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Pain, psychological distress and deteriorated family economy follow traumatic amputation among war casualties in Gaza ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-029892

Article Type: Research

Date Submitted by the 19-Feb-2019 Author:

Complete List of Authors: Heszlein-Lossius, Hanne; The Arctic University of , Tromsø, Norway, Institute of Clinical Medicine Al-Borno, Yahya; Al-Shifa Hospital Shaqqoura, Samar; Al-Shifa Hospital Skaik, Nashwa; Al-Shifa Hospital Giil, Lasse; Haraldsplass Diakonale Sykehus AS Gilbert, Mads; The Arctic University of Norway, Tromsø, Norway, Clinic of Emergency Medicine

ACCIDENT & EMERGENCY MEDICINE, ETHICS (see Medical Ethics), Keywords: Health & safety < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, INTENSIVE & CRITICAL CARE http://bmjopen.bmj.com/

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1 2 3 Pain, psychological distress and deteriorated family economy follow traumatic 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 amputation among war casualties in Gaza 6 7 8 Hanne Heszlein-Lossius, MD1*, Yahya Al-Borno, MD2, Samar Shaqqoura MD2, Nashwa Skaik, MD2, Lasse 9 Melvaer Giil, MD3, Mads Gilbert, MD, PhD 1,4 10 11 12 13 1 The Anaesthesia and Critical Care Research Group, Institute of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway 14 15 2 Al-Shifa Medical Centre, Gaza Strip, occupied Palestinian territory 16 3 Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway 17 18 4 Clinic of Emergency Medicine,For University peer Hospital of North review Norway, Tromsø, Norway only 19 20 21 22 *Corresponding author 23 Hanne Heszlein-Lossius 24 25 UiT The Arctic University of Norway 26 Tromsø, Norway 27 E-mail: [email protected] 28 29 30 31 32 Keywords: amputees; Gaza; GHQ-12; poverty; Israel; military incursion; Palestine; rehabilitation; trauma; 33 unemployment, global health 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 ABSTRACT 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 Objectives: The aim of this study was to explore determinants of psychosocial distress and 7 8 pain in patients who have survived severe extremity amputation in Gaza. 9 10 11 Setting: This study was conducted in a secondary care rehabilitation center in Gaza, 12 13 Palestine. The clinic is Gaza’s sole provider of artificial limbs. 14 15 16 Participants: We included 254 civilian who had survived but lost one or more 17 18 limb(s) during militaryFor incursions peer from 2006-2016. review We included only patients with surgically 19 20 treated amputation injuries who attended physical rehabilitation at a specialist prosthesis 21 22 center in Gaza. Amputees with injuries prior to 2006 or non-military related injuries were 23 excluded. 24 25 We assessed their pain and psychological stress using the General Health Questionnaire 26 27 (GHQ-12). We used income, amputation severity scored by proximity to torso, current 28 employment status, loss of family-members and loss of home as independent variables. 29 30 31 32 Results: The amputees median age was 23 years at the time of trauma, while a median of 4.3 33 34 years had passed from trauma to study inclusion. Nine of ten were male, while 43 were 35 children when they were amputated (17 % ≤ 18 years). One hundred and ninety-one (75 %) 36 http://bmjopen.bmj.com/ 37 were unemployed and 112 (44 %) reported unemployment caused by being amputated. Pain 38 39 was the most frequent complaint, and 80 amputees (32 %) reported to suffer from daily pain. 40 41 Family income was significantly correlated with the physical pain (Odds ratio (OR) = 0.54, CI 42 = 0.36 to 0.80, p= 0.002). Psychological distress was higher among unemployed amputees (β 43 44

0.31, CI 0.07 to 0.54, p = 0.011). We found no association between psychological distress on September 25, 2021 by guest. Protected copyright. 45 46 (GHQ-scores) and the extent of the initial amputation. 47 48 49 Conclusion: Pain and psychological distress following war-related extremity amputation of 50 51 one or more limbs correlated stronger with deteriorated family economy and being 52 53 unemployed than with the anatomical and medical severity of extremity amputations. 54 55 56 57 58 59 60

