastole) ([LVIDd] Z-score: 0.22 ± 0.74, n = 7 vs. -0.93 ± 1.0, n = 11, P = 0.0059), and diminished left ventricular posterior wall dimension (diastole) ([LVPWDd, in mm]: 5.0 ± 0.6, n = 7 vs. 5.7 ± 0.8, n = 11, P = 0.0183), when compared to subjects with normal or borderline QTc prolongation. Similar ECG and echocardiographic abnormalities were seen in Slc6a8-/y mice. Additionally, Slc6a8-/y mice had diminished survival (65%). CONCLUSION: Prolonged QTc and abnormal echocardiographic parameters consistent with developing cardiomyopathy are seen in some male subjects with CTD. Slc6a8-/y mice recapitulated these cardiac abnormalities. Male CTD subjects may be at increased risk for cardiac dysfunction and sudden death.

Review of the efficacy of infrared thermography for screening infectious diseases with applications to COVID-19.

Purpose: The recent coronavirus disease 2019 (COVID-19) pandemic, which spread across the globe in a very short period of time, revealed that the transmission control of disease is a crucial step to prevent an outbreak and effective screening for viral infectious diseases is necessary. Since the severe acute respiratory syndrome (SARS) outbreak in 2003, infrared thermography (IRT) has been considered a gold standard method for screening febrile individuals at the time of pandemics. The objective of this review is to evaluate the efficacy of IRT for screening infectious diseases with specific applications to COVID-19. Approach: A literature review was performed in Google Scholar, PubMed, and ScienceDirect to search for studies evaluating IRT screening from 2002 to present using relevant keywords. Additional literature searches were done to evaluate IRT in comparison to traditional core body temperature measurements and assess the benefits of measuring additional vital signs for infectious disease screening. Results: Studies have reported on the unreliability of IRT due to poor sensitivity and specificity in detecting true core body temperature and its inability to identify asymptomatic carriers. Airport mass screening using IRT was conducted during occurrences of SARS, Dengue, Swine Flu, and Ebola with reported sensitivities as low as zero. Other studies reported that screening other vital signs such as heart and respiratory rates can lead to more robust methods for early infection detection. Conclusions: Studies evaluating IRT showed varied results in its efficacy for screening infectious diseases. This suggests the need to assess additional physiological parameters to increase the sensitivity and specificity of non-invasive biosensors.

Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy.

BACKGROUND: GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. METHODS: We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. RESULTS: We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon-intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. CONCLUSIONS: We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.

Triple Wollaston-prism complete-Stokes imaging polarimeter.

Imaging polarimetry is emerging as a powerful tool for remote sensing in space science, Earth science, biology, defense, national security, and industry. Polarimetry provides complementary information about a scene in the visible and infrared wavelengths. For example, surface texture, material composition, and molecular structure will affect the polarization state of reflected, scattered, or emitted light. We demonstrate an imaging polarimeter design that uses three Wollaston prisms, addressing several technical challenges associated with moving remote-sensing platforms. This compact design has no moving polarization elements and separates the polarization components in the pupil (or Fourier) plane, analogous to the way a grating spectrometer works. In addition, this concept enables simultaneous characterization of unpolarized, linear, and circular components of optical polarization. The results from a visible-wavelength prototype of this imaging polarimeter are presented, demonstrating remote sensitivity to material properties. This work enables new remote sensing capabilities and provides a viable design concept for extensions into infrared wavelengths.

Atypical autonomic dysreflexia during robotic-assisted body weight supported treadmill training in an individual with motor incomplete spinal cord injury.

CONTEXT/OBJECTIVE: A 41-year-old man with a history of C6 American Spinal Injury Association (ASIA) Impairment Scale (AIS) C spinal cord injury (SCI), enrolled in an Institutional Review Board (IRB)-approved, robotic-assisted body weight-supported treadmill training (BWSTT), and aquatic exercise research protocol developed asymptomatic autonomic dysreflexia (AD) during training. Little information is available regarding the relationship of robotic-assisted BWSTT and AD. FINDINGS: After successfully completing 36 sessions of aquatic exercise, he reported exertional fatigue during his 10th Lokomat intervention and exhibited asymptomatic or silent AD during this and the three subsequent BWSTT sessions. Standard facilitators of AD were assessed and no obvious irritant identified other than the actual physical exertion and positioning required during robotic-assisted BWSTT. CONCLUSIONS/CLINICAL RELEVANCE: Increased awareness of potential silent AD presenting during robotic assisted BWSTT training for individuals with motor incomplete SCI is required as in this case AD clinical signs were not concurrent with occurrence. Frequent vital sign assessment before, during, and at conclusion of each BWSTT session is strongly recommended.

Cover slip external cavity diode laser.

A 671 nm diode laser with a mode-hop-free tuning range of 40 GHz is described. This long tuning range is achieved by simultaneously ramping the external cavity length with the laser injection current. The laser output pointing remains fixed, independent of its frequency because of the cover slip cavity design. This system is simple, economical, robust, and easy to use for spectroscopy, as we demonstrate with lithium vapor and lithium atom beam experiments.

Diffraction of 0.5keV electrons from free-standing transmission gratings.

A nanostructured grating was used to diffract a low-energy (500 eV) electron beam, and the current transmitted into the zeroth diffraction order was greater than 5% of the incident beam current. This diffraction efficiency indicates that the 55-nm-wide grating bars absorb electrons but the 45-nm-wide slots between bars transmit electron de Broglie waves coherently. The diffraction patterns can be asymmetric, and can be explained by a model that incorporates an electrostatic potential energy for electrons within 20 nm of the grating structure calculated by the method of images.

Matter-wave decoherence due to a gas environment in an atom interferometer.

Decoherence due to scattering from background gas particles is observed for the first time in a Mach-Zehnder atom interferometer, and compared with decoherence due to scattering photons. A single theory is shown to describe decoherence due to scattering either atoms or photons. Predictions from this theory are tested by experiments with different species of background gas, and also by experiments with different collimation restrictions on an atom beam interferometer.

Observation of atom wave phase shifts induced by van der Waals atom-surface interactions.

The development of nanotechnology and atom optics relies on understanding how atoms behave and interact with their environment. Isolated atoms can exhibit wavelike (coherent) behavior with a corresponding de Broglie wavelength and phase which can be affected by nearby surfaces. Here an atom interferometer is used to measure the phase shift of Na atom waves induced by the walls of a 50 nm wide cavity. To our knowledge this is the first direct measurement of the de Broglie wave phase shift caused by atom-surface interactions. The magnitude of the phase shift is in agreement with that predicted by Lifshitz theory for a nonretarded van der Waals interaction. This experiment also demonstrates that atom waves can retain their coherence even when atom-surface distances are as small as 10 nm.

Phase 1 clinical trial of apical membrane antigen 1: an asexual blood-stage vaccine for Plasmodium falciparum malaria.

Apical membrane antigen 1 (AMA1), a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. A phase 1 trial was conducted with 30 malaria-naive volunteers to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of recombinant proteins based on sequences from the FVO and 3D7 clones of Plasmodium falciparum. The proteins were expressed in Pichia pastoris and adsorbed on Alhydrogel. Ten volunteers in each of three dose groups (5 mug, 20 mug, and 80 mug) were vaccinated in an open-label study at 0, 28, and 180 days. The vaccine was well tolerated, with pain at the injection site being the most commonly observed reaction. Anti-AMA1 immunoglobulin G (IgG) was detected by enzyme-linked immunosorbent assay (ELISA) in 15/28 (54%) volunteers after the second immunization and in 23/25 (92%) after the third immunization, with equal reactivity to both AMA1-FVO and AMA1-3D7 vaccine components. A significant dose-response relationship between antigen dose and antibody response by ELISA was observed, and the antibodies were predominantly of the IgG1 isotype. Confocal microscopic evaluation of sera from vaccinated volunteers demonstrated reactivity with P. falciparum schizonts in a pattern similar to native parasite AMA1. Antigen-specific in vitro inhibition of both FVO and 3D7 parasites was achieved with IgG purified from sera of vaccinees, demonstrating biological activity of the antibodies. To our knowledge, this is the first AMA1 vaccine candidate to elicit functional immune responses in malaria-naive humans, and our results support the further development of this vaccine.

rDEN4delta30, a live attenuated dengue virus type 4 vaccine candidate, is safe, immunogenic, and highly infectious in healthy adult volunteers.

BACKGROUND: The live attenuated dengue virus type 4 (DEN-4) vaccine candidate virus rDEN4 Delta 30 was previously found to be safe and immunogenic at a dose of 10(5) plaque-forming units (pfu). METHODS: In a follow-up placebo-controlled phase 2 clinical trial, rDEN4 Delta 30 was administered as a single inoculation to 3 separate dose cohorts (10(3) pfu, 10(2) pfu, or 10(1) pfu), for further evaluation. Each dose cohort consisted of 20 vaccinees and 4 placebo recipients. Volunteers were monitored closely for adverse events, and serum was collected on study days 28 and 42 for determination of neutralizing antibody titer. RESULTS: The vaccine was well tolerated at all doses studied. The most common adverse events observed were a transient asymptomatic rash in >50% of vaccinees and a mild neutropenia in approximately 20% of vaccinees. No vaccinee developed a dengue-like illness. The vaccine was highly infectious and immunogenic, with 95%-100% of vaccinees in each dose cohort developing a >/=4-fold increase in titers of serum neutralizing antibodies against DEN-4. CONCLUSIONS: The rDEN4 Delta 30 vaccine is safe and induced an antibody response that was broadly neutralizing against genotypically diverse DEN-4 viruses. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation.