Space and Man

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Is an appendix essential ‘expeditionary kit’? Benivolem aut insidiator? Dr Rowena Christiansen for the Graduate Certificate in Space Studies (20 June 2016)

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The Context: Expeditionary Medicine

‘From the far corners of the Earth to the stars’ Slide 2

The ISS and Earth Analogs • The ISS

• Antarctica

• Bed Rest Studies

• Human-Related Altitude • Desert RATS Chamber Complex (Research & Technology Studies)

• NEEMO (NASA Extreme Environment Mission Operations)

Slide 3

• Human Exploration Research Analog (HERA)

The appendix: benivolem aut insidiator? • Benivolem: a benevolent friend who cares for us – New knowledge about the function of the appendix: • Supports gut immune function; • Supports gut health; and • Reduces the risk of developing a variety of serious diseases;

OR?? • Insidiator: one who lies in ambush intending us harm • Risk of developing acute appendicitis; • Risk of perforation and abscess; and • Special challenges in remote expeditionary settings.

Slide 4

The first ‘Mind Map’

Slide 5

The current ‘Mind Map’ (novel project)

Slide 6

The current ‘Mind Map’ (novel project) Six key sections: 1. Mission planning, policies and procedures; 2. Prevention and Non-Surgical Prophylaxis; 3. Appendiceal Function and Immune System Factors; 4. Diagnosis of Appendicitis and Operative vs Non-Operative Management; 5. Prophylactic Surgery: Risks and Consequences [Surgical Complications]; and 6. Prophylactic Surgery: Risks and Consequences [Long-term health outcomes]. Slide 7

Section 1: Mission planning, policies and procedures • NASA’s ‘Human Research Roadmap’: – 33 key risks to human health & performance

• • • •

Mission location Human or robotic? Longitudinal planning Risk assessment: – General mission risks – Medical/health risks

Slide 8

• Acute appendicitis not one of them but – prophylactic appendicectomy has been raised as a possible requirement for long-duration spaceflight – Antarctic parallels.

Section 1: Mission planning, policies and procedures • Policies and procedures: – Medical equipment, resources, personnel, training and levels of redundancy;

– Selection of expeditioners;

– Personalised risk assessment (different health risks depending on age and gender). Slide 9

Section 1: Mission planning, policies and procedures • Ethical Issues:

– Can compulsory appendicectomy be justified for employment purposes? – Who pays? Who insures? – What if the expeditioner becomes disabled or dies? – What if the outcome prevents the expeditioner from taking part in the mission or affects future employment prospects? – More about outcomes later … Slide

Section 1: Mission planning, policies and procedures • More questions to be answered … Section 1: Mission planning, policies and procedures. Some issues for future research 1

Approach to detailed risk assessments for both mission and medical events for human spaceflight and remote expeditionary locations such as Antarctica, submarines and oil platforms;

2

The overall statistical risk of adverse events in space/analog environments;

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The risk of medical adverse events in these same settings;

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Review of statistics of appendicitis incidence/prevalence in the general population and space/analog environments, including distribution according to age, gender and ethnicity;

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Whether there is a particular risk profile for appendicitis according to age, gender and/or ethnicity which may be helpful in predicting overall risk for a particular expeditioner (and whether there is any genetic predisposition or a tendency to 'run in families');

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Policies and procedures in place for space/analog environments relevant to the issues covered in the ‘Mind Map’ and those identified by new and emerging research;

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Useful data, publications and ‘lessons learned’ from analog environments;

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Consideration of multiple levels of ‘medical redundancy’ and medical training for expedition personnel;

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Medical equipment and facilities for space/analog environments, including compact and portable diagnostic aids/’apps’;

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Remotely controlled diagnosis and surgery;

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Approach to selection of expeditioners for space/analog environments;

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Personalised risk assessment for expeditioners; and

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Ethical, legal and human rights issues around surgical body modifications as a pre-condition of employment.

(Further consideration of the future research parameters for this section can be found in Appendix A.)

Slide 11

Section 2: Prevention and Non-Surgical Prophylaxis • What do we know about the causes of appendicitis? • Can we predict it? • Can we prevent it? • Is there any helpful prophylaxis against appendicitis, for instance: – – – –

Slide 12

Prebiotics or probiotics; Vitamin D; Particular dietary approaches; or Antibiotics?

Section 2: Prevention and Non-Surgical Prophylaxis • Is there any helpful prophylaxis against appendicitis, for instance: – Vitamin D; – Particular dietary approaches (‘Risk of inadequate nutrition is one of the 33 HRP risks); or – Antibiotics?

Slide 13

Section 2: Prevention and Non-Surgical Prophylaxis • Is there a relationship between the gut microbiome and the risk of developing appendicitis? • What happens to the gut microbiome in extreme environments, and does prophylaxis (as above) help?

Slide 14

Slide 15

Section 2: Prevention and Non-Surgical Prophylaxis • More questions to be answered … Some issues for future research: 14. Whether there are any factors which are helpful for predicting appendicitis; 15. Whether anything is helpful in preventing appendicitis; 1

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16. Whether there is any helpful prophylaxis against appendicitis, for instance prebiotics or probiotics , Vitamin D, particular dietary approaches or antibiotics; 17. Whether these measures result in fewer instances of suspected acute appendicitis; 18. Whether there is any research related to the impact of the gut microbiome on the risk of developing appendicitis; 19. Whether there is any research related to changes in the gut microbiome in extreme environments and whether any such changes can be modulated through the use of prebiotics and/or probiotics; and 20. Whether the use of probiotics together with antibiotics would achieve the dual purpose of prophylaxis against appendicitis and maintaining a healthy gut microbiome. 1

Prebiotics (i.e. non-digestible substrates), from: Butel M-J. Probiotics, gut microbiota and health. Médecine et maladies infectieuses. 2014: 1–8. 2 Probiotics (i.e. live micro-organisms), from Butel, op.cit.

Slide 16

Section 3: Appendiceal Function and Immune System Factors • The “Risk of Adverse Health Event Due to Altered Immune Response” is one of NASA’s 33 key human health and performance’ risks. • Fact: The human immune system does not work as well as normal in extreme environments. • Research findings: Environmental stressors (including those associated with extreme environments) can contribute to the development of inflammatory bowel disease. • Question: Does this also apply to expeditioners living and working in extreme environments? Slide 17

Section 3: Appendiceal Function and Immune System Factors • What does this have to do with the appendix?

• Long thought to be vestigial, or useless, research started back in the mid-1970s is increasingly showing that the appendix is an important part of the gut immune system. Slide 18

Section 3: Appendiceal Function and Immune System Factors

• So where is my appendix?

• What does it do?

Slide 19

Section 3: Appendiceal Function and Immune System Factors

• So what does that mean? – In evolutionary terms appears to have evolved to have a purpose; – Contains stem cells which can repair damage; – Contains infection-fighting immune cells which prevent inflammation and damage to the appendix (especially important for people with compromised immune systems*); and – A reservoir for ‘good bacteria’ to repopulate the gut after infection to repair the microbiome. [*People develop compromised immune systems in extreme environments (and potentially also beforehand during the stress of training).] Slide 20

Section 3: Appendiceal Function and Immune System Factors

• So what does that mean? – In effect a ‘friendly Trojan Horse’ that stands by ready to release an army of ‘good bacteria’ into the gut (via a biofilm ‘slide’).

Slide 21

Section 3: Appendiceal Function and Immune System Factors

• More questions to be answered … Section 3: Appendiceal Function and Immune System Factors. Some issues for ongoing and future research 21

How immune function is compromised in extreme environments;

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The function of the appendix and how it contributes to immune function and gut health;

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Is the presence of a healthy appendix protective in terms of gut health and immune function?;

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Does the immune suppression encountered in extreme environments increase the risk of developing inflammatory bowel disease, especially if this is added to an appendicectomy, and could the presence of a normal appendix potentially be protective?; and

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Do other environmental factors encountered during expeditions in extreme environments increase the risk of developing inflammatory bowel disease, especially if this is added to an appendicectomy, and could the presence of a normal appendix potentially be protective?

(Further consideration of the future research parameters for this section can be found in Appendix A.)

Slide 22

Section 4: Diagnosis of Appendicitis and Operative vs Non-Operative Management • Diagnosis - how we be sure that it is appendicitis? – Good clinical examination: • History of symptoms and signs (including fever, loss of appetite, nausea, classic story of pain starting at umbilicus and moving to the right lower quadrant); • Thorough physical examination; and • Scoring systems and algorithms.

Slide 23

Section 4: Diagnosis of Appendicitis and Operative vs Non-Operative Management • Laboratory tests – These may be limited – Possible access to portable tests

• Imaging: – Ultrasound • May be available in expedition setting e.g., ISS, Antarctica, submarines • Possible access to portable device

– CT scan – MRI scan • These will only be available in health facilities

Slide 24

Section 4: Diagnosis of Appendicitis and Operative vs Non-Operative Management • So what is appendicitis? – Literally, an inflamed appendix!

Slide 25

Section 4: Diagnosis of Appendicitis and Operative vs NonOperative Management • So what can we do about it? – Some cases will resolve spontaneously – Other management options include: Initial treatment of appendicitis

Recurrence of symptoms

With abscess present/developing

Appendicectomy (open or laparoscopic)

More surgery

Percutaneous drainage + antibiotics

Intravenous antibiotics

Appendicectomy (delayed/interval) 1

Percutaneous drainage + antibiotics

Intravenous antibiotics

More antibiotics

Percutaneous drainage + antibiotics

Intravenous antibiotics

More antibiotics

Percutaneous drainage + antibiotics2

1

Di Saverio S, Sibilio A, Giorgini E, Biscardi A, Villani S, Coccolini F, Smerieri N, Pisano M, Ansaloni L, Sartelli M, Catena F, Tugnoli G. The NOTA Study (Non Operative Treatment for Acute Appendicitis) Prospective Study on the Efficacy and Safety of Antibiotics (Amoxicillin and Clavulanic Acid) for Treating Patients With Right Lower Quadrant Abdominal Pain and Long-Term Follow-up of Conservatively Treated Suspected Appendicitis. Ann Surg. 2014; 260: 109–117. 2 Hornez E, Geilief G, Entine F, Ottomani S, Monchal T, Meusnier F, Platel JP, De Carbonnieres H, Thouard H. Is there still a benefit to operate appendiceal abscess on board French nuclear submarines? Military Medicine. 2009: 174(8): 874-5.

Slide 26

Section 4: Diagnosis of Appendicitis and Operative vs Non-Operative Management • What is appendicectomy?

Slide 27

• What about using antibiotics instead – simple, yes?

Section 4: Diagnosis of Appendicitis and Operative vs Non-Operative Management • Well, not actually …

Slide 28

• Wait for spontaneous resolution? (fears re antibiotic resistance) • Accurate diagnosis? • Uncomplicated? • Recurrence – surgery vs more antibiotics? • Abscess management? • Relative costs? • Extreme Environments?

Section 5: Prophylactic Surgery - Risks and Consequences [Surgical Complications] • Back to ethics – risks of harm resulting in death or disability… • Surgery under anaesthetic – postoperative infection, structural damage, haemorrhage, adverse drug reactions, airway compromise, equipment malfunction, and operator error. • Loss of the positive immuno-protective role that the appendix is suspected to play with regard to gut health. Slide 29

Section 5: Prophylactic Surgery - Risks and Consequences [Surgical Complications] • Is there much evidence relating to prophylactic appendicectomy? – Not obviously, but there are a lot of ‘negative’ (3.3% - 37.25% in surveyed research) and ’incidental’ (with other surgery) appendicectomies: – Arguably analogous in absence of a better alternative; – Not much evidence appears to distinguish between types, but one study (Gough et al.) noted lower rates of post-operative infection with a non-inflamed appendix; and – Studies lack consideration of new knowledge about function of appendix. Slide 30

Section 5: Prophylactic Surgery - Risks and Consequences [Surgical Complications] • A 2014 Swedish study by Andersson found that, for open and laparoscopic appendicectomies: – 5.5 to 8.5% of patients will turn out to have a normal appendix; – 5.8 to 6.9% will require readmission within 30 days; – 8.8 to 9.8% will experience some sort of surgical complication; – 1.1 to 1.9% will have some sort of medical complication; and – 3.5 to 3.7% will acquire an infectious complication.

• At first pass, this means 26 to 29.6% of patients will experience some sort of complication (approximately 1:4 to 1:3). • Prophylactic surgery will also carry some risk burden. • Immune suppression (extreme environments) may potentially also play a role. Slide 31

Section 5: Prophylactic Surgery - Risks and Consequences [Surgical Complications] • The range of possible complications is very broad: Operative or post-operative complications [study date and first author]

Misdiagnosis Delay in surgery Post-operative fever Bleeding/Hemorrhagic complication/Wound hematoma Acute GI ulcer or upper/lower GI bleed pRBC transfusion Cardiovascular complication Chest pain Atrial fibrillation Myocardial infarction Cardiac arrest Syncope Wound infection/Superficial surgical site infection (SSI) Wound rupture/early hernia Leakage of appendicle stump Intra-abdominal infection/abscess Bowel perforation Accidental cut, puncture, perforation, laceration or hemorrhage Bowel obstruction Ileus (no resumption of diet within 5 days) Pulmonary/venous embolus/DVT Pulmonary edema/ Acute respiratory distress syndrome Pneumonia Urinary tract infection Renal insufficiency/failure Hypo/hyperkalemia Macrohematuria Elevated liver enzymes Septicemia/septic shock Bacteremia Other infections Nausea, vomiting, diarrhea /Acute gastroenteritis (upper/lower) Reintubation/Ventilator (>48 hours) Drug hypersensitivity reaction Extra pyramidal symptoms/Leg hypoesthesia Readmission Reoperation/ Reopening surgical site Death/mortality

Kotaluoto 1 (2016)

Svensson 2 (2016)

Tashiro 3 (2016)

van Rossem 4 (2016)

Chen 5 (2015)

Fair 6 (2015)

Sadot 7 (2013)

X X X

X X

X X X

X X X X X X

X X X X X X X

X

X

X

X

X

X

X X X

X X

X

X X X

X

X

X/X

X X

X X X

X X X/X

X

X/X

X X X X/X X X X X X X X

X X/X/X X/X

X X X

X X

X X X

X

X X

X X/X X X X

Table 12: Tabulation of Operative and Post-Operative Complications.

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Kotaluoto et al., op. cit. Svensson JF, Patkova B, Almström M, Eaton S, Wester T. Outcome after introduction of laparoscopic appendectomy in children: A cohort study. J Pediatr Surg. 2016; 51: 449–453. 3 Tashiro J, Einstein SA, Perez EA, Bronson SN, Lasko DS, Sola JE. Hospital preference of laparoscopic versus open appendectomy: Effects on outcomes in simple and complicated appendicitis. J Pediatr Surg. 2016 (in press) http://dx.doi.org/10.1016/j.jpedsurg.2016.02.028. 4 van Rossem, op.cit. 5 Chen C-C, Ting C-T, Tsai M-J, Hsu W-C, Chen P-C, Lee M-D, Liu M-H, Shih H-C. Appendectomy timing: Will delayed surgery increase the complications? Journal of the Chinese Medical Association 2015; 78: 395-399. 6 Fair BA, Kubasiak JC, Janssen I, Myers JA, Millikan KW, Deziel DJ, Luu MB. The impact of operative timing on outcomes of appendicitis: a National Surgical Quality Improvement Project analysis. The American Journal of Surgery. 2015; 209: 498-502.

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Slide 32

Section 5: Prophylactic Surgery - Risks and Consequences [Surgical Complications] • Complications are often immediate or short-term, but can also linger into the medium or long-term (death being the ‘worst-case’ scenario). • These complications can have lifestyle and employment implications. • Example: Post-operative wound infections are common and can be severe:

Slide 33

Section 5: Prophylactic Surgery - Risks and Consequences [Surgical Complications] • More questions to be answered … Section 5: Prophylactic Surgery: Risks and Consequences [Surgical Complications]. Some issues for ongoing and future research

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Surgical complications (statistical risk and temporal/patient-related profiles) associated with appendicectomy generally, such as anaesthetic complications, infection, haemorrhage, gut perforation, death or disability;

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Surgical complications (statistical risk and profiles) associated with a ‘negative appendicectomy’ where a macroscopically/histologically normal appendix is removed;

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Surgical complications (statistical risk and profiles) associated with incidental/prophylactic appendicectomy;

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Surgical complications (statistical risk and profiles) associated with appendicectomies carried out on expeditioners in extreme environments;

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Effects of pre-deployment training on expeditioner immune function;

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Effect of immune dysregulation on complication rate;

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Case studies relating to such complications in the astronaut or expeditioner populations;

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Availability of a standard data set for reporting of appendicectomy complications;

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Availability of any meta-analyses of appendicectomy complications.

(Further consideration of the future research parameters for this section can be found in Appendix A.)

Slide 34

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • Even with an apparent full recovery from surgery, still ongoing (statistically-based) risks associated with an appendicectomy: – Fibrous adhesions often develop inside the abdomen as a result of surgery (Ellis – 93%); so – Ongoing risk of developing a small bowel obstruction. – Andersson re adhesions and SBO: • Risk highest in short to medium-term; and • Enduring risk 1.45% at 15 years and 1.3% at 30 years.

– Could have implications for prophylactic surgery timing in expeditioners. Slide 35

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • What do adhesions look like?

Slide 36

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • Adhesion risk will be of concern to mission planners • Case study - astronaut Chris Hadfield: – Childhood appendectomy age 11; • Severe pain and intestinal blockage in 1990; • Abdominal pain in 2011 – laparoscopic surgery revealed a 4cm adhesion (repaired);

– While training for ISS Expedition 35, NASA doctors worried about complications of laparoscopic procedure and wanted further exploratory surgery; – Hadfield refused as felt unnecessary and risky; – Impasse eventually resolved through ultrasound examination (normal).

Slide 37

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • Increased risk of other long-term health outcomes:

Long-term effects of appendicectomy [study date and first author] Adverse

Increased risk

May result in increased risk

Adhesions (small bowel obstructions) 1 [2014 Andersson , 2 2012 Ouaïssi , 2001 Andersson*3, 1997 4 Ellis ]

Clostridium difficile infection severity/recurrence 5 6 7 risk [2015 Yong , 2013 Clanton , 2011 Im ]

Breast cancer (Females) [1975 8 Lee ]

Adult Still's Disease [1996 Sampalis ]

Crohn's Disease [2016 Perone , 2008 Kaplan , 2007 Kaplan*20, 2004 Loftus21, 2003 Andersson22]

Chronic lymphocytic leukaemia 23 (CLL) [1988 Linet ]

Clostridium difficile infection 24 severity/recurrence risk [2013 Fujii ]

Hodgkin Lymphoma [2016 Perone]

Colon cancer (Females) [1975 Lee]

Female fertility [1999 Andersson25]

18

19

26

Neutral result

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Protective

9

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Irritable bowel syndrome [2008 Sleator , 2001 27 Reshetnikov ]

Crohn’s Disease [2001 Frisch ]

Hodgkin's Disease [1991 Gledovic ]

Ischaemic heart disease/acute myocardial 30 infarction [2016 Perone, 2015 Chen , 2011 Janszky 31 (surgery under age 20) ]

Hodgkin Lymphoma (surgery under age 20) [2016 Mohammadi32]

Multiple sclerosis [2014 Eftekharian (Iran)], [2011 Roshanisefat34 (Sweden)]

Multiple sclerosis (MS) (if surgery under age 20) 35 [2013 Lunny ]

Hodgkin Lymphoma (Nodular Sclerosis type) [2016 Mohammadi]

Rheumatoid arthritis [1994 Moens , 37 38 1986 Linos , 1983 Patel ]

Myeloma (Males) [2016 Mohammadi]

Ulcerative colitis [2015 Lee (Korea), 2001 Frisch]

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Non-Hodgkin's Lymphoma [2003 Cope ]

Ulcerative colitis [2016 10 Perone, 2016 Sahami , 11 2015 Vcev , 2014 Lai, 2011 Roshanisefat, 2007 de Saussure12, 2005-7 Matsushita 13, 2004 14 15 Danese , 2004 Hallas , 2004 Loftus, 2001 Andersson16, 1997 Russel17]

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36

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Oesophageal adenocarcinoma [2016 Song41] Pulmonary tuberculosis [2014 Lai42] Rheumatoid arthritis [2016 Perone, 1985 43 44 Fernandez-Madrid , 1979 Gottlieb ] Rheumatoid arthritis (Females) [2015 Tzeng45] Right colonic cancer (Females) [1991 Grobost46] Stomach cancer [2003 Cope] Type II Diabetes (new-onset) (surgery under age 47 65) [2015 Wei ] Venous Thromboembolism [2016 Humes48] *Paper specifically mentions a risk profile relating to ‘negative appendicectomy’ (which might be considered as analogous to a ‘prophylactic appendicectomy’).

Slide 38 1

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • Increased risk of other long-term health outcomes:

Slide 39

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • Increased risk of other long-term health outcomes:



Slide 40

Venous thromboembolism

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • Not just one but many serious diseases with an increased risk after appendicectomy; • Implications not just for expedition medicine but also medical practice generally; • Some risks can manifest quite early after surgery (e.g., Chen et al. – 3 years for ischaemic heart disease), which could have employment continuity implications; • Could also be relevant for settling another celestial body where facilities to treat and manage serious chronic diseases will be limited; • Chen et al. suggest: “… this underscores the need for more serious clinical decision-making in removing the appendix. Regular monitoring for IHD is also recommended for patients who have undergone an appendectomy”. Slide 41

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • More questions to be answered … Section 6: Prophylactic Surgery: Risks and Consequences [Long-Term Health Outcomes]. Some issues for ongoing and future research

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Long-term sequelae (or complications) associated with appendicectomy (statistical risk and profile), such as deficit in gut immune function/gut health, adhesions, and an increased risk of specific/serious diseases;

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Any data pertaining to a risk profile for long-term consequences associated with ‘negative appendicectomy’;

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Any data pertaining to a risk profile for long-term consequences associated with ‘incidental appendicectomy’;

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Any data pertaining to a risk profile for long-term consequences associated with ‘prophylactic appendicectomy’;

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Any data pertaining to a compounding effect of exposure to extreme environments and adverse long-term health outcomes associated with appendicectomy;

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Any studies considering strategies to ameliorate the risk of adverse long-term health outcomes associated with appendicectomy, e.g., prebiotics or probiotics;

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Case studies or research papers relating to such long-term consequences in the astronaut or expeditioner populations;

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Any cost-benefit analyses looking at the relative cost of providing non-operative management of appendicitis as against the long-term cost of managing a serious chronic health condition; and

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Availability of any meta-analyses of risks of adverse long-term health outcomes associated with appendicectomy.

(Further consideration of the future research parameters for this section can be found in Appendix A.)

Slide 42

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • In conclusion: – A complex issue, and the risk-benefit profile is likely to be different in different circumstances; – Important considerations include: • New knowledge about a beneficial function for the appendix; • A range of treatment modalities to consider; • The risk of complications related to surgery; and • Emerging research about the risk of long-term health consequences from appendicectomy.

– There are implications not only for expedition medicine, but also for medical practice generally and for health economics, e.g., maybe less surgery = less chronic disease. Slide 43

Section 5: Prophylactic Surgery - Risks and Consequences [Long-term health outcomes] • Benivolem aut insidiator? There is certainly an increasing body of evidence to suggest that, as a general rule, the appendix does us more good than harm. • Perhaps it is possible to dream of a ‘paradigm change’ where, when appendicitis is suspected, we first reach for the antibiotics rather than the scalpel. “I can’t believe that!” said Alice. “Can’t you?” the Queen said in a pitying tone. “Try again: draw a long breath, and shut your eyes.” Alice laughed. “There’s no use trying” she said: “one can’t believe impossible things.” “I daresay you haven’t had much practice,” said the Queen. “When I was your age, I always did it for half-an-hour a day. Why, sometimes I’ve believed as many as six impossible things before breakfast.” Slide 44

References (further sources in Paper and Appendix B) • •

Microsoft Publisher Clip Art used throughout the presentation. Cover page: –



Slide 3: – – – –







14. Good and bad bacteria 1&2: http://www.freegrab.net/Gut-health%20good-bad.jpg [Accessed 17.06.2016]

Slide 15: – –

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12. Vitamin D: http://dconheels.com/wp-content/uploads/2013/04/vitamind550.jpg [Accessed 17.06.2016] 13. Vitamin D capsules: http://www.medicalnewstoday.com/articles/161618.php?page=2 [Accessed 17.06.2016]

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10. Ethics 1: https://www.asme.org/getmedia/700e0777-13ad-486d-ba10-0b1437597280/Embedding_Ethics_in_Engineering_Education-hero.jpg.aspx [Accessed 17.06.2016] 11. Ethics 2: http://m.c.lnkd.licdn.com/mpr/mpr/p/6/005/06f/2fe/1266653.jpg [Accessed 17.06.2016]

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7. Medical kit: http://www.oceanmedix.com/oceanmedix/html/Cruiser%20Kit%20-%20open.jpg [Accessed 17.06.2016] 8. Medical training: http://medicalcareerspecialist.com/wp-content/uploads/2015/03/Health.jpg [Accessed 17.06.2016] 9. Selection: http://www.usaswimming.org/_Rainbow/images/_SafeSport/BackgroundScreenGraphic.png [Accessed 17.06.2016]

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6. Highwayman: https://d24g2nq85gnwal.cloudfront.net/images/authors/civil.jpg [Accessed 17.06.2016]

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1. Finding Nemo: http://ecx.images-amazon.com/images/I/816EM11hxGL._SL1090_.jpg [Accessed 17.06.2016] 2. ISS (external): https://upload.wikimedia.org/wikipedia/commons/8/81/STS132_undocking_iss2.jpg [Accessed 17.06.2016] 3. ISS (internal): http://pindex.com/uploads/post_images/original/image_5629.jpg [Accessed 17.06.2016] 4. Starship Enterprise: http://2.bp.blogspot.com/fcrqWicqwMY/UialEovw0KI/AAAAAAAARq0/FVxcnJQjOiE/s1600/Screen+UFO,+UFOs,+sighting,+sightings,+alien,+aliens,+NASA,+Aurora,+Borealis,+orb,+orbs,+ paranormal,+Justin+Bieber,+Selena+Gomez,+news,+space,+top+secret,+gossip,+sept,+2013,++Shot+2013-09-04+at+9.49.54+AM.png [Accessed 17.06.2016] 5. NASA’s Earth analogs: NASA Human Research Program (HRP). Working with HRP/Roadmap/Data Archive. Available from: http://www.nasa.gov/hrp/research [Accessed 24.05.2016]

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Aurora and mountains: http://thewowstyle.com/56-incredibly-beautiful-travel-pictures/; http://www.nasa.gov/image-feature/stargazing-from-theinternational-space-station; and Earth and Moon: http://www.nasa.gov/sites/default/files/thumbnails/image/3-as08-14-2383a.jpg [All accessed 14 June 2016]

15. Gut microbiome: http://foodcompass.co.nz/wp-content/uploads/2016/02/difference-between-prebiotics-and-probiotics-683x1024.jpg [Accessed 17.06.2016] 16: Probiotics: https://static2.stuff.co.nz/1354142237/173/8014173.jpg [Accessed 17.06.2016]

References (further sources in Paper and Appendix B) •

Slide 18: –



Slide 19: – – – – –





Gough IR, Morris MI, Pertnikovs EI, Murray MR, Smith MB, Bestmann MS. Consequences of removal of a "normal" appendix. Med J Aust. 1983 Apr 16; 1(8): 370-2.

Slide 31: –

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31. Appendicectomy: http://s.hswstatic.com/gif/appendix-4.jpg [Accessed 17.06.2016] 32. Antibiotics: http://cdn.kevinmd.com/blog/wp-content/uploads/shutterstock_280962767.jpg [Accessed 17.06.2016]

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28. Inflamed appendix: https://captainmaybe.files.wordpress.com/2011/07/appendectomy-photo-2.jpg [Accessed 17.06.2016] 29. Appendicitis model: http://www.dallasnews.com/lifestyles/health-and-fitness/health/20150606-antibiotics-work-for-appendicitis-study-finds.ece [Accessed 17.06.2016] 30. Appendicitis drawing: https://www.nlm.nih.gov/medlineplus/images/appendicitis.jpg [Accessed 17.06.2016]

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26. Ultrasound: https://i.ytimg.com/vi/JWpnT9hjBow/maxresdefault.jpg [Accessed 17.06.2016] 27. Normal ultrasound: http://image.slidesharecdn.com/appendicitis-131108053533-phpapp02/95/imaging-in-appendicitis-24-638.jpg?cb=1383932143 [Accessed 17.06.2016]

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23. Trojan Horse: http://www.apser.es/wp-content/uploads/2015/09/Captura-de-pantalla-2015-09-23-a-las-10.36.03.png [Accessed 17.06.2016] 24. Reservoir for good bacteria: http://www.nytimes.com/2007/12/09/magazine/09_4_appendix.html?_r=0 [Accessed 17.06.2016] 25. Biofilm: https://www.biofilm.montana.edu/resources/images/biofilm-control-strategies/microbial-biofilms-sticking-together-success.html [Accessed 17.06.2016]

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18. Location of appendix: http://www.buzzle.com/img/articleImages/310730-6231-12.jpg [Accessed 17.06.2016] 19. Realistic appendix: http://f.tqn.com/y/evolution/1/S/v/3/-/-/87310641.jpg [Accessed 17.06.2016] 20. Lymphatic histology: http://image.slidesharecdn.com/021609-mvelkey-lymphaticsystemhistology-110716171830-phpapp01/95/021609-lymphatichistology-26-728.jpg?cb=1310836925 [Accessed 17.06.2016] 21. Immune cells: https://s-media-cache-ak0.pinimg.com/236x/8a/06/21/8a062117fa6988b1b2a0dff568005312.jpg[Accessed 17.06.2016] 22. Immune cells (strip): http://www.wehi.edu.au/sites/default/files/Illuminate-newsletter-122015-h_10.jpg [Accessed 17.06.2016]

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17. Appendix cartoons: http://www.allspeciesfitness.com/2014/07/appendix-aesthetics.html [Accessed 17.06.2016]

Andersson RE. Short-term complications and long-term morbidity of laparoscopic and open appendicectomy in a national cohort. BJS. 2014; 101: 1135–1142.

References (further sources in Paper and Appendix B) •

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39. Chris Hadfield suited up: http://www.macleans.ca/wp-content/uploads/2013/05/MAC21_HADFIELD07.jpg [Accessed 17.06.2016] 40. Chris Hadfield with guitar: https://i.ytimg.com/vi/TJIZlAehgJY/maxresdefault.jpg [Accessed 17.06.2016] 41. Chris Hadfield ‘Space Oddity’: http://dailysoundtrack.s3.amazonaws.com/wp-content/uploads/2013/10/chris-hadfield-space-oddity.jpg [Accessed 17.06.2016]

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35. Pathophysiology of SBO: http://image.slidesharecdn.com/pathopysiologyofofintestinalobstruction-130405054615-phpapp02/95/pathopyshiology-ofintestinal-obstruction-chirantan-mandal-medical-college-kolkata-15-638.jpg?cb=1365140844 [Accessed 17.06.2016] 36. Adhesions to abdominal wall: http://verwachsungen.de/db/img/adhesions/examples/11_2.jpg [Accessed 17.06.2016] 37. Single adhesion: http://library.med.utah.edu/WebPath/jpeg4/GI030.jpg [Accessed 17.06.2016] 38. Twisted adhesions: http://ee_ce_img.s3.amazonaws.com/cache/ce_img/media/remote/ce_img/https_ee_channel_images.s3.amazonaws.com/articlefigures/13955/article-g03_400_299.jpg [Accessed 17.06.2016]

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33. Wound infection: https://captainmaybe.files.wordpress.com/2011/07/appendectomy-photo-3.jpg [Accessed 17.06.2016] 34. Pyoderma gangrenosum: http://www.jpgmonline.com/article.asp?issn=0022-3859;year=2015;volume=61;issue=1;spage=42;epage=43;aulast=Faghihi [Accessed 17.06.2016] Slide 34: Ellis H. The clinical significance of adhesions: focus on intestinal obstruction. Eur J Surg Suppl. 1997; (577):5-9. Andersson RE. Short-term complications and long-term morbidity of laparoscopic and open appendicectomy in a national cohort. BJS. 2014; 101: 1135–1142. Andersson RE. Small bowel obstruction after appendicectomy. Br J Surg. 2001 Oct; 88(10):1387-91.

42. Crohn’s Disease and Ulcerative Colitis: http://qsota.com/wp-content/uploads/2015/03/Crohns-disease-causes-symptoms-and-treatment.jpg [Accessed 17.06.2016] 43. Crohn’s Disease: https://i.ytimg.com/vi/k0kRSF80PJ0/maxresdefault.jpg [Accessed 17.06.2016] 44. Inflammatory Bowel Disease: http://info.dhcla.com/Portals/219289/images/inflammatory%20bowel%20disease%20crohn's%20and%20ulcerative%20colitis.jpg [Accessed 17.06.2016] 45. NHL 1 & 2: https://s-media-cache-ak0.pinimg.com/736x/9b/11/98/9b11983fb97411ee804731087e96c8de.jpg, http://www.cancer.gov/images/cdr/live/CDR629626.jpg [Accessed 17.06.2016] 46. Angina: http://www.epainassist.com/images/Article-Images/Irritable-Bowel-Syndrome-final.jpg [Accessed 17.06.2016] 47. C. difficile: http://img.medicalxpress.com/newman/gfx/news/hires/2015/stalkingawil.jpg [Accessed 17.06.2016] 48. Hodgkin’s Lymphoma: http://images.slideplayer.com/9/2495581/slides/slide_4.jpg [Accessed 17.06.2016] 49. C. difficile: http://image.slidesharecdn.com/cdiffpresentation2013-140919090338-phpapp02/95/clostridium-difficile-c-diff-is-more-difficult-than-everpresentation-by-j-thomas-lamont-md-harvard-medical-school-2-638.jpg?cb=1411118725 [Accessed 17.06.2016]

References (further sources in Paper and Appendix B) •

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Chen CH, Tsai MC, Lin HC, Lee HC, Lee CZ, Chung SD. Appendectomy increased the risk of ischemic heart disease.

J Surg Res. 2015 Dec; 199 (2):435-40.

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50. Multiple Sclerosis: https://upload.wikimedia.org/wikipedia/commons/2/2a/Multiple_Sclerosis.png [Accessed 17.06.2016] 51. TB 1 & 2: http://img2.tfd.com/mk/T/X2604-T-50.png, http://image.slidesharecdn.com/59701bd9-4950-4ae1-b971-977f553b5c95-150609062444-lva1app6892/95/pulmonary-tuberculosis-14-638.jpg?cb=1433831208 [Accessed 17.06.2016] 52. Type 2 Diabetes 1 & 2: http://www.aboutthemcat.org/images/biology/type-2-diabetes.png, http://img.medscape.com/slide/migrated/editorial/cmecircle/2006/5523/images/dagogo-jack/slide004.gif [Accessed 17.06.2016] 53. Rheumatoid Arthritis: http://www.physio-pedia.com/images/d/d5/RA_stages.png [Accessed 17.06.2016] 54. Irritable Bowel Syndrome: http://www.epainassist.com/images/Article-Images/Irritable-Bowel-Syndrome-final.jpg [Accessed 17.06.2016]

55. Alice ‘Through the Looking Glass’: https://www.opendemocracy.net/conspiracy/suspect-science/stephan-lewandowsky/alice-through-looking-glassmechanics-rejection-of-climate-science

Elements

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