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 Summary box 7 8 Strengths and limitations of this study 9 10  The use of self-reported reasons for unemployment is a potential weakness in this 11 12 study. 13 14  The lack of longitudinal data also poses limitations. The most recent cases we 15 included were in an early stage of treatment and rehabilitation and would probably be 16 17 more unlikely to be able to work. 18 For peer review only 19  We also have a potential risk of selection bias as some amputees sustained fatal 20 21 injuries while others with minor injuries (like finger/toe amputations) may not have 22 been referred for rehabilitation. 23 24  Strengths of this study include a representative sample of the patients attending 25 26 rehabilitation in Gaza, a response rate of 99 %, the close cooperation with the local 27 28 staff and the conduction of the study in Arabic. 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 BACKGROUND 6 7 War- and armed conflict-related injuries can cause increased mortality, morbidity and 8 disability.1 Poverty resulting from physical war injuries is frequent and further amplifies the 9 10 burden of trauma for victims and families.2 Injuries from wars and conflicts are contributing 11 12 to the global burden of disease and pose important public health problems in particular in low 13 1- 3 14 and middle-income countries (LMIC), such as in Palestine. Increasing numbers of survivors 15 with conflict-related extremity amputations are living in a number of countries, and their 16 17 injuries remain a significant problem to health services following wars.4-5 Limb loss due to 18 For peer review only 19 military attacks is a sudden, brutal life changing event for both amputees and families. As 20 stated by Clasper and colleagues: Traumatic amputations remain one of the most emotionally 21 22 disturbing wounds of conflict. 5 These wounds may be followed not only by pain and loss of 23 24 function, but also decreased chances of being employed with ensuing loss of income and 25 6-7 26 poverty. 27 This study was conducted in the Gaza Strip which has seen four major military incursions 28 29 since 2006 (Operation Summer Rain 2006, Operation Cast Lead 2008-09, Operation Pillar of 30 31 Defense 2012, Operation Protective Edge 2014).8-10 According to the Palestinian Central 32 11 33 Bureau of Statistics (PCBS), 10369 Palestinians have been killed from 2000 to 2016. 34 A shattered local economy, very high unemployment rates and increasing number of 35 36 traumatic injuries from recurrent military attacks on Gaza is aggravated by the siege enforced http://bmjopen.bmj.com/ 37 38 by military blockade since 2007. 39 Loss of income and poverty predicts poor outcomes after trauma-related amputations.6, 12-13 40 41 The negative impact of traumatic life events, such as war, is more severe among the 42 43 Palestinians in Gaza who also have a low family income.14 44 on September 25, 2021 by guest. Protected copyright. 45 Life satisfaction following traumatic limb amputation is closely related both to the ability to 46 return to work and to adequate rehabilitation. 15-16 47 48 We wanted to study the impact of psychosocial factors (income, unemployment) on 49 50 psychological distress and pain in Palestinian patients who had sustained traumatic extremity 51 amputations and were attending rehabilitation in Gaza. 52 53 54 55 56 57 58 59 60

