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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Suggested Citation:"Report ." National Academies of Sciences, Engineering, and Medicine. 2018. Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report. Washington, DC: The National Academies Press. doi: 10.17226/24953.
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Page 38

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

HEALT AND MEDI TH ICINE DIVISIOON Board on Health Scienc and Policy o ces Decem mber 28, 2017 7 John Charles, Ph.D. C Lyndo B. Johnson Space Cente on n er 2101 NASA Parkw N way Housto TX 77058 on, 8 Dear Dr. Charles: D Th National Academies of Sciences, Engineering, and Medici he A o ine (the National Acade N emies), at the request of th National A e he Aeronautics annd Space Administration (NASA) and with g guidance from the Nation m nal Acade emies’ Standin Committe on Aerospa Medicine and the Med ng ee ace e di- cine of Extreme Environments, established the Commit o E ttee to Revie ew NASA Evidence Reports on Human Health Risks. This letter report is A’s H h s t the fif in a series of five reports and com fth s mpletes the N National Acadde- mies’ independent review of the more tha 30 eviden reports th t an nce hat NASA has compile on human health risks f long-dura A ed for ation and expllo- ration spaceflights (IOM, 2014, 2015, 2016; NASEM, 20 017). This 2017 letter report examin five of NA r nes ASA’s eviden reports: nce 1. Risk of Bone Fracture Due to Spac ceflight-Induc Changes to ced Bone (Sibonga et al., 2017a) 2. Risk of Ear Onset Ost rly teoporosis Du to Space F ue Flight (Sibonnga et al., 2017b) 3. Risk of Carrdiac Rhythm Problems Du uring Spacefllight (Lee et a al., 2017) 4. Risk of Ren Stone Form nal mation (Sibon and Pietr nga rzyk, 2017) 5. Risk of Ad dverse Health Outcomes a h and Decreme ents in Perfoor- mance Due to In-Fligh Medical C e ht Conditions (A Antonsen et a al., 2017) 1 PREPUBLIC P CATION CO OPY: UNCORRECTED PROOFS

2 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS COMMITTEE’S TASK AND OVERARCHING ISSUES To review the five NASA evidence reports, the National Academies assembled an 11-member committee with expertise in aerospace medi- cine, occupational health, clinical care, human performance and human factors, internal medicine, endocrinology, physiology and exercise science, musculoskeletal health, orthopedics, aerospace engineering, otolaryngolo- gy, and biomedical informatics. Committee biographical sketches are in- cluded in Appendix B. The committee’s task, detailed in Box 1, was to review each evi- dence report and provide responses to nine specific questions. In sum- mary, this report examines the quality of the evidence, analysis, and overall construction of each report; identifies existing gaps in report con- tent; and provides suggestions for additional sources of expert input. This report builds on the 2008 Institute of Medicine (IOM) report Review of NASA’s Human Research Program Evidence Books: A Letter Report, which assessed the process for developing NASA’s evidence reports and provided an initial and brief review of NASA’s original evidence report.1 The committee approached its task by analyzing each evidence re- port’s overall quality, which included the report’s readability, its internal consistency, the source and breadth of the evidence it cited, its identifica- tion of existing knowledge and research gaps, the expertise of its authors, and, if applicable, the report’s response to recommendations from the 2008 IOM letter report previously described. The committee again commends NASA for advising report authors to explicitly note the categories of evidence—ranging from expert opinion to data from controlled trials—that were relied on in these reports. This practice is now followed comprehensively in most, although not all, re- ports; the exceptions are noted in relevant sections below. As noted in pri- or letter reports (IOM, 2014, 2015, 2016), substantial variability exists among individual evidence reports in the formatting, internal consistency, and completeness of the references, making it difficult to compare the evi- dence for related human health risks that is cited in the different reports. NASA is encouraged to select a preferred citation format for all evidence reports and to require all writing teams to use that format. 1 The original evidence book was “a collection of evidence reports created from the in- formation presented verbally and discussed within the NASA HRP [Human Research Program] in 2006” (NASA, 2013). PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 3 BOX 1 Review of NASA’s Evidence Reports on Human Health Risks Statement of Task NASA has requested a study to provide an independent review of more than 30 evidence reports on human health risks for long-duration and ex- ploration spaceflight. The evidence reports, which are publicly availa- ble, are categorized into five broad categories: (1) behavioral health and performance; (2) human health countermeasures (with a focus on bone metabolism and orthopedics, nutrition, immunology, cardiac and pulmo- nary physiology); (3) radiation; (4) human factors issues; and (5) explora- tion medical capabilities. The reports are revised on an ongoing basis to incorporate new scientific information. In conducting this study, an ad hoc committee will build on the 2008 Institute of Medicine (IOM) report Review of NASA’s Human Research Program Evidence Books. That report pro- vided an assessment of the process used for developing the evidence re- ports and provided an initial review of the evidence reports that had been completed at that time.. Each year, NASA staff will identify a set of evidence reports for commit- tee review. Over the course of the study all evidence reports will be re- viewed. The committee will hold an annual scientific workshop to receive input on the evidence reports it is reviewing that year and an update on the recent literature. The committee will issue an annual letter report that addresses the following questions relevant to each evidence report: 1. Does the evidence report provide sufficient evidence, as well as sufficient risk context, that the risk is of concern for long-term space missions? 2. Does the evidence report provide evidence that the named gaps are the most critical presented? 3. Are there any additional gaps or aspects to existing gaps that are not addressed for this specific risk? 4. Does the evidence report address relevant interactions among risks? 5. Is input from additional disciplines needed? 6. Is the breadth of the cited literature sufficient? 7. What is the overall readability and quality? 8. Is the expertise of the authors sufficient to fully cover the scope of the given risk? 9. Has the evidence report addressed previous recommendations made by the IOM in the 2008 Letter Report? In addition to analyzing the content of individual letter reports, the committee also gathered evidence from existing literature and relevant experts in the field. The committee held two conference call meetings and one in-person meeting, with the latter held in conjunction with a public workshop (see Appendix A). The committee invited individuals PREPUBLICATION COPY: UNCORRECTED PROOFS

4 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS with expertise related to the relevant evidence reports to analyze NASA’s evidence reports and engage in discussions with the committee at the workshop, focusing on the questions enumerated by NASA in the study task. This report, which follows the format of the prior letter reports, in- cludes the committee’s responses to each of the questions listed in its statement of task for each of the five evidence reports. Although no for- mal recommendations are included in this report, the committee’s obser- vations are intended to help inform and improve NASA’s ongoing efforts to update the content of individual evidence reports. THE NASA HUMAN RESEARCH ROADMAP The evidence reports reviewed in this National Academies’ report are part of a larger roadmap process developed and under implementa- tion by NASA’s Human Research Program. The goals of the program are to investigate and mitigate “the highest risks to human health and per- formance, providing essential countermeasures and technologies for hu- man space exploration” (NASA, 2017). As outlined in Figure 1, the evidence reports are the first part of the roadmap, which is followed by clarifying the risks, specifying the research gaps that exist in addressing those risks, implementing research tasks, and obtaining deliverables. These steps are then assessed to ascertain the progress that has been made in preventing or mitigating the specific risks to astronaut health. NASA updates its progress on risk reduction for a range of design refer- ence missions—missions on the International Space Station (ISS) in low Earth orbit, lunar visits or habitation, deep space sorties, deep space journey or habitation, and planetary visits or habitation (e.g., Mars)—by identifying the extent to which there is evidence that the plans for that mission will comply with existing crew health standards or that counter- measures exist to control the risk (NASA, 2015). PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LE ETTER REPORT T 5 FIGUR 1 NASA’s human researc roadmap. RE ch SOURC Adapted from NASA, 20 CE: fr 014. RIS OF BONE FRACTUR DUE TO SK E RE SPACEFL LIGHT-IND DUCED CHA ANGES TO B BONE Bo ones break when an appli force exce w ied eeds bone str rength. Thus, a , fractur may occur— re —and freque ently does—e even in young healthy bon g nes if they are subjected to sufficient force. When bones have been weaken y d t n ned by ostteoporosis, th amount of force requir to break them becom he f red mes signifi icantly lower. The key for paramete relevant to bone fractu rce ers o ure include the duration direction, and onset of the applied f n, a force as well as the ma aximum load of the bone. Major factor influencing bone streng rs g gth include bone densi and archi ity itecture. Oste eoporosis is commonly e en- counteered and treat in terrestri medicine, and in that context it is ty ted ial yp- ically associated wi hormonal deprivation ( ith (i.e., as often appears during menop pause or in hypogonadal males), agin or the ad h ng, dministration of glucoccorticoids or other medica ations. There is also a som mewhat small ler body of literature and research pertaining to the osteoporo induced b o a p osis by skeleta unloading, and to its dia al agnosis and trreatment. In s space, exposu ure to miccrogravity is associated with bone los due prima w ss arily to the dde- creased formation of new bone and to change in bone stru o a es ucture that m may weake bones (see the review of the NASA evidence report on osteop en po- rosis below) that may weaken bo b ones. PREPUBLIC P CATION CO OPY: UNCORRECTED PROOFS

6 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS This report, Risk of Bone Fracture Due to Spaceflight-Induced Changes to Bone, discusses the evidence documenting losses in bone mineral density associated with microgravity (Sibonga et al., 2017a). It discusses mechanisms of fracture (concentrating primarily upon falls), the effect of fractional gravity (such as the moon or Mars) upon the con- sequences of a fall, and the possible ability of a space suit to alter the fracture risk associated with a fall. It applies a probabilistic risk measure, the “Factor of Risk,” to estimate the likelihood of a fracture. Two terms that are used in terrestrial medicine that may be concep- tually useful in the discussion of this report are fragility fracture and atypical fracture. Fragility fractures may occur when bone weakened by osteoporosis breaks more easily than expected. Atypical fractures are rare, and are associated with the long-term use of antiresorptive agents. These may become relevant if slow recovery from microgravity-induced bone loss requires prolonged therapy. A fragility fracture is judged to have occurred if an impact (such as a fall from a standing height) that would not normally be expected to cause a fracture does result in a frac- ture. An atypical fracture refers to a certain type of peculiar fracture (such as midshaft femur fractures) that has been reported after prolonged antiresorptive therapy despite recovery of bone mass as assessed by a DXA (dual-energy X-ray absorptiometry) scan. Atypical fractures pro- vide evidence that a DXA measurement of bone density does not ade- quately address bone architecture and that information on other qualities of bone, such as composition and turnover, is needed to better understand and estimate bone strength and fracture risk. Other modalities, such as quantitative computed tomography (QCT) and magnetic resonance imag- ing (MRI), provide more information on bone architecture than DXA but are not as easily performed (particularly in flight). Both the development of osteoporosis and its evaluation are intimately linked to fracture risk. Issues regarding osteoporosis and its assessment are discussed in greater detail in the evidence report, Risk of Early Onset Osteoporosis Due to Space Flight (Sibonga et al., 2017b) and in the committee’s review of that report later in this document. Atypical fractures, albeit rare, further raise the possibility that excessive reliance on antiresorptive therapy may not result in complete avoidance of fractures despite reassuringly good bone density measurements on DXA. PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 7 Does the Evidence Report Provide Sufficient Evidence, as Well as Sufficient Risk Context, That the Risk Is of Concern for Long-Term Space Missions? Both the risk and the context are delineated. In Part II the evidence report acknowledges the uncertainties surrounding the microgravity- associated loss of bone mineral density (BMD) as measured by DXA scan and the difficulties associated with that measurement, particularly during a mission (so as to allow the adjustment of countermeasures for an individual astronaut). It then goes on to state, “The risk of fracture during a mission cannot be estimated with any level of certainty until the probabilities of overloading bones during the missions are understood” (Sibonga et al., 2017a, p. 4).” Thus, the context for concern is well stated. The body of evidence in the report relates to observed changes in av- erage bone mineral density (aBMD) using DXA. These changes, which are derived primarily from measurements before and after exposure to microgravity, demonstrate a variable pattern of loss and recovery among astronauts.The limitations of DXA, including the variability among indi- viduals in DXA scores, are discussed in the evidence report on osteopo- rosis. Much of the body of the report deals with the Factor of Risk index that assesses the ratio of applied load to the failure load of bone. The in- dex incorporates the direction and magnitude of force into a probabilistic model that is as yet untested beyond low Earth orbit. The committee felt that this continued reliance on the Factor of Risk is a concerning over- simplification. The ratio of imposed load to fracture load misses many important factors. For example, when stating that the risk of fracture in low earth orbit is negligible, the authors consider both the absence of fracture reports to date and the low loading imposed by a fall in reduced gravity. However, the latter ignores the risk associated with a sudden deceleration of the astronaut and the impact imposed by spacecraft accel- eration, either during orbital maneuver or docking or associated with landing on another surface (for further information see Caldwell et al., 2012). It also fails to consider the possibility of crush (due to inertia), collision, and the other types of injuries (with fracture component) asso- ciated with heavy equipment operation. A substantial concern about the report is the possibility of falsely as- suming, based on the absence of fractures in past human spaceflight, that the risk of fractures in future missions is nil or negligible. In fact, the exposure to bone-breaking loads during falls or collisions is certainly PREPUBLICATION COPY: UNCORRECTED PROOFS

8 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS larger for unbalanced astronauts maneuvering on a planetary surface than for those working in microgravity. Furthermore, a close examination of the Factor of Risk projections shows a significant chance of, for example, a wrist fracture occurring during a future Mars mission. Such a fracture may be sustained, when an individual falls, and puts out an arm to break the fall, thus sparing, per- haps, a femoral neck fracture. Fractures thus appear, even with this mod- el, to be sufficiently likely to require effective management (Nelson et al., 2009). Although there is an emphasis throughout the report on hip (femur) fracture due to falling, a relatively athletic individual may have time to throw out an arm and break his or her fall, thus, as previously noted, preventing hip fracture but sustaining a fractured wrist instead (see, for example, Stepaniak et al., 2014). Similarly, there is a risk of rib or other fracture when an astronaut falls against or impacts a protruding object due to his or her own movement or from sudden lateral or vertical accel- eration of the spacecraft, including elements of the spacesuit and its equipment. The future risk of bone fracture will surely rise in the era of exten- sive human exploration of planets and return to the moon, and, later, in the era of working on other planetary bodies rather than merely visiting them. Adjusting to movement on a planetary body after transit in zero-G will require time and care that may, at least transiently, interfere with balance and thereby increase risk of falls and thus fractures (Chappell et al., 2017). In terrestrial medicine it is recognized that the risk of fractures in elderly patients is significantly higher in those with visual, propriocep- tive, and neurovestibular issues. All of these sensory systems may be impaired in astronauts walking and working on a planetary body, under fractional gravity after a prolonged zero-G transit (Bloomberg et al., 2016). One look at an episode of repeated trips and falls during Apollo 17 shows that there is a risk of bone fracture that is incompletely under- stood (e.g., YouTube, 2007). Walking, running, or darting about in al- tered gravity is likely to lead to unexpected impacts and consequent bone fracture. The risk of impact (crush injuries) associated with operating machinery and moving large masses is mentioned, but insufficiently ad- dressed. There are post-flight concerns as well. The evidence report on osteo- porosis (Sibonga et al., 2017b) clearly documents the observed changes in bone mineral density associated with exposure to microgravity, and, additionally, provides evidence that the bone density lost may not be re- PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 9 gained even after 3 years of follow-up (Amin et al., 2010, 2011). Such failure to regain lost bone mineral density may lead to an increased risk of fracture as astronauts age. Does the Evidence Report Provide Evidence That the Named Gaps Are the Most Critical Presented? The evidence report correctly identifies three critical gaps, to which the committee suggests adding others, below. Are There Any Additional Gaps or Aspects to Existing Gaps That Are Not Addressed for This Specific Risk? The committee considered the following additional gaps to be signifi- cant: • What is the best measure(s) of bone health for the astronaut pop- ulation, both pre-flight and in-flight? • Is there a threshold for protection from bone loss as it is unlikely that the risk of bone loss will ever be zero. At what point are the pharmaceutical and/or exercise countermeasures considered ade- quate to reduce this risk? • What are the maximum G-forces and force vectors that might precipitate a fracture during launch or landing at any phase of a beyond-Earth-orbit mission? • What is the risk of fracture during exercise activity, including the ARED (advanced resistive exercise device)? • What is the appropriate management of fractures that occur dur- ing a mission? • What lessons can be learned from pharmacologic manipulation of bone metabolism to attempt to enhance fracture healing in os- teoporotic adults in terrestrial medicine? • What can be learned from the clinical history of osteoporosis and fractures in the quadriplegic/paraplegic population? Extensive data are available from bed-rest studies in healthy volunteers; however, these data could be supplemented by the clinical mod- els and experience gained in fracture management of other popu- lations with osteoporosis. PREPUBLICATION COPY: UNCORRECTED PROOFS

10 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS • What countermeasures should be investigated for extended dura- tion missions? Considering the risk as well as the benefit of us- ing extensive resistive exercise as the primary microgravity countermeasure, should emphasis also be placed on alternative countermeasures for extended duration missions? • How can bone health be monitored during long-duration mis- sions? Is urinary calcium excretion an adequate marker, or do other metrics need to be developed so that countermeasures can be tailored to the needs of each individual astronaut? • How should countermeasures, including the use of anabolic or antiresorptive pharmaceuticals, be altered if deterioration in bone health measures or fracture occurs during mission? • What can be applied from bedrest studies in humans and tail- suspended studies in rodents? How can these models be used to evaluate pharmacologic interventions? • Can suit design help ameliorate fractures due to falls or colli- sions? • What is best way to immobilize a fracture so that an astronaut can continue mission-related activities including, if necessary, donning an extra-vehicular activity (EVA) suit? Does the Evidence Report Address Relevant Interactions Among Risks? The report clearly identifies the interaction between the risk of frac- ture and the risk of premature osteoporosis, which is the subject of a sep- arate report. To the extent that calcium mobilized from the skeleton will be excreted in the urine, the changes that occur in bone are related to the risk of renal stone formation (Sibonga and Pietrzyk, 2017). The report also alludes to task analysis and task design, which were the topics of a separate evidence report (Sandor et al., 2013). Although radiation both weakens bones that are in the radiation field and can impair healing, the threshold for such clinical impairment (ap- proximately 20 Grays [Gy] in clinical medicine) appears unlikely to be achieved during likely mission scenarios (Engleman et al., 2006). Fracture management during a mission clearly interfaces with the “Medical Care” report (Antonsen et al., 2017). That report accurately identified fractures as a major concern for management during a mission. The lack of information concerning the best ways to manage a fracture PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 11 during a mission needs to be addressed in greater detail in some part of the evidence reports. To that goal, the committee recommends that the Fracture Report be expanded to include the risk and the management of fractures with an emphasis on fracture management during space missions. It would then naturally include more evidence about management of osteoporotic frac- tures and a discussion about the management of fractures in microgravity (e.g., the possible use of pharmacologic agents or other adjuncts to frac- ture healing). What Is the Overall Readability and Quality? The report is well written, readable, and benefits from the expertise of the authors. Is the Breadth of the Cited Literature Sufficient? The evidence report goes into depth on many of the relevant studies, including bed-rest studies, and has an extensive bibliography. In the next update of this evidence report references could be added from the terres- trial experience with the treatment of fractures in osteoporotic individu- als (e.g., Molvik and Kahn, 2015; Hegde et al., 2016) or in those with metabolic bone diseases; in particular, the (largely experimental) liter- ature on the use of anabolic agents to facilitate fracture healing (e.g., Aspenberg et al., 2010; Ominsky et al., 2011; Jin et al., 2015), and the assessment and management of fractures in spinal cord injury patients with quadriplegia or paraplegia (de Bruin et al., 2000; Zehnder et al., 2004; Coupaud et al., 2015; Grassner et al., 2017). References to the ex- tensive literature on tail-suspended rodents could also be included. Is the Expertise of the Authors Sufficient to Fully Cover the Scope of the Given Risk? Is Input from Additional Disciplines Needed? As noted, the addition of individuals with expertise in orthopedic surgery and endocrinology (specifically bone metabolism and pharmaco- logic means to enhance healing when fractures occur) would strengthen the disciplinary expertise relevant to this topic. PREPUBLICATION COPY: UNCORRECTED PROOFS

12 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS Has the Evidence Report Addressed Previous Recommendations Made by the IOM in the 2008 Letter Report? The addition of this and other evidence reports related to bone de- mineralization reflect the growing recognition that this issue is of signifi- cance. Because this risk was not pulled out as a separate chapter in the 2008 Letter Report, the risk was not critiqued specifically. However, 2008 report recommendations relevant to the elevation of fracture risk due to bone loss are discussed in the early onset osteoporosis report re- view that follows. RISK OF EARLY ONSET OSTEOPOROSIS DUE TO SPACE FLIGHT As is documented in the 2017 Evidence Report, Risk of Early Onset Osteoporosis Due to Space Flight (Sibonga et al., 2017b), and summa- rized in a recent publication (Orwoll et al., 2013), a major limitation to long-duration spaceflight is the rapid and sustained loss of bone, a loss that at least by QCT assessments may not be readily reversible on return to earth. For unknown reasons the rate of bone loss and subsequent re- covery are quite variable among subjects. Although ARED and/or bisphosphonate therapy may ameliorate the bone loss, the data provided suggest that the protection is not complete, and such preventive measures carry their own risks. Although at this point existing data from astronauts do not show bone loss to the level that meets the definition of osteoporo- sis, the loss of bone during spaceflight and the variable recovery on re- turn to earth could, with time, subject astronauts to an increased fracture risk even in a 1g environment. Does the Evidence Report Provide Sufficient Evidence, as Well as Sufficient Risk Context, That the Risk Is of Concern for Long-Term Space Missions? The report provides compelling evidence that during spaceflight bone loss is rapid and, to the extent that data are available, continuous with no evidence of a plateau. These data are well illustrated in figures 9 and 10 of the report. Table 2 of the evidence report lists the percent bone PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 13 loss per month in a number of different skeletal locations, with the most rapid losses in the hip and lumbar spine, as assessed by DXA. Bone loss in these regions averages from 1.06 to 1.56 percent per month (LeBlanc et al., 2000), far exceeding the rate of bone loss even in females in the early postmenopausal period. DXA is an areal measurement that includes cortical and trabecular bone. Changes in trabecular bone are generally more rapid than those in cortical bone. QCT, on the other hand, is a vol- umetric determination suitable for the assessment of trabecular bone and so is more sensitive to changes in bone than DXA. When QCT was used to assess bone loss, the rate of bone loss was found to be greater than that shown by DXA, with a mean bone loss of -2.7 percent per month of the trabecular bone at the femoral neck (Lang et al., 2004). Although bone loss can be partially mitigated by ARED alone and in combination with alendronate as shown in the study by LeBlanc and colleagues (2013), knowledge about the degree to which such preventive measures are ef- fective is generally incomplete and there is variability among individuals (see figure 18 of the evidence report). Furthermore, it will be important to consider the options for countermeasures in spaceflight situations in which extensive exercise may not be feasible due to the size of the spacecraft or other factors. The report provides compelling evidence that the rate and degree to which bone is lost is highly variable from person to person as seen in the large standard deviations in rates of bone loss summarized in tables 2 (p. 17) and 4 (p. 21). Similarly, the rate of recov- ery of bone after landing was quite variable among the astronauts, alt- hough when DXA measurements were used, the recovery seemed to approach baseline after about 3 to 4 years (figure 12, p. 23, of the evi- dence report provides data from a 2007 study by Sibonga and col- leagues). However, more recent QCT data suggests that after an initial recovery, there was resumption of loss of bone in the spine and hip, with no evidence for recovery by 4 years, although these results varied sub- stantially among the different subjects (Orwoll et al., 2013). This implies that some if not all astronauts face an increased risk of developing osteo- porosis and fractures as they age. Does the Evidence Report Provide Evidence That the Named Gaps Are the Most Critical Presented? The seven listed gaps capture many of the critical issues that, if bet- ter understood, could help in monitoring and/or mitigation of bone loss, in enhancing recovery, and in decreasing the risk of subsequent fractures. PREPUBLICATION COPY: UNCORRECTED PROOFS

14 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS These gaps are apparent from the data presented in the evidence report, although they are not necessarily flagged as such in the report. Thus, they could be highlighted more effectively in the report itself. Are There Any Additional Gaps or Aspects to Existing Gaps That Are Not Addressed for This Specific Risk? Several additional gaps that flow from the data are reported but are not currently listed as gaps: • The reasons for the heterogeneity of bone loss, response to pre- ventive measures, and recovery need to be better understood. As noted above, both the loss of bone and the rate of recovery after landing varied considerably among subjects. At this point no ob- vious effort has been made to understand this variability. How- ever, being able to determine which subjects will experience greater bone loss during spaceflight or have a decreased ability to recover the lost bone on landing could help tailor screening or preventive measures to reduce the risk of osteoporosis. • Better methods need to be developed to predict prior to space- flight which subjects are likely to be high-rate bone losers or have problems recovering of bone post flight. This relates to the above gap, as understanding the mechanisms underlying the var- iability will be essential for developing such predictive methods. • The report should discuss the influence of changes in muscle composition on bone and on the risk of falling. The evidence re- port does not include a discussion of the role of muscle function and composition as altered by spaceflight, although this was the subject of earlier evidence reports. Strong muscles help protect against falls in the terrestrial environment, and they may provide a compressive load that helps maintain some bone strength. An analysis of the interaction between bone and muscle is achieving much greater attention in the musculoskeletal literature (e.g., Cardozo and Graham, 2017). • The report does not take advantage of plausible models of im- mobilization in younger adults. For example, one could consider models such as those involving spinal cord injuries with chronic paraplegia or quadriplegia or prolonged immobilization models with recovery in both young adults and in preclinical animal PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 15 models. Paraplegia from spinal cord injuries, like spaceflight, re- sults in rapid bone loss. Research into the prevention of such bone loss and into rehabilitation methods for restoring bone that has been lost could inform the space program (Coupaud et al., 2015). Moreover, work with animal models for investigating the mechanisms for bone loss during simulated weightlessness is ongoing and can provide insights that may be incorporated into future bedrest or spaceflight trials (Meakin et al., 2014). Does the Evidence Report Address Relevant Interactions Among Risks? The report briefly alludes to changes in hormonal regulators of bone and mineral metabolism, and it also discusses the increase in urine calci- um that occurs during microgravity. The accompanying report on renal stones (Sibonga and Pietrzyk, 2017) shows how the increase in urinary calcium could contribute to an increased risk of kidney stones or of nephrocalcinosis or both. Similarly this report briefly discussed changes in hip strength (of the femur) as predicted by finite element analysis which could lead to changes in stance or fall loads predisposing an indi- vidual to fracture. As previously noted, missing from the report were da- ta on muscle strength and composition prior to flight, immediately after the flight, and at any later time points as well as discussion of the poten- tial influence of muscle strength and composition on bone strength and fall risk. Cross references to the evidence report on reduced muscle mass (Ploutz-Snyder et al., 2015) would be helpful. Changes in vestibular function, which are associated with exposure to altered gravity, affect balance and the likelihood of falling but are hardly mentioned in the re- port. A discussion of physiological stress responses to spaceflight and their potential impact on bone loss was missing and should be added. Spaceflight involves unique activities, such as EVA, that could increase the risk of fractures not generally considered in the evaluation of osteo- porosis risk factors on Earth, so that task analysis and the unique risks posed to the skeleton by these spaceflight activities could have been fur- ther discussed. Furthermore, there was no mention of nutritional influ- ences on bone health in light of the limits on diet imposed by long-term spaceflight were not mentioned. PREPUBLICATION COPY: UNCORRECTED PROOFS

16 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS What Is the Overall Readability and Quality? The authors are to be commended for the excellent quality of the writing and organization of this evidence report. Is the Breadth of the Cited Literature Sufficient? The literature cited and reviewed covers the breadth of the topic and it is current. Is the Expertise of the Authors Sufficient to Fully Cover the Scope of the Given Risk? Is Input from Additional Disciplines Needed? Overall, the expertise of the authors is sufficient, but including an expert in muscle physiology, especially one interested in the bone/muscle interface, would have been useful. Although the report reflects the input of the bone-focused metabolic, epidemiologic, and imaging disciplines well, input from muscle physiologists and nutritionists might be worth- while to include. Has the Evidence Report Addressed Previous Recommendations Made by the IOM in the 2008 Letter Report? Many of the recommendations made and the issues raised in the 2008 report have not been incorporated into the current report. Examples include the lack of using appropriate ground-based models such as mod- els of chronic spinal cord injuries. Similarly, the issues of the heteroge- neity of individuals regarding bone loss and recovery were mentioned in the 2008 report, but no further study of these biologic responses has been made. Developing better monitoring in flight for bone loss was recom- mended, but the evidence report does not discuss progress on this issue. Further consideration of nutritional, metabolic (hormonal), and stress factors on bone loss was mentioned in the 2008 report, but no apparent progress or even consideration of these factors was obvious in the current evidence report. PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 17 RISK OF CARDIAC RHYTHM PROBLEMS DURING SPACEFLIGHT The NASA evidence report Risk of Cardiac Rhythm Problems Dur- ing Spaceflight was first published in 2009. The risk of cardiac rhythm problems has been identified by NASA for at least four decades and was included in the IOM’s 2008 review as “Cardiac Rhythm Problems.” The committee’s analysis of the current evidence report (Lee et al., 2017) recapitulates and expands on many of the conclusions made in the 2008 review. The committee had workshop presentations (see Appendix A) from three practicing cardiologists who provided extensive commentary to supplement the committee’s analysis. Cardiac arrhythmias are a normal part of life. They occur throughout the day in most individuals. Thus the presence of cardiac arrhythmias during spaceflight should not be seen as different from the arrhythmias dealt with in contemporary cardiovascular medicine, which makes clear distinctions between significant and non-significant arrhythmias. Generally speaking, cardiac arrhythmias are categorized according to their potential substrates: 1. Changes in automaticity. There is no evidence that this occurs in space 2. The triggering of depolarizations in cardiac myocytes (e.g., af- terdepolarizations). These are generally of no physiological con- sequence, even when they are coupled to form brief, but spontaneously terminating, runs of arrhythmic beats (e.g., ven- tricular tachycardia). 3. Re-entry phenomena that lead to sustained cardiac rhythm dis- turbances. The substrate for these arrhythmias is an anatomical or functional boundary with an area of absolute refractoriness, such as focal scarring (i.e., tissue fibrosis). Since its inception, this evidence report has relied on the “biological model” of sudden cardiac death (Myerburg et al., 1989), where structural abnormalities interact with functional alterations, such as electrolyte dis- turbances or neuro-humoral modulation, to generate an environment that increases the likelihood that arrhythmias will be initiated or sustained, or both. This model serves as a justification for considering both the sub- strate and the trigger for arrhythmias that might pose an increased risk of sudden death. PREPUBLICATION COPY: UNCORRECTED PROOFS

18 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS In patients with coronary artery disease, the arrhythmogenic sub- strate is clear: a myocardial infarction or scar leading to focal areas of delayed conduction—a necessary condition for a reentry current. For patients with apparently normal ventricular function, reentry is often not the mechanism of arrhythmia development. Rather, arrhythmias in these patients are more often caused by delayed after-depolarizations, and the triggered activity may be mediated via catecholamines (Lerman et al., 1996). Indeed, this observation supports the suggestion that sustained, life-threatening arrhythmia is strongly associated with underlying cardi- ovascular disease, and that NASA should abandon arrhythmia as a driver of astronauts’ cardiovascular risk profile. Thus, contemporary clinical decisionmaking considers arrhythmia to be a “fact of life,” stratifies the need to consider clinical intervention when hemodynamic function may be compromised (e.g., sustained ven- tricular tachycardia, ventricular fibrillation, severe bradyarrhythmias, or pulseless electrical activity), and embraces a more holistic approach to screening for cardiovascular risk and disease with an emphasis on prima- ry prevention. Does the Evidence Report Provide Sufficient Evidence, as Well as Sufficient Risk Context, That the Risk Is of Concern for Long-Term Space Missions? There is sufficient evidence to conclude that arrhythmia will occur prior to spaceflight and during most, if not all, phases of spaceflight and extraterrestrial exploration. The available evidence supports the conclu- sion that these arrhythmias are neither life-threatening nor any different from what would occur in the general population of healthy people (Convertino and Cooke, 2005). The available evidence does not support the conclusion that space- flight is, or enables, a unique arrhythmogenic substrate. The report pro- vides no definitive evidence that spaceflight is associated with increased frequency or complexity of cardiac arrhythmias either during or after flight. In fact, two flight investigations cited in the report indicated that the frequencies of arrhythmias during either intravehicular or extravehic- ular operations were virtually the same as the frequencies measured be- fore flight. While there is sufficient evidence that pre-existing cardiovascular disease poses a risk to the health and safety of astronauts that increases with mission duration, there is insufficient evidence to conclude that the PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 19 risk of arrhythmia is amplified by long-term space missions. It is also acknowledged that cardiovascular events can be of great concern during space exploration because the continuity of care is affected by communi- cation time and distance from Earth. Does the Evidence Report Provide Evidence That the Named Gaps Are the Most Critical Presented? The risk is poorly contextualized, with disproportionate weight given to clinically minor observations. Benign, non-sustained, and infrequent arrhythmias are an expected part of spaceflight. Other gaps are not named. There is a significant gap in evidence in the failure to provide any association of the existence of post-flight arrhythmias with occur- rence during flight. And most importantly, there is a gap in associating arrhythmia risk with pre-existing cardiovascular disease, not acquired arrhythmias in space. Are There Any Additional Gaps or Aspects to Existing Gaps That Are Not Addressed for This Specific Risk? Less consideration is given to the overall cardiovascular risk profile of astronauts and flight crews, which can be improved with primary pre- vention (screening) that includes cardiac imaging, coronary artery calci- um scanning, an assessment of valve function, and Holter monitoring. Furthermore, tissue fibrosis can be gauged with cardiac MRI. A greater emphasis in the evidence report on the risk of atrial fibrillation is sup- ported by contemporary experience in cardiology, cardiac electrophysi- ology, and epidemiology, particularly by the substantial and growing prevalence of atrial fibrillation in the middle-aged general population. Furthermore, medical management strategies for atrial fibrillation that occurs during long-duration spaceflight need to be explored. The lack of data from missions of exploration-class duration is notable, but this situa- tion should improve as the ISS experimental manifest is completed. A consideration of non-ischemic changes in cardiac health (e.g., atrial fi- brillation, stress cardiomyopathy) as a component of primary prevention could be included as a research gap. Finally, greater consideration should be given to post-flight assessment and long-term follow-up. PREPUBLICATION COPY: UNCORRECTED PROOFS

20 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS Does the Evidence Report Address Relevant Interactions Among Risks? The evidence report adequately presents human and animal space- flight and ground-based experimental data in an attempt to link relevant interactions of arrhythmia factors such as age, gender, fluid shifts, de- creased cardiac mass (remodeling), QT interval prolongation, electrolyte disturbances, elevated sympatho-adrenal activity, oxidative stress, pre- existing cardiovascular disease, and genetic abnormalities in cardiac ex- citation–contraction coupling. In addition, the report includes routine physical stressors such as exercise, lower-body negative pressure, and extra-vehicular activity as possible confounding factors that might in- crease the occurrence of arrhythmias. Nevertheless, the evidence does not support the hypothesis that these potential interactions contribute to a clinically important change in cardiovascular risk. What Is the Overall Readability and Quality? The overall readability and quality of the report is good. The reada- bility could be improved by including a specific section that enumerates the gaps in knowledge. The current report places the burden on the read- er to extract gaps. Is the Breadth of the Cited Literature Sufficient? The bibliography appears to include a thorough description of pub- lished literature documenting non-threatening arrhythmias during space- flight. However, it appears to lack sources from the literature on the difference between benign and life-threatening arrhythmias and the rap- idly expanding role of prevention in modern cardiovascular medicine. The report makes extensive reference to a recent paper by Delp and colleagues (2016) that reviewed mortality in Apollo astronauts. This pa- per has been the subject of considerable controversy because of its retro- spective nature, lack of hypothesis, small sample size, and questionable epidemiological technique. While the risk of accelerated cardiovascular disease from high LET (linear energy transfer) ionizing radiation may be of concern, it is difficult to accept this paper as definitive “evidence.” In fact, NASA has invested considerable resources in its space radiation program to determine whether in fact there are any cardiac risks associ- ated with space radiation exposure since this is considered uncertain at PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 21 space-relevant doses at this time. The background for this work is sum- marized in the NASA evidence report Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure (Patel et al., 2016). Thus, in view of the current lack of evidence that arrhythmia occur- rence during spaceflight is a particularly significant clinical problem, a more holistic approach to cardiovascular risk (which would incorporate a discussion of arrhythmia) might be considered. Is the Expertise of the Authors Sufficient to Fully Cover the Scope of the Given Risk? Is Input from Additional Disciplines Needed? The authors have expertise in human physiology and are clearly fa- miliar with the literature and reports that provide detailed information about the occurrence of cardiac arrhythmias in astronauts and cosmo- nauts. However, the author expertise could be improved by including cardiovascular clinician-scientists who have greater familiarity with the current literature and operational expertise in cardiovascular risk stratifi- cation and in recognizing and treating cardiovascular disease. The authors should include experts in cardiology. As cardiovascular medicine evolves, the evidence book should portray a contemporary view of cardiovascular risk (not just arrhythmia risk) as reflected in cur- rent practice. This perspective would maximize the utility of the report for NASA flight surgeons who assess health risk prior to, during, and after long-term spaceflight. Has the Evidence Report Addressed Previous Recommendations Made by the IOM in the 2008 Letter Report? Some recommendations made in 2008, such as the need for better te- lemetry and improved preflight screening methods, have been incorpo- rated into the current report. However, the general recommendation to refocus the report so that it addresses cardiac health holistically, rather than focusing solely or primarily on arrhythmias, has not been addressed in the current report. PREPUBLICATION COPY: UNCORRECTED PROOFS

22 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS RISK OF RENAL STONE FORMATION The evidence report on the risk of renal stone formation suggests that astronauts may be at an increased risk for forming kidney stones due to changes in bone metabolism, dehydration, nutrition, and the supersatura- tion of urine salts. Should a stone become symptomatic in flight, the con- sequences to the mission and the health of the astronaut could range from performance reduction to acute, life-threatening illness. The single doc- umented report of a renal stone during flight occurred in a Russian cos- monaut and 32 stones have been reported post-flight in U.S. astronauts (as of mid-2016). Countermeasures to reduce the risk of renal stone for- mation in flight include the administration of potassium citrate, increased hydration, diets low in oxalates and animal proteins, and the maintenance of bone minerals (thus avoiding increased calcium excretion by the kid- neys) through bisphosphonates and resistive exercise. Models have been developed to predict the risk of stone formation in flight for specific mis- sion scenarios and diagnostic ultrasound is available in-flight for routine monitoring. Nevertheless, gaps remain in the knowledge base concerning the magnitude of the risk and the effectiveness of proposed countermeas- ures in reducing the risk of symptomatic renal stones in flight. Does the Evidence Report Provide Sufficient Evidence, as Well as Sufficient Risk Context, That the Risk Is of Concern for Long-Term Space Missions? The authors provide clear evidence that astronauts experience in- creased supersaturation of salts in their urine during flights due to altered bone metabolism and dehydration, which may increase the risk of renal stone formation. It is currently unclear whether flight increases the risk of forming renal stones, because the reported incidence of renal stones post-flight is similar to the prevalence of kidney stones in the U.S. gen- eral population (Scales et al., 2012). The report presents the renal stone formation risk in the historical context and discusses strategies and coun- termeasures currently used to reduce the risk of renal stone formation. Furthermore, the report details the computer models designed to predict the likelihood of a renal stone event for various expedition mission sce- narios. The report concludes with an identification of knowledge and implementation gaps. PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 23 While it seems logical that bone demineralization might contribute to an increased risk of renal stone formation through hypercalcuria (the in- creased urinary excretion of calcium), the committee believes that the contribution of bone demineralization to the renal stone risk may be overstated. The authors state, “the risk for renal stone formation is inti- mately linked to hypercalciuria induced by the unbalanced bone resorp- tion during the uncoupled bone remodeling in space” which suggests that eliminating bone loss will eliminate the risk of renal stone formation. However, ground-based studies suggest that renal stone formation is more complicated. The supersaturation of salts and crystallization is known to occur in normal urine. In most people, these crystals pass harmlessly from the body, but in others, these crystals are retained in the kidney and form stones. When hypercalciuria and salt supersaturation are induced in laboratory “kidneys,” crystal organization and aggregation does not match what is found in human kidney stones. Ground-based studies indicate that genetics, diet, and hydration all contribute to the risk of stone formation; however, the relative contributions of the individual factors are not understood, and there are likely additional factors that have not yet been identified. Therefore, while urine supersaturation is necessary for stone formation, the process is complex and this uncertain- ty as to what causes stones to form should be reflected in the report. Due to the emphasis on the hypercalciuria risk of renal stones, the report focuses on mitigation strategies for calcium oxalate stones. Potas- sium citrate, the only approved operational countermeasure for flight, addresses the risk of calcium oxalate stones as well as the risk of uric acid stones by raising urine pH. However, the changes in urine chemistry from the administration of potassium citrate may increase the risk of forming calcium phosphate or brushite stones (Krieger et al., 2015). This possibility should be addressed in the report. Furthermore, the report de- votes an entire paragraph to the use of bisphosphonates to “inhibit bone loss” and theoretically “mitigate renal stone formation” (p. 17). Word choice should be critically evaluated in this paragraph to ensure that the relationship between bone loss and renal stone formation is not overstated. Finally, while the report focuses on describing, quantifying, and pre- venting renal stone formation in flight, it is unlikely that the risk will ev- er be completely eliminated. This is reflected in the NASA evidence report Risk of Adverse Health Outcomes and Decrements in Performance Due to In-Flight Medical Conditions (Antonsen et al., 2017), in which the development of renal stones was listed as one of three particular risks specifically cited as a potential issue requiring management during long- PREPUBLICATION COPY: UNCORRECTED PROOFS

24 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS duration missions beyond low earth orbit. New technologies have been developed to treat renal stones and some may be suitable for use during a mission (e.g., Simon et al., 2016). These technologies should be dis- cussed in this report. Does the Evidence Report Provide Evidence That the Named Gaps Are the Most Critical Presented? The seven gaps identified by the evidence report are well-supported as being critical to determining the risk of renal stone formation in space. However, the committee recommends some changes in the presentation of the gaps. For example, Gap B6 (What are the contributing factors oth- er than loss of bone mineral density?) could be reworded to “What are the contributing factors?” so that the loss of bone mineral density is not overemphasized. Perhaps ongoing research will suggest that dehydration is a larger contributing factor than the loss of bone mineral density. Ad- ditionally, Gap B8 (Do pharmaceuticals work effectively in spaceflight to prevent renal stones?) and Gap B16 (Can inhibitors of stone formation be sufficiently provided through dietary sources?) could be reworded to reflect that it is unlikely that the renal stone risk will ever be zero. For example, the question could be framed as, At what point are the pharma- ceutical countermeasures or delivery of inhibitors through dietary sources considered good enough at reducing the risk of renal stones? Furthermore, Gap B9 (What is the frequency of post-flight stone for- mation; the incidence and types of stones; and the time course of stone formation? How does stone formation correlate with food intake and hydration status?) could be separated into two gaps with one focused on food and hydration. The first part of Gap B9 could be extended to in- clude micro-structure in addition to incidence and composition (rather than type) as stones are heterogeneous composites of crystals and micro- structural differences compared to Earth may help elucidate the mecha- nisms of stone formation in spaceflight. Are There Any Additional Gaps or Aspects to Existing Gaps That Are Not Addressed for This Specific Risk? The gaps included in the evidence report include many of the gaps that are the most important to address. An additional gap that should be listed is: “How does the increased urine retention of spaceflight (and thus the retention of the crystals of supersaturated salts) influence the risk of PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 25 renal stone formation?” Urinary retention has occurred in spaceflight and required bladder catheterization; this would likely increase the risk of renal stone formation as well as other urological conditions. Another gap to consider including in the evidence report is: “Do supplements or other pharmaceuticals under investigation for spaceflight contribute to renal stone formation?” Furthermore, the lack of understanding of the factors that contribute to the risk of renal stone formation suggests that a gap should still exist that addresses the numerical modeling of kidney stone formation in microgravity. The report includes a literature summary of modeling kidney stone formation in microgravity, but these models will likely be improved by further research into the factors that contribute to stone formation which can then be incorporated into the model. The fidelity of the reporting of symptomatic kidney stones in the U. S. astronaut corps, particularly for retired astronauts, should be addressed and is perhaps within the scope of Gap B5. Does the Evidence Report Address Relevant Interactions Among Risks? The evidence report focuses on the contribution of altered bone me- tabolism to kidney stone formation. The associated risks that are not di- rectly discussed include those discussed in separate evidence reports: Risk of Inadequate Nutrition (Smith et al., 2015); Risk of Adverse Health Outcomes and Decrements in Performance due to Inflight Medical Ca- pabilities (Antonsen et al., 2017); Risk of Ineffective or Toxic Medica- tions due to Long Term Storage (Wotring, 2011); and Risk of Adverse Health Effects due to Host-Microorganism Interactions (Ott et al., 2016) (in the case of struvite stones that arise from bacterial infection). These associated risks should be considered, particularly for countermeasures such as dietary stone inhibitors, technologies to treat stones, and pharma- cological agents intended to reduce stone formation such as potassium citrate. Should a kidney stone be suspected in flight and particularly if ultrasonic treatments for kidney stones are used, an additional interaction is discussed in the NASA evidence report Risk of Performance Errors Due to Training Deficiencies (Barshi and Dempsey, 2016). These risks should be directly referenced in the report for improved clarity. PREPUBLICATION COPY: UNCORRECTED PROOFS

26 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS What Is the Overall Readability and Quality? The overall readability and quality of the report are very good, with well-organized data presented in a thoughtful and concise manner. Is the Breadth of the Cited Literature Sufficient? The bibliography includes a good selection of the space life sciences literature on the risk of renal stone formation but is lacking sources from the urology literature on the stone formation process and current practic- es for preventing stones. Newer techniques for stone analysis, including micro computed tomography and spectroscopy on stones from astro- nauts, could give additional information as to the differences in the stone formation process in flight as opposed to on Earth. Additionally, recent research evaluating technologies to study stones, identifying early miner- alogical and cellular mechanisms, and assessing the effectiveness and potential side effects of treatments such as potassium citrate should be included. A few examples include (but are not limited to) Robinson et al., 2009; Williams et al., 2010; Boonla et al., 2014; Gul and Monga, 2014; Shoag and Eisner, 2014; Wang et al., 2014; Evan et al., 2015; and Zisman et al., 2015. Is the Expertise of the Authors Sufficient to Fully Cover the Scope of the Given Risk? Is Input from Additional Disciplines Needed? The authors have expertise in bone metabolism, human physiology, and biochemistry, which is important when discussing renal physiology. The report could be improved by including a practicing urologist and nephrologist who could update the report with current practices for treat- ing and preventing stones on Earth as well as the current understanding of factors that contribute to renal stone formation. Additional disciplines in the form of practicing urologists and neph- rologists or experts in stone formation on Earth would greatly add to the report. As currently written, questions remain as to the current under- standing of the stone formation process as well as to the standard practic- es for preventing stones on Earth. Aviation medicine has strict requirements for pilots with regards to the diagnosis of renal stones and strategies to prevent stones may be possible to implement in spaceflight. PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 27 Has the Evidence Report Addressed Previous Recommendations Made by the IOM in the 2008 Letter Report? The evidence report did not fully address the previous recommenda- tions made by the IOM in the 2008 letter report. The propensity for renal stones pre-flight was brought up in the previous report, and the authors were encouraged to look for other factors that contribute to stone for- mation, including genetic pre-disposition and dietary factors. In addition, the report notes that the risk report focused on hypercalciuria, a focus that is continued in the 2017 version of the report. As noted in the current report, NASA has made an effort to address the real incidence (as op- posed to symptomatic incidence) of renal stones, which was noted in the 2008 report. Data are still forthcoming on the real incidence of renal stones. RISK OF ADVERSE HEALTH OUTCOMES AND DECREMENTS IN PERFORMANCE DUE TO IN-FLIGHT MEDICAL CONDITIONS The introductory section of the evidence report Risk of Adverse Health Outcomes and Decrements in Performance Due to In-Flight Med- ical Conditions succinctly states: “Given that medical conditions/events will occur during human spaceflight missions, there is a possibility of adverse health outcomes and decrements in performance in mission and for long term health” (Antonsen et al., 2017, p. 5). NASA, through its Human Research Program’s Exploration Medical Capabilities Element, is specifically concerned with establishing evidenced-based methods of monitoring and maintaining astronaut health. Essential to completing this task is the advancement in techniques that identify, prevent, and treat any health threats that might occur during space missions. The evidence report is organized to discuss the risks and challenges of designing medical capabilities for exploration missions. Constraints include those on designing habitats, communications, telemetry, data, and the lack of evacuation capability. A section noting the utility of a Concept of Operations (ConOps) for a Transit Mission to Mars (empha- sis added) is used to highlight the fact that such a ConOps does not cur- rently exist, though relevant work that is available includes the 2009 Space Medicine Exploration Medical Condition List, the predictive Inte- PREPUBLICATION COPY: UNCORRECTED PROOFS

28 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS grated Medical Model, an Exploration Medical Conditions Concept of Operations and Exploration Medical Capability Element updated in 2014, and Telemedicine Operational Concepts for Human Exploration Missions, also from 2014. The report notes some of the ethical consid- erations resulting from medical capability constraints and discusses the application of the principles of protection of the rights and welfare of research subjects. In discussing exploration mission medical systems, the evidence re- port focuses on modeling and predicting risks, the components of the medical mission (with an extensive discussion of onboard pharmaceuti- cals, including the relevant results from research done on shelf life, bioa- vailability, and radiation effects), and system capabilities (with discussions on maintaining musculoskeletal and cardiovascular condi- tioning and the potential need for rehabilitation functions for long- duration missions). The report also discusses the need for autonomous decision support and for onboard knowledge resources to support diag- nosis and treatment. The report further includes a detailed discussion of risk mitigation that highlights three conditions deemed to be high risk for exploration-class missions—bone fracture, dust exposure, and renal stone formation—as well as of mitigating risk through the selection of a physician astronaut, continuing education, and just-in-time training for medical procedures. The report concludes with a listing of 13 research knowledge gaps. Does the Evidence Report Provide Sufficient Evidence, as Well as Sufficient Risk Context, That the Risk Is of Concern for Long-Term Space Missions? At a basic level, the expectation of illnesses and injuries occurring during an extended duration mission and the need to diagnose and treat these effectively is self evident. In that regard, it is impossible to imagine the risk of inadequate medical capabilities would not be of concern. However, this is such a broad topic that the evidence report is a some- what eclectic sampler of topics relevant to medical conditions expected to be associated with exploration class missions rather than a comprehen- sive overview. The strengths of this report include the thorough descrip- tion of NASA’s exploration medical capabilities work, the discussion of constraints regarding medical capabilities, the depth and detail of data provided on pharmaceutical bioavailability and shelf life, the summary of approaches to training and simulation, and the narrative on planetary PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 29 dust. However, these strengths are offset to some extent by substantial issues of risk context that are at best unclear, and at worst confusing. The lack of clarity begins with the report’s title, which focuses on in- flight medical conditions, when a more accurate title might encompass the entire mission; the report would then logically be divided into mis- sion phases, only some of which would be in-flight. The lack of clarity is also reflected in the text, as some of the contributing authors have clearly narrowly interpreted the topic as being restricted solely to a transit mis- sion without a surface landing. In contrast, other NASA Mars Expedition Design Reference Missions detail a descent to the Mars surface and a shorter or longer-term stay before returning (Drake, 2009; NASA, 2015). The failure to acknowledge the range of potential missions leads to in- consistencies in the report’s content. For example, sections of the report focus exclusively on the two transit, or cruise, phases of a human plane- tary expedition, but the report also includes a surface risk (i.e., dust ex- posure) among the three risks selected for more detailed discussion, and it cites experience from analogous conditions on Earth, such as Antarctic research stations. The report ignores nearly all of the medical risks of a potential long-term surface operation. The expectation of the committee, which would likely mirror the ex- pectation of most non-specialist readers, is that medical capability should be viewed as an end-to-end continuum for exploration class missions. Because none of the other risk reports address this topic holistically, there is an opportunity for this report to provide that broad perspective, and thus the committee is concerned about the narrow scope of the report as written. This or another risk report (such as the evidence report on the risk of injury due to EVA operations [Chappell et al., 2017]) should ad- dress the numerous potential work tasks and risks of Mars surface opera- tions, which include construction, the operation of excavation equipment, maintenance inside and outside the surface habitat, mechanized traverses to conduct geological/biological research, the deployment of solar and possibly nuclear electric facilities and distribution busses, the operation of well-drilling rigs and coring devices, and the loading of fuel produced on the surface to propel the ascent vehicle to Mars orbit at the end of the surface phase. The types of tasks that will be conducted during surface operations are dangerous when conducted on Earth and frequently result in serious injury; the danger and risk of injury will be compounded on the surface of Mars. A vast array of health and medical conditions could be faced during a human expedition to Mars, as discussed throughout the full set PREPUBLICATION COPY: UNCORRECTED PROOFS

30 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS of evidence reports, including trauma incidents, decompression sickness resulting from suit punctures, dental emergencies, radiation incidents, electrocution, hazardous materials exposure, and the death of a crew member. The expedition physician must be prepared with training and tools to treat all of these situations, and more. Viewing these requirements as distinct from those of the transit phases of a Mars mission seems illogical and prone to result in ineffi- ciencies and redundancies in HRP’s research and development agenda and in any operational decisions made on the basis of knowledge gener- ated by HRP efforts. The report should also emphasize preventive and health promotion approaches to spaceflight medical capabilities. The committee notes that the pro-active optimization of human functions, not simply diagnosing and treating diseases or outcomes, should be at the center of the design of health-related capabilities for long-duration missions. The committee believes that the understanding of risk context would be strengthened by addition or revision of the following • The addition of quantitative estimates of risks of specific condi- tions to bolster the largely qualitative assertions made in the re- port. The committee noted that risk estimates are available in many of the references cited by the report and some are available in Appendix Table 1, but these have not been incorporated into the narrative report text. Similarly, the inclusion of quantitative data from analog environments would strengthen the report. • A discussion of trauma, which is statistically the most frequently encountered health condition to date. This should include space suit trauma and should address trauma outside and in the suit, in- corporating the lessons learned in this area from work already done by NASA, with cross references to other relevant evidence reports (e.g., Chappell et al., 2017). Candidate scenarios in this regard would also include surgical emergencies such as a com- minuted fracture and surgical abdomen due to a perforated vis- cus (e.g., perforated ulcer). • Additional data and discussion about the prevalence of similar risks and mitigation strategies in partial gravity environments, as the nature of the health risks in a number of areas is reasonably well understood in micro-gravity. PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 31 • Additional content in the areas of cardiovascular diseases, psy- chology, and behavior. • Descriptions of additional diagnostic modalities of imaging other than ultrasound. • A revision of the assessment of commercially available electron- ic health record systems to highlight instead the unique function- al requirements of a system that provides both decision support and the clinical documentation of care for exploration class missions. • Clarification of the discussions regarding personalized medicine and an acknowledgement of the need for further research in this area. The report notes: Personalized medicine as a field is in its infancy. In ter- restrial medicine other federal agencies are working to realize the potential of this field in the larger medical arena (Hamburg and Collins, 2010). For NASA, addi- tional research on genetic and genomic information to inform personalized medicine poses both logistical and regulatory challenges. (p. 28) The committee believes that making “personalized medicine” synonymous with the use of genetic and genomic information does not do NASA a service, since there are many aspects of the effective personalization of risk assessment, customized coun- termeasures optimized for individuals, and modifications of ther- apy that do not depend on genomic data. An example is using the monitoring of urinary calcium to target exercise and pharmaceu- tical countermeasures to individuals showing patterns of excre- tion associated with future health problems, rather than having the same countermeasures done by everyone. Because all of the commonly used terms, such as “individualized” or “personalized medicine,” and “precision medicine” are unclear with respect to whether they incorporate genetic and genomic data, the commit- tee recommends that HRP simply and explicitly describe genetic data in any context in which they are used or investigated and not rely on there being a common understanding of these more generally used and imprecise terms. Additionally, the need for further research in this area, including on individual variation PREPUBLICATION COPY: UNCORRECTED PROOFS

32 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS that arises from genetic and other factors, should be acknowl- edged (Schmidt and Goodwin, 2013). Does the Evidence Report Provide Evidence That the Named Gaps Are the Most Critical Presented? The 13 topic areas addressed by the gaps enumerated in section VIII of the evidence report are all highly relevant to the development of medi- cal capabilities for exploration class missions. The steps needed for the resolution of these 13 existing gaps are not articulated nor is the desired end state or requirement clearly stated. The committee also found that the gaps as currently worded may be worded too broadly. For example, the description of gap Med02 says: “We do not have the capability to pro- vide a safe and effective pharmacy for exploration missions” (Antonsen et al., 2017, p. 51). This contrasts with the extensive quantitative data provided in the report text on the topic of pharmaceuticals, and focusing on the specific needs in understanding pharmacokinetics and pharmaco- dynamics in the space environment would be beneficial. Stating the gaps as such broad generalizations does not seem useful in informing the next steps for HRP. In their current form, the descrip- tions of the gaps also appear to discount the accumulated experience to date on health and medical care–related issues. A reading of the gaps stated in other HRP risk reports should facilitate finding a more actiona- ble formulation of the gaps. Are There Any Additional Gaps or Aspects to Existing Gaps That Are Not Addressed for This Specific Risk? The committee suggests that NASA consider adding the following to the list of existing gaps: • The development of a fundamental risk health risk matrix for ex- ploration missions, with associated risk mitigation measures di- rected to key phases of the operations: earth launch, zero-G, transit, landing G, partial-G at destination, remote launch, zero-G transit, landing. The risk matrix could include the estimated probability of occurrence of each condition and its mission im- pact if it occurs. Such a modular matrix could be adapted to mis- sion architecture as needed. PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 33 • The development of decision-support principles for making di- agnoses of health conditions in space, particularly in settings of long communications latency or lost communications. • Understanding the relevance of health care delivery models in austere and chaotic environments that face the stark reality of limited inventory, such as refugee camps, the battlefield use of medics, and military models involving prolonged field care. • The development of effective methods for administering anes- thesia (both local and regional block) and for the conducting of emergency surgery. In this regard, a workshop participant noted that one backpack gets most emergency surgery done. • The development of balanced mitigation strategies for engineer- ing and biomedical risks. Although engineering risk would often appear to trump other risks, there are purely humanitarian rea- sons to address biomedical risks. In addition, risks accumulate mathematically so that even apparently small risks can become significant. • The development of standards of care for exploration medicine focused on pragmatic decision making, rather than terrestrial standards of care. • The development of an atlas of clinical procedures for space- flight including definitions and effective methods for teaching these procedures. • The evaluation of the utility of clinical training models for ex- tended duration missions that employ just-in-time- and simula- tion-based training, particularly for uncommon conditions. • The development of training approaches to maintaining profi- ciency with manual skills (e.g., intravenous insertion), particular- ly those that are expected to have different methods from those used for terrestrial medical care. • The development of protocols for treating common injuries such as fractures that might enable crewmembers to continue partici- pating in team activities, including the use of a pressure suit if required, thus minimizing the risk to the mission as well as opti- mizing the health outcome for the individual astronaut. PREPUBLICATION COPY: UNCORRECTED PROOFS

34 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS Does the Evidence Report Address Relevant Interactions Among Risks? The report addresses in its introductory section the interaction of risks and tradeoffs involved in provisioning limited medical capability for missions affected by long communications latency and an inability to provide medical evacuations. In addition the detailed sections on bone fracture, dust exposure, and renal stone formation address risk interac- tions for those conditions. Because mission medical capabilities have potential interactions with essentially all of HRP’s health risks other than perhaps the long-term risk of cancer and other degenerative diseases, a comprehensive health risk matrix as suggested above could serve as a concise mechanism for representing all important risk interactions. What Is the Overall Readability and Quality? The committee found much of the report to be well-written and un- derstandable. However, the writing is uneven and could use tighter edit- ing for grammar and readability with more limited reliance on acronyms. Furthermore, the committee took note of the reference to the Challenger disaster as a “mishap,” which trivializes the tragedy and appears to imply that it was an unavoidable accident when subsequent analyses found that much could have been done through engineering and through fostering a culture of safety. With respect to both readability and consistency with other NASA program documents, the committee notes that in 2017 no one refers to human space exploration as “manned spaceflight.” Is the Breadth of the Cited Literature Sufficient? Overall, the cited literature in the report is broad and reflective of more recent Shuttle/ISS experience. There is a breadth of NASA tech- nical material from Gemini, Apollo, Skylab, and NASA-Mir missions that is worthy of review in the context of mitigating the health risks of beyond-Earth-orbit missions. Literature that could be reviewed for incor- poration into the report includes publications pertaining to critical care, to anesthesia in space based on parabolic flight, to ISS animal research and to analog environments. Specific additional references that could help inform the quantitative estimation of risk of various health condi- tions associated with exploration class missions include Buckey (2006) and Stuster (2010). PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 35 Is the Expertise of the Authors Sufficient to Fully Cover the Scope of the Given Risk? Is Input from Additional Disciplines Needed? The expertise of the current authors appears to match the scope of the report as written. Additional input from those with operational medi- cal care delivery experience, particularly NASA flight surgeons and phy- sician astronauts, could do much to help portray the value—and limits— of real world experience in formulating the research and development agenda for this area of focus in NASA’s Human Research Program. The Mars expedition task analysis that is currently being conducted by Stuster and colleagues for NASA’s Human Factors & Behavioral Per- formance Element (under NASA Grant Number NNX15AW34G) has generated a 1,130 item task inventory that could help inform the likelihood and type of injury and illness during expedition-class space missions. Has the Evidence Report Addressed Previous Recommendations Made by the IOM in the 2008 Letter Report? The chapter of the 2008 report most closely aligned with the current report is titled “Inability to Adequately Treat an Ill or Injured Crew Member.” The overall assessment of the 2008 committee was that this topic was in “an early stage of development” and that “a detailed list of gaps will do much to illuminate the directions in which research and de- velopment will be going within NASA” (IOM, 2008, p. 80). The current risk report has added a list of gaps, but as noted above they are not as detailed as they need to be in order to assess the knowledge needed. The 2008 report stated that the evidence report “describes a neces- sary, but not sufficient, overall approach to the provisioning of autono- mous health care resources and, at least as importantly, the enumeration of conditions that will be left untreated during exploration-class missions.” This assessment remains true of the current report. SUMMARY This is the fifth of five letter reports that have reviewed the series of NASA’s evidence reports on human health risks. This letter report reviewed five evidence reports and provided the committee’s responses to the ques- PREPUBLICATION COPY: UNCORRECTED PROOFS

36 REVIEW OF NASA’S EVIDENCE REPORTS ON HUMAN HEALTH RISKS tions detailed in the statement of task. The evidence reports are quite thor- ough in their review of the evidence of spaceflight risks, although they vary in format and in the consistency and quality of the writing. With respect to the closely related reports on Fracture and Osteoporo- sis, the committee believes that the report appropriately develops the risk context, but that there is an over-reliance on the Factor of Risk model. A better model for fracture risk would include more of the anticipated risk factors associated with long-duration missions. Osteoporosis is correctly mentioned as a contributing factor, but it is not adequately considered as something to monitor and address during a long mission beyond low Earth orbit. The relationship of such weakening to fracture risks and to require- ments for countermeasures and for in-flight monitoring should be empha- sized. Input from the field of endocrinology (bone metabolism) should be sought. Current countermeasures, including ARED and antiresorptive agents, are not fully adequate to prevent bone loss and potential fractures (Orwoll et al., 2013) and significant bone loss occurs in some individuals even with ARED and bisphosphonates (Orwoll, 2013). As with most risks, there is significant individual variability in DXA scores before and after exposure to microgravity as well as in long-term recovery after return to Earth. This variability may be due to genetic, epigenetic, hormonal, or other influences, and it provides an opportunity to apply the principles of personalized medicine. Attention needs to be paid to these and other in- dividual variations as relevant to each risk. The management of fractures during a mission should be included in the evidence report on bone frac- ture. Obviously, life-long monitoring for subsequent fractures (e.g., fragili- ty fractures) in former astronauts is important, but this might fit more naturally into the evidence report on osteoporosis. Additional input from the field of orthopedics would be helpful. In two of the areas reviewed—cardiac rhythm problems and renal stone formation—the reports convey a traditional view of underlying phys- iology that has been substantially revised by contemporary medical sci- ence, and thus a more substantial reformulation of these risk reports is warranted. In particular, the arrhythmia report should be refocused to in- corporate current understanding of which mechanisms of arrhythmia cause clinically insignificant arrhythmias and to add a more comprehensive de- scription of other cardiac risks. Finally, the report on medical care would benefit from greater clarity in risk context including consideration of all of the phases of a mission and all the different possible mission architectures. Risks associated with sur- face operations, many of which are dangerous when performed on Earth PREPUBLICATION COPY: UNCORRECTED PROOFS

2017 LETTER REPORT 37 and might be more so on the surface of another planetary body, are not adequately considered. The concept of personalized medicine should be expanded to include more than just the incorporation of genetic and ge- nomic information into preventive and therapeutic strategies. The committee has noted throughout its series of five reports that conveying the information on the interactions across risk domains is one of the biggest challenges for the NASA evidence reports. The set of evi- dence reports could benefit from a more systematic approach to consider- ing interactions with other risks. NASA should consider adding a standardized section or table in each report that shows the relationship of the risk described in the report with all other risks, noting whether and how each is related to the main topic of the report. The committee greatly appreciates the opportunity to review the evi- dence reports and applauds NASA’s commitment to improving the quali- ty of its reports. The evidence reports provide the basis for the work of NASA’s Human Research Program, and the in-depth review that they provide will contribute to improving the health and performance of fu- ture astronauts and enhancing future human spaceflight endeavors. Sincerely, Carol E. H. Scott-Conner, Chair Daniel R. Masys, Vice Chair Committee to Review NASA’s Evidence Reports on Human Health Risks PREPUBLICATION COPY: UNCORRECTED PROOFS

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This is the fifth, and final, in a series of letter reports that provide an independent review of the more than 30 evidence reports that NASA has compiled on human health risks for long-duration and exploration spaceflights. This letter report reviews five evidence reports and examines the quality of the evidence, analysis, and overall construction of each report; identifies existing gaps in report content; and provides suggestions for additional sources of expert input.

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