Special Operations and Space Medicine for a Joint Future.

This paper is designed to introduce, propose, inform, and advocate enhanced relationships between the medical communities of special operations and space. Although each provides service support in different roles and functions, similarities in both the operational context and in medical care are notable. During a recent interaction, significant relationship potential was discovered by both communities, and recommendations for greater engagement are proposed herein. By identifying and appreciating similarities and understanding history, key actors, and authorities to analyze and realize opportunities will enable us to find synergy for the development of like efforts and goals. Collaboration in research on the limits of human performance and medical support to the most austere and challenging operational environments may benefit both communities in different but productive ways. Establishing and increasing cooperation will also meet command strategic intent, explore and advance a policy concept, initiate a relationship between unique medical communities, and provide a tangible success for the advancement of operational support.

Nourishing the brain on deep space missions: nutritional psychiatry in promoting resilience.

The grueling psychological demands of a journey into deep space coupled with ever-increasing distances away from home pose a unique problem: how can we best take advantage of the benefits of fresh foods in a place that has none? Here, we consider the biggest challenges associated with our current spaceflight food system, highlight the importance of supporting optimal brain health on missions into deep space, and discuss evidence about food components that impact brain health. We propose a future food system that leverages the gut microbiota that can be individually tailored to best support the brain and mental health of crews on deep space long-duration missions. Working toward this goal, we will also be making investments in sustainable means to nourish the crew that remains here on spaceship Earth.

Ethically cleared to launch?

Rules are needed for human research in commercial spaceflight.

Who gets to decide?: Substitute decision making following severe brain injury with communication impairment.

Purpose: In our prior study (Malhi et al., 2021), we demonstrated that cognitive ability may be masked by communication impairments. We used binary choice (i.e., yes/no) neuropsychological tests to assess cognitive functioning in four patients with severe brain injury and communication impairments. In this study, we aimed to better understand the decision-making process of their substitute decision makers (SDMs). Methods: We interviewed SDMs - two SDMs were supporting patients in the minimally conscious state, one SDM was supporting a patient who had locked-in syndrome and was an augmentative communication user, and the last SDM was supporting a patient who was an alternative communication user. Results: SDMs were performing various roles ranging from making all decisions to simply being the vocal advocate (for the augmentative and alternative communication users). SDMs described heuristics they used to make decisions, and all identified auditory comprehension capabilities as being an important element for decision making. Conclusion: We argue that if mode of communication is established and utilized, and binary choice neuropsychological tests are used to ascertain cognitive functioning, SDMs may more confidently make low/medium stakes decisions based on the present condition and context, rather than solely on past wishes and values before capacity was in question.

Processes for Designing Innovative Biomedical Hardware to Use in Space and on Earth.

The new era of space exploration is increasing the astronaut's number and diversity in low orbit and beyond. The influx of such a diverse crew population will also increase the need for medical technologies to ensure safe and productive missions. Such a need represents a unique opportunity to innovate and develop diagnostics and treatment tools to meet future needs. Historically, terrestrial regulatory oversight of biomedical design processes was considered separate from spaceflight regulatory processes because it did not address spaceflight constraints. These constraints challenge the creative development of unique solutions for use in space. Translation between healthcare innovation in spaceflight to healthcare on Earth and vice versa requires understanding the commonalities, unique needs and constraints. This manuscript provides a framework for comparing Earth-space design processes and a perspective on the best practices to improve healthcare equity and health outcomes.

Thinking without speaking: Neuropsychological testing with individuals who have communication impairments.

Cognitive ability may be masked by communication impairments. This study aimed to assess cognitive functioning using binary choice (i.e., yes/no) neuropsychological tests in patients with communication impairments. Four participants underwent neuropsychological testing. Two participants were in the minimally conscious state (MCS), one participant had locked-in syndrome and was an alternative communication user, and one participant was an augmentative communication user. There was better performance in all cognitive domains for the augmentative and alternative communication (AAC) users (who performed like the non-communication impaired normative data) compared to the MCS participants. However, using established yes/no communication methods, MCS participants performed above chance on a measure of memory and performance on measures of auditory comprehension was variable. Auditory comprehension appeared to be more influenced by working memory demands for the MCS participants than for the AAC users. For emotional functioning, the AAC users endorsed lower mood compared to the MCS participants. The results support the need to assess cognition, communication, as well as capacity in individuals with communication impairments with the consultation of a neuropsychologist and a speech-language pathologist.

Brain Health: A Concept Analysis.

The concept of brain health has been inconsistently used across disciplines. This concept analysis sought to clarify brain health and construct a unified definition that may lead to consistent use of this concept. The analysis used Walker and Avant's framework to identify scholarly reports on the concept of brain health from various electronic databases. Building on the identified data sources, brain health can be understood as the brain's ability to optimally adapt to internal and external human conditions through cognitive and emotional responses across one's lifespan, which result in sustainable positive changes in brain structures and functional features. This analysis emphasized that maintaining brain health has positive implications on an individual's lifelong quality of health, independence, and delaying cognitive decline. By clarifying uses and definitions of the concept of brain health, this concept analysis may enable researchers and clinicians to evaluate and interpret the concept related data consistently.

Reduced Hippocampal Glutamate and Posterior Cingulate N-Acetyl Aspartate in Mild Cognitive Impairment and Alzheimer's Disease Is Associated with Episodic Memory Performance and White Matter Integrity in the Cingulum: A Pilot Study.

Identification of biological changes underlying the early symptoms of Alzheimer's disease (AD) will help to identify and stage individuals prior to symptom onset. The limbic system, which supports episodic memory and is impaired early in AD, is a primary target. In this study, brain metabolism and microstructure evaluated by high field (7 Tesla) proton magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI) were evaluated in the limbic system of eight individuals with mild cognitive impairment (MCI), nine with AD, and sixteen normal elderly controls (NEC). Left hippocampal glutamate and posterior cingulate N-acetyl aspartate concentrations were reduced in MCI and AD compared to NEC. Differences in DTI metrics indicated volume and white matter loss along the cingulum in AD compared to NEC. Metabolic and microstructural changes were associated with episodic memory performance assessed using Craft Story 21 Recall and Benson Complex Figure Copy. The current study suggests that metabolite concentrations measured using 1H-MRS may provide insight into the underlying metabolic and microstructural processes of episodic memory impairment.

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study.

BACKGROUND: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams. METHODS: The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here. RESULTS: The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020. CONCLUSION: Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.

Évaluation complète d'une étude de cohorte canadienne portant sur la démence et la neuro-dégénérescence. Contexte : L'évaluation globale de la neuro-dégénérescence et de la démence (COMPASS-ND), étude de cohorte du Consortium canadien en neuro-dégénérescence associée au vieillissement (CCNV), représente une initiative nationale visant à promouvoir la recherche portant sur la démence et à soutenir les programmes de recherche des équipes du CCNV. Totalisant 2310 sujets recrutés partout au pays, cette cohorte longitudinale regroupe des individus fortement « phénotypés ¼ qui présentent diverses formes de démence et de pertes de mémoire légères. En plus de sujets âgés dont les fonctions cognitives sont intactes, ces 2310 sujets ont permis de valider les hypothèses formulées par les équipes du CCNV. Méthodes : Nous avons utilisé de nombreux documents pour décrire cette étude : le protocole de la COMPASS-ND ; la demande initiale de subvention ; le cinquième rapport d'étape semi-annuel du CCNV soumis aux Instituts de recherche en santé du Canada (IRSC) en décembre 2017 ; ainsi que d'autres documents produits à la suite de modifications consécutives à la mise en œuvre de ce projet. Résultats: L'étude de cohorte COMPASS-ND du CCNV inclut des participants de partout au Canada dont les divers états cognitifs sont associés à des maladies neurodégénératives ou au risque d'en souffrir. Ils feront l'objet d'un large éventail d'examens expérimentaux, cliniques, génétiques et d'imagerie afin d'aborder de manière spécifique les causes, le diagnostic, le traitement et la prévention de ces états cognitifs chez les personnes âgées. Les données obtenues à la suite d'évaluations cliniques et cognitives, ainsi que celles issues d'échantillons biologiques, d'imagerie cérébrale, de tests génétiques et de dons de cerveaux, seront utilisées pour tester les hypothèses générées par les équipes de recherche du CCNV et d'autres chercheurs canadiens. Cette étude constitue donc à ce jour l'étude canadienne la plus complète et la plus ambitieuse au sujet de la démence. La présentation des données initiales ayant eu lieu en 2018, la cohorte devrait atteindre sa taille maximale d'ici à 2020.Conclusion : La disponibilité des données de l'étude COMPASS-ND stimulera considérablement la recherche sur la démence au Canada au cours des prochaines années.

Correction to: The Toronto cognitive assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

Upon publication of this article [1], it was brought to our attention that one of the 303 participants in the normative study should have been deleted from the database.

The Toronto Cognitive Assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

BACKGROUND: A need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals. METHODS: We obtained normative data on the TorCA (n = 303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (n = 50/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community. RESULTS: The TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivity 92%; specificity 91%). Paper and iPad version scores were equivalent. CONCLUSIONS: The TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI.

Subjective rating of executive functions in mild Alzheimer's disease.

OBJECTIVES: Subjective cognitive decline is considered to be a core feature of pre-Alzheimer's disease (AD) conditions, the vast majority of literature having focused on memory concerns. Neuropsychological studies have implicated executive dysfunction on objective performance measures in AD, but no research has evaluated whether individuals with AD have concerns about their executive functions and whether it differs from their caregiver's concerns. In the present study, we sought to evaluate self- and informant ratings of executive functioning in patients with mild AD. METHOD: Participants were 23 patients with mild AD and 32 healthy elderly controls (HC) and their informants who completed the Behavior Rating Inventory of Executive Function - Adult version. RESULTS: Patients with AD and their informants reported greater executive dysfunction than the HC group and their informants, respectively, and patients reported greater difficulty than their informants. The largest effect size for both self- and informant ratings was obtained for the Working Memory scale. CONCLUSIONS: These findings indicate that subjective cognitive concerns in mild AD extend beyond the memory domain to executive functions. That greater difficulty was endorsed by patients than their informants suggests that at least in the mild stage of AD some awareness of executive dysfunction may be maintained in some patients. Implications for clinical care are discussed.

Taoist Tai Chi® and Memory Intervention for Individuals with Mild Cognitive Impairment.

OBJECTIVE: It was hypothesized that a combined Taoist Tai Chi (TTC) and a memory intervention program (MIP) would be superior to a MIP alone in improving everyday memory behaviors in individuals with amnestic mild cognitive impairment (aMCI). A secondary hypothesis was that TTC would improve cognition, self-reported health status, gait, and balance. METHOD: A total of 48 individuals were randomly assigned to take part in MIP + TTC or MIP alone. The TTC intervention consisted of twenty 90 min sessions. Outcome measures were given at baseline, and after 10 and 22 weeks. RESULTS: Both groups significantly increased their memory strategy knowledge and use, ratings of physical health, processing speed, everyday memory, and visual attention. No preferential benefit was found for individuals in the MIP + TTC group on cognition, gait, or balance measures. CONCLUSIONS: Contrary to expectations, TTC exercise did not specifically improve cognition or physical mobility. Explanations for null findings are explored.

Caring for a Person With Amnestic Mild Cognitive Impairment.

While much of the literature on caregiver burden has focused on caregiving for people living with Alzheimer's disease (AD) there is little information on the experience of caring for a loved one living with amnestic Mild Cognitive Impairment (aMCI), the group most likely to convert to AD. A hermeneutic phenomenological approach was used to understand the organizing principles that give experiences of being form and meaning in the lifeworld. Study findings highlight the precarious nature of caregiver role acquisition and the heterogeneity that is present among informal care providers. Specifically, the findings suggest that the wearing of multiple situational masks is required by the carer to cope with accumulated progressive losses suffered as they continually adjust to their new and evolving carer identity. Support groups specific to the carers of those living with aMCI are needed in an effort to remove these masks and to validate this unique caregiving experience.

Correcting the MoCA for education: effect on sensitivity.

OBJECTIVE: The goal of this study was to quantify the impact of the suggested education correction on the sensitivity and specificity of the Montreal Cognitive Assessment (MoCA). METHOD: Twenty-five outpatients with dementia and 39 with amnestic mild cognitive impairment (aMCI) underwent a diagnostic evaluation, which included the MoCA. Thirty-seven healthy controls also completed the MoCA and psychiatric, medical, neurological, functional, and cognitive difficulties were ruled out. RESULTS: For the total MoCA score, unadjusted for education, a cut-off score of 26 yielded the best balance between sensitivity and specificity (80% and 89% respectively) in identifying cognitive impairment (people with either dementia or aMCI, versus controls). When applying the education correction, sensitivity decreased from 80% to 69% for a small specificity increase (89% to 92%). The cut-off score yielding the best balance between sensitivity and specificity for the education adjusted MoCA score fell to 25 (61% and 97%, respectively). CONCLUSIONS: Adjusting the MoCA total score for education had a detrimental effect on sensitivity with only a slight increase in specificity. Clinically, this loss in sensitivity can lead to an increased number of false negatives, as education level does not always correlate to premorbid intellectual function. Clinical judgment about premorbid status should guide interpretation. However, as this effect may be cohort specific, age and education corrected norms and cut-offs should be developed to help guide MoCA interpretation.

Visual stability of laser vision correction in an astronaut on a Soyuz mission to the International Space Station.

UNLABELLED: This report documents the effects of photorefractive keratectomy (PRK) in an astronaut during a 12-day Russian Soyuz mission to the International Space Station in 2008. Changing environmental conditions of launch, microgravity exposure, and reentry create an extremely dynamic ocular environment. Although many normal eyes have repeatedly been subject to such stresses, the effect on an eye with a relatively thin cornea as a result of PRK has not been reported. This report suggests that PRK is a safe, effective, and well-tolerated procedure in astronauts during space flight. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight.

PURPOSE: To describe the history, clinical findings, and possible etiologies of ophthalmic findings discovered in 7 astronauts after long-duration space flight, and document vision changes in approximately 300 additional astronauts. DESIGN: Retrospective, observational examination of ophthalmic findings in 7 astronauts and analysis of postflight questionnaires regarding in-flight vision changes in approximately 300 additional astronauts. PARTICIPANTS: Seven astronauts with ophthalmic anomalies upon return from long-duration space missions to the International Space Station and 300 additional astronauts who completed postflight questionnaires regarding in-flight vision changes. METHODS: Before and after long-duration space flight, all 7 subjects underwent complete eye examinations, including cycloplegic and/or manifest refraction and fundus photography. Six underwent postmission optical coherence tomography (OCT) and magnetic resonance imaging (MRI); 4 had lumbar punctures (LP). Approximately 300 astronauts were queried regarding visual changes during space missions. MAIN OUTCOME MEASURES: Refractive change, fundus photograph examination, retina OCT, orbital MRI, LP opening pressures, and examination of visual acuity data. RESULTS: After 6 months of space flight, 7 astronauts had ophthalmic findings, consisting of disc edema in 5, globe flattening in 5, choroidal folds in 5, cotton wool spots (CWS) in 3, nerve fiber layer thickening by OCT in 6, and decreased near vision in 6 astronauts. Five of 7 with near vision complaints had a hyperopic shift ≥+0.50 diopters (D) between pre/postmission spherical equivalent refraction in 1 or both eyes (range, +0.50 to +1.75 D). These 5 showed globe flattening on MRI. Lumbar punctures performed in the 4 with disc edema documented opening pressures of 22, 21, 28, and 28.5 cm H(2)O performed 60, 19, 12, and 57 days postmission, respectively. The 300 postflight questionnaires documented that approximately 29% and 60% of astronauts on short and long-duration missions, respectively, experienced a degradation in distant and near visual acuity. Some of these vision changes remain unresolved years after flight. CONCLUSIONS: We hypothesize that the optic nerve and ocular changes we describe may result from cephalad fluid shifts brought about by prolonged microgravity exposure. The findings we report may represent parts of a spectrum of ocular and cerebral responses to extended microgravity exposure. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors.

The mammalian target of rapamycin (mTOR) pathway is implicated widely in cancer pathophysiology. Dual inhibition of the mTOR kinase complexes mTORC1 and mTORC2 decreases tumor xenograft growth in vivo and VEGF secretion in vitro, but the relationship between these two effects are unclear. In this study, we examined the effects of mTORC1/2 dual inhibition on VEGF production, tumor angiogenesis, vascular regression, and vascular regrowth, and we compared the effects of dual inhibition to mTORC1 inhibition alone. ATP-competitive inhibitors OSI-027 and OXA-01 targeted both mTORC1 and mTORC2 signaling in vitro and in vivo, unlike rapamycin that only inhibited mTORC1 signaling. OXA-01 reduced VEGF production in tumors in a manner associated with decreased vessel sprouting but little vascular regression. In contrast, rapamycin exerted less effect on tumoral production of VEGF. Treatment with the selective VEGFR inhibitor OSI-930 reduced vessel sprouting and caused substantial vascular regression in tumors. However, following discontinuation of OSI-930 administration tumor regrowth could be slowed by OXA-01 treatment. Combining dual inhibitors of mTORC1 and mTORC2 with a VEGFR2 inhibitor decreased tumor growth more than either inhibitor alone. Together, these results indicate that dual inhibition of mTORC1/2 exerts antiangiogenic and antitumoral effects that are even more efficacious when combined with a VEGFR antagonist.

Neuropilin-1 is essential for enhanced VEGF(165)-mediated vasodilatation in collateral-dependent coronary arterioles of exercise-trained pigs.

BACKGROUND/AIMS: Exercise training enhances vasodilatation to vascular endothelial growth factor (VEGF(165)) in collateral-dependent coronary arterioles. Interaction of VEGF receptor 2 (VEGFR-2) and the non-tyrosine-kinase receptor, neuropilin-1 has been reported to potentiate VEGF(165)-mediated signaling. In the current study, we tested the hypotheses that neuropilin-1 mediates the exercise-enhanced VEGF(165)-mediated vasodilatation in collateral-dependent arterioles and that neuropilin-1 and/or VEGFR-2 protein levels are increased in these arterioles. METHODS: Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of miniature swine. Eight weeks after surgery, the animals were randomized into sedentary or exercise training (treadmill run; 5 days/week; 14 weeks) protocols. Coronary arterioles (approximately 100 microm diameter) were isolated from both collateral-dependent and control (left anterior descending) myocardial regions and studied by in vitro videomicroscopy or frozen for immunoblot analysis. RESULTS: Exercise-enhanced VEGF(165)-mediated vasodilatation in collateral-dependent arterioles was reversed by inhibition of the VEGF(165)-neuropilin-1 interaction. VEGF(121), which does not interact with neuropilin-1, induced similar vasodilatation in arterioles from all treatment groups. Immunoblot revealed significantly elevated VEGFR-1, VEGFR-2 and neuropilin-1 protein levels in collateral-dependent arterioles of exercise-trained pigs. CONCLUSIONS: Neuropilin-1 plays a vital role in the exercise-enhanced VEGF(165)-mediated vasodilatation of collateral-dependent coronary arterioles and is associated with increased neuropilin-1 receptor protein levels.

Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database.

Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), suitable to assess disease progression for multi-centre studies. This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T(1)-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimer's Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an epsilon 4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies.