The International Space Station: A Low-Earth Orbit (LEO) Test Bed for Advancements in Space and Environmental Medicine

Ground-based space analog projects such as the NASA Extreme Environment Mission Operations (NEEMO) can be valuable test beds for evaluation of experimental design and hardware feasibility before actually being implemented on orbit. The International Space Station (ISS) is an closed-system laboratory that orbits 240 miles above the Earth, and is the ultimate extreme environment. Its inhabitants spend hours performing research that spans from fluid physics to human physiology, yielding results that have implications for Earth-based improvements in medicine and health, as well as those that will help facilitate the mitigation of risks to the human body associated with exploration-class space missions. ISS health and medical experiments focus on pre-flight and in-flight prevention, in-flight treatment, and postflight recovery of health problems associated with space flight. Such experiments include those on enhanced medical monitoring, bone and muscle loss prevention, cardiovascular health, immunology, radiation and behavior. Lessons learned from ISS experiments may not only be applicable to other extreme environments that face similar capability limitations, but also serve to enhance standards of care for everyday use on Earth

Parasitic Infection and the Polarized Th2 Immune Response Can Alter a Vaccine-Induced Immune Response

The AIDS epidemic in the Developing World represents a major global crisis. It is imperative that we develop an effective vaccine. Vaccines are economically the most efficient means of controlling viral infections. However, the development of a vaccine against HIV-1 has been a formidable task, and in developing countries chronic parasitic infection adds another level of complexity to AIDS vaccine development. Helminthic and protozoan infections, common in developing countries, can result in a constant state of immune activation that is characterized by a dominant Th2 type of cytokine profile, high IgE levels, and eosinophilia. Such an immune profile may have an adverse impact on the efficacy of vaccines, in particular, an HIV-1 vaccine. Indeed, the CD8 cellular immune response and the corresponding Th1 type cytokines that enhance the CD8 cellular immune response are important for clearing many viral infections. It is believed that an antigen specific CD8 cellular immune response will be an important component of an HIV-1 vaccine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63250/1/104454903767650685.pd

Developing an Intervention for Fall-Related Injuries in Dementia (DIFRID): an integrated, mixed-methods approach

Background Falls in people with dementia can result in a number of physical and psychosocial consequences. However, there is limited evidence to inform how best to deliver services to people with dementia following a fall. The aim of the DIFRID study was to determine the feasibility of developing and implementing a new intervention to improve outcomes for people with dementia with fall-related injuries; this encompasses both short-term recovery and reducing the likelihood of future falls. This paper details the development of the DIFRID intervention. Methods The intervention was designed using an integrated, mixed-methods approach. This involved a realist synthesis of the literature and qualitative data gathered through interviews and focus groups with health and social care professionals (n=81). An effectiveness review and further interviews and observation were also conducted and are reported elsewhere. A modified Delphi panel approach with 24 experts was then used to establish a consensus on how the findings should translate into a new intervention. After feedback from key stakeholders (n=15) on the proposed model, the intervention was manualised and training developed. Results We identified key components of a new intervention covering three broad areas: • Ensuring that the circumstances of rehabilitation are optimised for people with dementia • Compensating for the reduced ability of people with dementia to self-manage • Equipping the workforce with the necessary skills and information to care for this patient group Consensus was achieved on 54 of 69 statements over two rounds of the Delphi surveys. The statements were used to model the intervention and finalise the accompanying manual and protocol for a feasibility study. Stakeholder feedback was generally positive and the majority of suggested intervention components were approved. The proposed outcome was a 12-week complex multidisciplinary intervention primarily based at the patient’s home. Conclusions A new intervention has been developed to improve outcomes for people with dementia following a fall requiring healthcare attention. The feasibility of this intervention is currently being tested. Trial registration ISRCTN41760734 (16/11/2015

DNA prime Listeria boost induces a cellular immune response to SIV antigens in the rhesus macaque model that is capable of limited suppression of SIV239 viral replication

AbstractDNA vaccines and recombinant Listeria monocytogenes that express and secrete SIV Gag and Env antigens were combined in a nonhuman primate prime-boost immunogenicity study followed by a challenge with SIV239. We report that recombinant DNA vaccine delivered intramuscularly, and recombinant L. monocytogenes delivered orally each individually have the ability to induce CD8+ and CD4+ T cell immune responses in a nonhuman primate. Four rhesus monkeys were immunized at weeks 0, 4, 8, and 12 with the pCSIVgag and pCSIVenv DNA plasmids and boosted with SIV expressing L. monocytogenes vaccines at weeks 16, 20, and 28. Four rhesus monkeys received only the L. monocytogenes vaccines at weeks 16, 20, and 28. A final group of monkeys served as a control group. Blood samples were taken before vaccination and 2 weeks post each injection and analyzed by ELISPOT for CD4+ and CD8+ T cell responses. Moderate vaccine induced SIV-specific cellular immune responses were observed following immunization with either DNA or L. monocytogenes vectors. However, the SIV antigen-specific immune responses were significantly increased when Rhesus macaques were primed with SIV DNA vaccines and boosted with the SIV expressing L. monocytogenes vectors. In addition, the combined vaccine was able to impact SIV239 viral replication following an intrarectal challenge. This study demonstrates for the first time that oral L. monocytogenes can induce a cellular immune response in a nonhuman primate and is able to enhance the efficacy of a DNA vaccine as well as provide modest protection against SIV239 challenge

Updated Benefits for Humanity, Third Edition (B4H3), from the International Space Station (ISS)

In 2018, the International Space Station (ISS) [Figure 1] partnership completed a revision for the third edition of the International Space Station Benefits for Humanity, a compilation of case studies of benefits being realized from ISS activities in the areas of human health, Earth observations and disaster response, innovative technology, global education, and economic development of space. The revision included new assessments of economic value and scientific value with more detail than the second edition. The third edition contains updated statistics on the impacts of the benefits as well as new benefits that have developed since the previous publication. This presentation will summarize the updates on behalf of the ISS Program Science Forum, which consists of senior science representatives across the ISS international partnership. An independent consultant determined the economic valuation (EV) of ISS research benefits case studies and the third edition contains the results. The process involved a preliminary assessment of economic, social, and innovation factors. A more detailed assessment followed, which included factors such as addressable market, market penetration, revenue generation, ability to leverage across other applications or customer groups, quality of life improvements, health benefits, environmental benefits, cultural and community cohesion, inspiration, new knowledge, novel approaches, creation of a unique market niche, and research leadership. Because of the unique microgravity environment of the ISS laboratory, the multidisciplinary and international nature of the research, and the significance of the investment in its development, analyzing ISS scientific impacts is an exceptional challenge. As a result, the ISS partnership determined the scientific valuation (SV) of ISS research using a combination of citation analyses, bibliometrics, and narratives of important ISS utilization results. Approximately 2,100 ISS results publications comprised of scientific journal articles, conference proceedings, and gray literature, representing over 5,000 authors and co-authors on Earth were used in this evaluation to enable the communication of impacts of ISS research on various science and technology fields across many countries. The publication also updates and expands the previously described benefits of research results in the areas of space commerce, technology development, human health, environmental change and disaster response, and education activities. Distinct benefits return to Earth from the only orbiting multidisciplinary laboratory of its kind. The ISS is a stepping-stone for future space exploration while also providing findings that develop low Earth orbit as a place for sustained human activity and improve life on our planet

European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part I:assessment

In 2011 a working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines for Tourette syndrome (TS). Now, we present an updated version 2.0 of these European clinical guidelines for Tourette syndrome and other tic disorders, part I: assessment. Therefore, the available literature has been thoroughly screened, supplemented with national guidelines across countries and discussions among ESSTS experts. Diagnostic changes between DSM-IV and DSM-5 classifications were taken into account and new information has been added regarding differential diagnoses, with an emphasis on functional movement disorders in both children and adults. Further, recommendations regarding rating scales to evaluate tics, comorbidities, and neuropsychological status are provided. Finally, results from a recently performed survey among ESSTS members on assessment in TS are described. We acknowledge that the Yale Global Tic Severity Scale (YGTSS) is still the gold standard for assessing tics. Recommendations are provided for scales for the assessment of tics and psychiatric comorbidities in patients with TS not only in routine clinical practice, but also in the context of clinical research. Furthermore, assessments supporting the differential diagnosis process are given as well as tests to analyse cognitive abilities, emotional functions and motor skills

Identification of a Novel Synaptic Protein, TMTC3, Involved in Periventricular Nodular Heterotopia with Intellectual Disability and Epilepsy

Defects in neuronal migration cause brain malformations, which are associated with intellectual disability (ID) and epilepsy. Using exome sequencing, we identified compound heterozygous variants (p.Arg71His and p. Leu729ThrfsTer6) in TMTC3, encoding transmembrane and tetratricopeptide repeat containing 3, in four siblings with nocturnal seizures and ID. Three of the four siblings have periventricular nodular heterotopia (PVNH), a common brain malformation caused by failure of neurons to migrate from the ventricular zone to the cortex. Expression analysis using patient-derived cells confirmed reduced TMTC3 transcript levels and loss of the TMTC3 protein compared to parental and control cells. As TMTC3 function is currently unexplored in the brain, we gathered support for a neurobiological role for TMTC3 by generating flies with post-mitotic neuron-specific knockdown of the highly conserved Drosophila melanogaster TMTC3 ortholog, CG4050/tmtc3. Neuron-specific knockdown of tmtc3 in flies resulted in increased susceptibility to induced seizures. Importantly, this phenotype was rescued by neuron-specific expression of human TMTC3, suggesting a role for TMTC3 in seizure biology. In addition, we observed co-localization of TMTC3 in the rat brain with vesicular GABA transporter (VGAT), a presynaptic marker for inhibitory synapses. TMTC3 is localized at VGAT positive pre-synaptic terminals and boutons in the rat hypothalamus and piriform cortex, suggesting a role for TMTC3 in the regulation of GABAergic inhibitory synapses. TMTC3 did not co-localize with Vglut2, a presynaptic marker for excitatory neurons. Our data identified TMTC3 as a synaptic protein that is involved in PVNH with ID and epilepsy, in addition to its previously described association with cobblestone lissencephaly

Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A.

INTRODUCTION: Valoctocogene roxaparvovec is an investigational AAV5-based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A. AIM: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795). METHODS: Men ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti-AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 1013 vg/kg dose, n = 7) and 4 years (4 × 1013 vg/kg dose, n = 6). RESULTS: Over the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was -0.14 (95% confidence interval [CI]: -.32 to .03) IU/dl/wk in the 6 × 1013 vg/kg cohort in year 5 and -.06 (95% CI: -.14 to .01) IU/dl/wk in the 4 × 1013 vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 1013 vg/kg cohort; all six Haemo-QOL-A domain scores increased. For the 4 × 1013 vg/kg cohort, high baseline Haemo-QOL-A scores persisted. CONCLUSION: These results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A

An international study exploring the experience of survivors of critical illness as volunteers within ICU recovery services

Objectives: Many clinicians have implemented follow-up and aftercare to support patients following ICU. Some of this care is supported and facilitated by peer volunteers. There is limited contemporary work that has explicitly explored volunteer roles within ICU recovery services or the experience of volunteers undertaking these roles. We sought to explore the experience of survivors of critical illness, as volunteers, involved in ICU recovery services and understand their motivation for undertaking these roles. Design: Qualitative exploration using in-depth semistructured interviews. The study design used an inductive content analysis process. We also documented the roles that were adopted by volunteers in each site involved in the study. Setting: Patients and caregivers were sampled from seven sites across three continents. Patients and Subjects: Patients and caregivers who had adopted peer-volunteering roles were undertaken. Interventions: None. Measurements and Main Results: Twelve patient and caregiver peer volunteers were interviewed. Four key themes were identified. These themes related to the experience of volunteers within ICU recovery services and their motivation for undertaking these roles: 1) self-belief and acceptance, 2) developing peer support, 3) social roles and a sense of purpose, and 4) giving back. Overwhelmingly, participants were positive about the role of the volunteer in the critical care setting. Conclusions: Peer volunteers undertake a variety of roles in ICU recovery services and during recovery more generally. These roles appear to be of direct benefit to those in these roles. Future research is needed to develop these roles and fully understand the potential impact on the service, including the impact on other patients