ALBERT

Description: A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

Description: Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G〉A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.

Description: NASA has concerns regarding the incidence and clinical significance of cardiac arrhythmias that could occur during long-term exposure to the spaceflight environment, such as on the International Space Station (ISS) or during a prolonged (e.g., up to 3 years) sojourn to Mars or on the Moon. There have been some anecdotal reports and a few documented cases of cardiac arrhythmias in space, including one documented episode of non-sustained ventricular tachycardia. The potential catastrophic nature of a sudden cardiac death in the remote space environment has led to concerns from the early days of the space program that spaceflight might be arrhythmogenic. Indeed, there are known and well-defined changes in the cardiovascular system with spaceflight: a) plasma volume is reduced, b) left ventricular mass is decreased, and c) the autonomic nervous system adapts to the weightless environment. Combined, these physiologic adaptations suggest that changes in cardiac structure and neuro-humoral environment during spaceflight could alter electrical conduction, although the evidence supporting this contention consists mostly of minor changes in QT interval (the time between the start of the Q wave and the end of the T wave on an electrocardiogram tracing) in a small number of astronauts after long-duration spaceflight. Concurrent with efforts by NASA Medical Operations to refine and improve screening techniques relevant to arrhythmias and cardiovascular disease, as NASA enters the era of exploration-class missions it will be critical to determine with the highest degree of certainty whether spaceflight by itself alters cardiac structure and function sufficiently to increase the risk of arrhythmias.

Description: The Visual Impairment and Intracranial Pressure (VIIP) syndrome affects 60% of astronauts returning from long-duration missions and is characterized by structural and functional changes of the eye (3). Upon entry into weightlessness, approximately two liters of fluid translocates from the lower body to the thorax and cephalad regions, potentially contributing to elevated intracranial and intraocular pressures. The choroid is the vasculature that supplies blood flow to the posterior part of the retina and has limited autoregulation. As a consequence these vessels may engorge during a cephalad fluid shift, contributing to structural changes in the retina. The purpose of this experiment was to quantify changes in choroid thickness during a fluid shift. In order to fulfill this objective, it was also necessary to improve the measurement technique for assessing choroid thickness.

Description: A subset of astronauts develop neuro-ocular structural and functional changes during prolonged periods of spaceflight that may lead to additional neurologic and ocular consequences upon return to Earth.

Description: Cardiovascular adaptations due to spaceflight are modeled with 6deg head-down tilt bed rest (BR) and result in decreased orthostatic tolerance. We investigated if high-intensity resistive and aerobic exercise with and without testosterone supplementation would improve the heart rate (HR) response to a 3.5-min stand test and how quickly these changes recovered following BR. During 70 days of BR male subjects performed no exercise (Control, n=10), high intensity supine resistive and aerobic exercise (Exercise, n=9), or supine exercise plus supplemental testosterone (Exercise+T, n=8; 100 mg i.m., weekly in 2-week on/off cycles). We measured HR for 2 min while subjects were prone and for 3 min after standing twice before and 0, 1, 6, and 11 days after BR. Mixed-effects linear regression models were used to evaluate group, time, and interaction effects. Compared to pre-bed rest, prone HR was elevated on BR+0 and BR+1 in Control, but not Exercise or Exercise+T groups, and standing HR was greater in all 3 groups. The increase in prone and standing HR in Control subjects was greater than either Exercise or Exercise+T groups and all groups recovered by BR+6. The change in HR from prone to standing more than doubled on BR+0 in all groups, but was significantly less in the Exericse+T group compared to the Control, but not Exercise group. Exercise reduces, but does not prevent the increase in HR observed in response to standing. The significantly lower HR response in the Exercise+T group requires further investigation to determine physiologic significance.

Description: More than 60% of US astronauts participating in Mir and early International Space Station missions (greater than 5 months) were unable to complete a 10min 80 deg headup tilt test on landing day. This high incidence of postspaceflight orthostatic intolerance may be related to limitations of the inflight exercise hardware that prevented high intensity training. PURPOSE: This study sought to determine if a countermeasure program that included intense lowerbody resistive and rowing exercises designed to prevent cardiovascular and musculoskeletal deconditioning during 70 days of 6 deg head-down tilt bed rest (BR), a spaceflight analog, also would protect against post BR orthostatic intolerance. METHODS: Sixteen males participated in this study and performed no exercise (Control, n=10) or performed an intense supine exercise protocol with resistive and aerobic components (Exercise, n=6). On 3 days/week, exercise subjects performed lower body resistive exercise and a 30min continuous bout of rowing (greater than or equal to 75% max heart rate). On 3 other days/week, subjects performed only highintensity, intervalstyle rowing. Orthostatic intolerance was assessed using a 15min 80 deg headup tilt test performed 2 days (BR2) before and on the last day of BR (BR70). Plasma volume was measured using a carbon monoxide rebreathing technique on BR3 and before rising on the first recovery day (BR+0). RESULTS: Following 70 days of BR, tilt tolerance time decreased significantly in both the Control (BR2: 15.0 +/- 0.0, BR70: 9.9 +/- 4.6 min, mean +/- SD) and Exercise (BR2: 12.2 +/- 4.7, BR70: 4.9 +/- 1.9 min) subjects, but the decreased tilt tolerance time was not different between groups (Control: 34 +/- 31, Exercise: 56 +/- 16%). Plasma volume also decreased (Control: 0.56 +/- 0.40, Exercise: 0.48 +/- 0.33 L) from pre to postBR, with no differences between groups (Control: 18 +/- 11%, Exerciser: 15 +/-1 0%). CONCLUSIONS: These findings confirm previous reports in shorter BR studies that the performance of an exercise countermeasure protocol by itself during BR does not prevent orthostatic intolerance or plasma volume loss. This suggests that protection against orthostatic intolerance in astronauts following longduration spaceflight will require an additional intervention, such as periodic orthostatic stress, fluid repletion, and/or lowerbody compression garments.

Description: The Spaceflight Associated Neuro-ocular Syndrome (SANS) is characterized by the development of optic disc edema, choroidal folds, cotton-wool spots, globe flattening, and/or refractive error changes greater than or equal to 0.75D during long-duration spaceflight to the International Space Station (ISS). It is hypothesized that these findings result from the headward fluid shift that occurs due to weightlessness. We can induce a headward fluid shift on Earth using positional changes and on ISS due to weightlessness. Lower-body negative pressure (LBNP) is used to reverse the headward fluid shift by drawing fluid into the lower body and can be used on Earth and on ISS.

Description: We will address the Human Factors and Performance Team, "Risk of performance errors due to training deficiencies" by improving the JIT training materials for ultrasound and OCT imaging by providing advanced guidance in a detailed, timely, and user-friendly manner. Specifically, we will (1) develop an audio-visual tutorial using AR that guides non-experts through an abdominal trauma ultrasound protocol; (2) develop an audio-visual tutorial using AR to guide an untrained operator through the acquisition of OCT images; (3) evaluate the quality of abdominal ultrasound and OCT images acquired by untrained operators using AR guidance compared to images acquired using traditional JIT techniques (laptop-based training conducted before image acquisition); and (4) compare the time required to complete imaging studies using AR tutorials with images acquired using current JIT practices to identify areas for time efficiency improvements. Two groups of subjects will be recruited to participate in this study. Operator-subjects, without previous experience in ultrasound or OCT, will be asked to perform both procedures using either the JIT training with AR technology or the traditional JIT training via laptop. Images acquired by inexperienced operator-subjects will be scored by experts in that imaging modality for diagnostic and research quality; experts will be blinded to the form of JIT used to acquire the images. Operator-subjects also will be asked to submit feedback to improve the training modules used during the scans to improve future training modules. Scanned-subjects will be a small group individuals from whom all images will be acquired.

Description: No abstract available