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1 2 3 MATERIAL AND METHODS 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 Study participants 8 We included 254 extremity amputees from Gaza in a cross-sectional study. Inclusion criteria 9 10 were one or several extremity amputations during 2006-2016 due to a military attack and 11 12 being a Palestinian resident above the age of 16 years at the time of inclusion. We screened 13 14 1170 patient records and excluded 915 amputees whose amputations were not related to war 15 or was sustained before 2006. The study was conducted at The Artificial Limb and Polio 16 17 Center (ALPC) in which is the sole place in the Gaza Strip where limb prostheses 18 For peer review only 17 19 are tailored and fitted. 20 We conducted a pilot study from June-Nov in 2014 where the first 90 patients who met the 21 22 inclusion criteria participated. The pilot study response rate was 99 %, and we followed up by 23 24 including all registered patients from ALPC who met the inclusion criteria. 18 The decision to 25 26 use ALPC as a study center had numerous advantages: It is located in central Gaza City, has 27 good facilities with running water and generators supplying electricity during the daily power 28 29 outages. It is a relatively safe place where the researchers and patients could meet without 30 31 travelling to other areas of Gaza during ongoing military incursions. The center provides 32 33 gratis services for the amputation patients, which was an important asset and prevented 34 recruitment of patients from being biased by patients’ financial situation. 35 36 Patients’ medical history was taken the patient filled in a printed questionnaire in Arabic. http://bmjopen.bmj.com/ 37 38 Questionnaires were designed for yes/no or Likert-scale graded answers. Illiterate patients had 39 the questions read out loud in Arabic. We used 12-question General Health Quality survey 40 41 (GHQ-12), a well validated questionnaire to assess mental health.19-20 The questionnaires were 42 43 completed before each included patient underwent a detailed clinical medical examination by 44 on September 25, 2021 by guest. Protected copyright. 45 an experienced physician. 46 47 48 Level of amputation and severity of injury 49 50 We classified the amputations with the commonly used orthopaedic terms: above or below the 51 extremity joints (reference). Every amputation was pictured by hand by the examiner on an 52 53 anatomical sketch in addition to being photographed. The amputations were classified in an 54 55 ordinal scale by an increasing order of severity based on proximity to the torso and number of 56 57 affected limbs. The ordinal scale was as follows: 1 = finger/toes/hands/feet; 2 = below knee or 58 below elbow; 3 = above knee or elbow; and 4 = bilateral amputation or amputation in both 59 60 lower and upper extremities or unilateral amputation at hip-level/shoulder-level

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 Pain 6 7 The patients provided details on the frequency of their pain during an average week. The 8 ordinal scale was as follows: 0= never pain, 1= pain one day a week or less, 2= pain two-three 9 10 days a week, 3= pain four-six days a week, and 4= pain every day. 11 12 13 14 Mental health 15 To assess mental wellbeing, we were advised by local Palestinian psychologists at the Gaza 16 17 Community Mental Health Center (GCMHC) to use the validated questionnaire GHQ-12. The 18 For peer review only 19 questionnaire is a 12-questions screening tool in Arabic commonly used to assess mental 20 distress in the general population in a community. It is self-administrated and easy to 21 22 complete. The Arabic version has been validated for use in Arab-speaking patients, and has 23 24 been used in previous studies in Gaza.19-20 25 26 27 Family income 28 29 We recorded family income from each patient’s self-reported questionnaires which included 30 31 the following alternatives: a total family income per month 0 = less than 700 New Israeli 32 * 33 Shekels (NIS) 1 = 800-1600 NIS 2 = 1700-2500 NIS 3= 2600-3400 NIS, and 4 = more than 34 3500 NIS. 35 36

* (100 NIS= 32 USD) http://bmjopen.bmj.com/ 37 38 39 Employment status 40 41 The self-reported employment status and patients perceived reason(s) for unemployment 42 43 (employed, no available job, student/housewife, unemployed due to injury) were documented. 44 on September 25, 2021 by guest. Protected copyright. 45 46 Ethics, consent and permission 47 48 We chose the ALPC as our local study base in agreement with the local health authorities, the 49 50 board of Gaza`s main hospital, Al-Shifa Hospital (Gaza’s trauma center), and the Director of 51 the ALPC. All patient completed written consent prior to participating. The study was 52 53 approved by the Regional Ethical Committee (approval number: 2016/1265/REK Nord) in 54 55 Norway and the Committee for Helsinki ethics approvals in Gaza. We reimbursed all 56 57 participants’ roundtrip travel expenses to ALPC. 58 59 60 Statistics

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1 2 3 Descriptive statistics are reported as mean and standard deviation (SD) for parametric data, 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 median and interquartile range (IQR) for non-parametric data. We consider a p-value <0·05 6 7 statistically significant. Frequencies are reported as percentage of the total study population 8 for groups and subgroups. Logistic and ordinal regressions were used for multivariate 9 10 analysis. Scoring methods for GHQ-12 were bi-modal (0-0-1-1). 11 12 Data analysis is conducted in SPSS Statistics version 22.0 (SPSS Inc., Chicago, IL, USA) and 13 14 STATA 15 (StataCorp. 2015. Stata Statistical Software: Release 15. College Station, TX: 15 StataCorp LP). 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 RESULTS 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 Patient demographics 8 Two-hundred and fifty-four patients participated in the study. Most of them were males in 9 10 their 20-ies, all Palestinians from Gaza. All participants were registered as patient at the 11 12 ALPC and had sustained one or more traumatic extremity amputations. Nearly nine of ten 13 14 patients had major amputations (n= 216, with 85 % above wrist or ankle). Seventeen percent 15 (n=43) had been hit and sustained amputation(s) during childhood (aged 18 years or younger, 16 17 Seventy-five percent (191) of the amputees were unemployed at the time of inclusion in the 18 For peer review only 19 study. 20 Thirty per cent of the amputees (76/254) were surviving on less than 700 New Israeli Shekel 21 22 monthly at the time of inclusion. 23 24 Table 1 summarizes the patient characteristics. 25 26 27 Psychological distress and unemployment 28 29 Among the 191 (75 %) unemployed patients, 112 (44 %) reported that their unemployment 30 31 was a direct result of the amputation injury. More than half of the amputees (55 %, n=135) 32 33 had GHQ-scores above the cut-off of 3 points indicative of psychological distress. Also, we 34 found psychological distress to be higher among amputees who considered themselves 35 36 unemployed due to the injury http://bmjopen.bmj.com/ 37 38 (β= 0.31, CI =0.07 to 0.54, p=0.011), bud we did not find any association between the level of 39 extremity amputation and level of psychological distress (GHQ-scores) (Table 2). 40 41 42 43 Pain and poverty 44 on September 25, 2021 by guest. Protected copyright. 45 Every third amputee (n=80, 32%) studied reported that they suffered from daily pain. 46 The frequency of physical pain correlated with low family income, also when adjusted for the 47 48 severity of the injury (OR= 0.54, CI = 0.36 to 0.80, p= 0.002, see Table 3 and Figure 1). 49 50 51 Psychological distress and pain 52 53 The frequency of pain was significantly associated with the level of psychological distress 54 55 (GHQ) among the participants. GHQ 12 scores increased among patients with frequent pain 56 57 (β= 0.30, CI = 0.12 to 0.49, p = 0.002). Also, self-reported pain increased among patients with 58 higher levels of psychological distress (OR = 2.40, CI= 1.48 to 3.39, p= 0.000). 59 60

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1 2 3 DISCUSSION 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 More than half of the traumatic amputees in this cross-sectional study from Gaza’s main 6 7 rehabilitation clinic reported psychological distress with GHQ-12 scores above the cut-off. 8 Psychological distress was clearly associated with financial deterioration following their loss 9 10 of work due to their extremity amputations. The frequency of pain was also higher among the 11 12 poorest patients, and increased with decreasing family income. On the other hand, the 13 14 anatomical extent and severity of the initial physical amputation trauma did not affect GHQ- 15 scores or the frequency of pain experienced by the amputees. 16 17 Unemployment due to injury and mental distress 18 For peer review only 19 The psychological distress increased significantly among the amputees who were unable to 20 21 continue work as a result of their limb loss. This finding is supported by WHOs previous 22 21 23 findings in Gaza, where GHQ-levels were higher among unemployed. 24 Three out of four patients in this study were unemployed. Close to half of them reported that 25 26 they currently were unemployed as a consequence of their physical disabilities caused by the 27 28 loss of limb(s). Unemployment was a major risk factor for depression and anxiety in 29 Jordanian amputees. 22 The long-term outcomes in 146 traumatic amputees in USA, showed 30 31 that 75 % had sustained change in occupation after amputation with more than half reporting 32 33 to be less paid in their new positions. 23 34 35 The unemployment among local Palestinian documented in our study is adding up to an 36 already exceptionally high unemployment rate in Gaza, reaching 43·6 % in 2018. 24-25 The http://bmjopen.bmj.com/ 37 38 increased poverty that followed after severe extremity amputation injury in this cohort of 39 40 amputees in Gaza, appears to be more important for psychological well-being than the extent 41 42 of the amputation. 43 44 Pain and low family income on September 25, 2021 by guest. Protected copyright. 45 46 We also found that low family income was the main predictor to determine how often the 47 48 amputees experienced pain. The frequency of pain increased among amputees who lived in 49 families with low income. Surprisingly, neither pain nor psychological distress were affected 50 51 by the extent of the initial physical trauma. Our findings are supported by the conclusion in 52 53 the study by Husum and colleagues on chronic pain in land mine accident survivors in 54 Cambodia and Kurdistan, where patient-related loss of income correlated with the rate of 55 56 chronic pain syndrome.7 Ferguson and colleagues studied the psychological adjustment after 57 58 amputation in landmine victims and found that the amputees recovery and acceptance of limb 59 26 60 loss were dependent on the patients economic situation. In the context of living with

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1 2 3 disabilities in a society where siege, occupation and recurrent military attacks are part of 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 everyday life, it is also important to acknowledge the effects of fundamental psychosocial 6 7 determinants of pain and psychological distress. 8 9 The most important factor to improve mental health among civilians in Gaza, is end the 10 27 11 occupation. 12 13 Social suffering such as unemployment and poverty are effects of the long-lasting siege of 14 Gaza which adds burdens to the lives of the amputees and their families. To ameliorate the 15 16 needs of the population of amputees, these issues requires a shift in the emphasis from narrow 17 18 medical indicators, Forinjury and peer illness to thereview lack of human securityonly and human rights 19 28 20 violations experienced by ordinary Palestinians. 21 22 23 24 25 Limitations and strengths 26 27 The use of self-reported reasons for unemployment is a potential weakness in this study. 28 29 The lack of longitudinal data also poses limitations. The most recent cases we included were 30 in an early stage of treatment and rehabilitation and would probably be more unlikely to be 31 32 able to work. We also have a potential risk of selection bias as some amputees sustained fatal 33 34 injuries while others with minor injuries (like finger/toe amputations) may not have been 35 referred for rehabilitation. However, due to the ongoing conflict, the lack of infrastructure and 36 http://bmjopen.bmj.com/ 37 sometimes incomplete medical records, it would be close to impossible to obtain a completely 38 39 representative set of data from the whole population of amputees. 40 41 Strengths of this study include a representative sample of the patients attending rehabilitation 42 at ALPC with a response rate of 99 %, the close cooperation with the local staff and the 43 44 conduction of the study in Arabic. on September 25, 2021 by guest. Protected copyright. 45 46 47 48 INTERPRETATION 49 More physical pain and decreased mental wellbeing correlated significantly with the more 50 51 unemployment and less family income (poverty) following traumatic extremity amputations 52 53 among Palestinians in Gaza. Poverty and unemployment after traumatic amputations and 54 disability are heavy, extra burdens adding to the trauma of the physical extremity amputation 55 56 itself. 57 58 59 60

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 DECLERATIONS 6 7 8 Ethics, consent and permission 9 10 All patient completed written consent prior to participating. The study was approved by the 11 12 Regional Ethical Committee (approval number: 2016/1265/REK Nord) in Norway and the 13 14 Committee for Helsinki ethics approvals in Gaza. 15 16 17 Consent to publish 18 For peer review only 19 Not applicable. 20 21 22 Availability of data and materials 23 24 The datasets used during the current study are not publically available as the authors did not 25 26 apply any ethical committees for the permission to share the data. In this particular context, 27 sharing of data could raise safety concerns for the participants in the study and thus 28 29 considered unethical. 30 31 32 33 Patients and Public Involvement 34 This research was done without patient involvement. Patients were not invited to comment 35 36 on the study design and were not consulted to develop patient relevant outcomes or interpret http://bmjopen.bmj.com/ 37 38 the results. Patients were not invited to contribute to the writing or editing of this document 39 for readability or accuracy. 40 41 42 43 Competing interests 44 on September 25, 2021 by guest. Protected copyright. 45 We declare no competing interests. 46 47 48 Funding 49 50 None. 51 52 53 Acknowledgements 54 55 We would like to thank the patients and their families for their time and efforts, Dr. Ali Watti 56 57 MD, Technical Coordinator of ALPC, Mrs. Neveen Alghussien, Data Entry Officer at ALPC, 58 Foaad Hamed, and the other very professional staff at ALPC for their invaluable 59 60 contributions.

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 Authors' contributions 6 7 Hanne Heszlein-Lossius contributed study design, data collection, data entry, data analysis, 8 interpretation of the results, the primary draft of the manuscript writing, editing the 9 10 manuscript, literature search and final approval of the manuscript. 11 12 13 14 Yahya Al-Borno contributed to study design, patient inclusion, data collection, data transfer, 15 revising the manuscript and final approval of the manuscript. 16 17 18 For peer review only 19 Samar Shaqqoura contributed to study design, patient inclusion, data collection, data transfer, 20 revising the manuscript and final approval of the manuscript. 21 22 23 24 Nashwa Skaik contributed to study design, patient inclusion, data collection, data transfer, 25 26 revising the manuscript and final approval of the manuscript. 27 28 29 Lasse Melvaer Giil contributed to the statistical analysis, interpretation of the results, 30 31 visualization of the data in figures, editing and revising and manuscript, and final approval of 32 33 the manuscript. 34 35 36 Mads Gilbert contributed the original research idea, the study design, interpretation of the http://bmjopen.bmj.com/ 37 38 results, revising and editing the manuscript, and final approval of the manuscript. 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 REFERENCES 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 8 9 10 11 12 13 14 1. M Mosleh, Dalal. K, Yousef Aljeesh et al. 2018 The Burden of war-injury in the Palestinian helath 15 care sector in Gaza Strip. BMC International Health and Human Rights 16 201818:28https://doi.org/10.1186/s12914-018-0165-3((accessed Aug 1 2018).) 17 2. K .Dalal, L. Svanström 2015 Economic Burden of Disability Adjusted Life Years (DALYs) of 18 Injuries. HealthFor, 7, 487-494. peer doi: 10.4236/health.2015.74058((accessed review only Aug 1 2018).) 19 3. C. Murray, G. King, A. Lopez, et al. 2002 Armed Conflict as a Public Health Problem BMJ 324; 20 346–349. http://j.mp/2oThkHL((accessed Aug 1 2018).) 4. C. Krueger, J. Wenke, J. Ficke Ten years at war: Comprehensive analysis of amputation trends. J 21 Trauma acute care surg. Dec 2012;73:438–44 22 5. Clasper, J., & Ramasamy, A. (2013). Traumatic amputations. British journal of pain, 7(2), 67-73. 23 6. Husum H, Resell K, Vorren G, Heng YV, Murad M, Gilbert M, Wisborg T. Chronic pain in land 24 mine accident survivors in Cambodia and Kurdistan. Soc Sci Med. 2002 Nov;55(10):1813-6. 25 7. H. Burger, Č. Marinček (2007) Return to work after lower limb amputation. Disability and 26 Rehabilitation 2007:29(17),1323–1329 27 8. B´tsleem Statistics. https://www.btselem.org/statistics ((accessed Aug 1 2017).) 28 9. United Nations Office for the Coordination of Humanitarian Affairs (OCHA). Key figures on the 29 2014 hostilities. www.ochaopt.org/content/key-figures-2014-hotilities ((accessed Aug 1 2018).) 30 10. United Nations Relief and Work Agency (UNWRA). Emergency appeal progress report July– 31 December 2006. https://www.unwra.org/sites/default/files/2010011814126.pdf ((accessed Aug 1 32 2018).) 33 11. Palestinian Central Bureau of Statistics. Killed Palestinians (Martyrs) in Al-Aqsa Uprising 34 (Intifada), by Year 2000- 2016 http://www.pcbs.gov.ps/Portals/_Rainbow/Documents/Mart_3e- 35 2016.htm ((accessed August 29 2018).) 36 12. Bosse MJ, MacKenzie EJ, Kellam JF, et al. An Analysis of Outcomes of Reconstruction or http://bmjopen.bmj.com/ 37 Amputation after Leg-Threatening Injuries. New England Journal of Medicine 2002; 347(24):1924– 38 31. 39 13. A. Ferguson, B. Richie, M.Gomez Psychological factors after traumatic amputation in landmine 40 survivors: The bridge between physical healing and full recovery. Disability and Rehabilitation 41 2004; 26:14–15, 931–938 42 14. B. El-Khodary, M. Samara. The effect of exposure to war-traumatic events, stressful life events, and 43 other variables on mental health of Palestinian children and adolescents in the 2012 . The 44 Lancet.2018;391,Special issue,S6. on September 25, 2021 by guest. Protected copyright. 45 15. K. Østlie, P. Magnus, O. Skjeldal, et al. Mental health and satisfaction with life among upper limb 46 amputees: a Norwegian population-based survey comparing adult acquired major upper limb 47 amputees with a control group, Disability and Rehabilitation 2011;33:17–18, 1594–1607 16. Z. B. Perkins, H. D. De’Ath, G. Sharp et al. Factors affecting outcome after traumatic limb 48 amputation. British Journal of Surgery 2012; 99:75–86 49 17. M. Abu Arisheh et al. Amputees The challenge faced by Gaza-strip amputees in seeking medical 50 treatment: A report from Gaza 2016. 51 https://reliefweb.int/sites/reliefweb.int/files/resources/Amputees-report-eng.pdf((accessed Oct 1 52 2018).) 53 18. H. Heszlein-Lossius et al. Life after conflict-related amputation trauma: a clinical study from the 54 Gaza Strip.BMC Int Health Hum Rights2018;18:34 55 19. El-Rufaie O, Daradkeh T. Validation of the Arabic versions of the thirty- and twelve-item General 56 Health Questionnaires in primary care patients. Br J Psychiatry 1996;169:662–4. 57 20. Al Hajjar B. Occupational stress among hospital nurses in Gaza-Palestine. 58 https://www.escholar.manchester.ac.uk/uk-ac-man-scw:189872 ((accessed Aug 10 2017).) 59 60

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1 2 3 21. United Nations Gaza Strip health assessment-WHO report 2009: The Question of Palestine. 4 https://www.un.org/unispal/document/gaza-strip-health-assessment-who-report/(accessed Oct 21 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 2018). 6 22. Z.Hawamdeh et al. Assessment of anxiety and depression after lower limb amputation in Jordaninan 7 patients. Neuropsychiatr dis treat. 2008;4:627-633 8 23. Pezzin et al. Outcomes of persons with traumatic amputations. Arch Phys Med Rehabil 9 2000;81:292-300 10 24. The World Bank in West Bank and Gaza. 11 http://www.worldbank.org/en/country/westbankandgaza/overview (accessed 09 September 2017). 12 25. Palestinian Central Bureau of Statistics: International Youth Day 12/08/2017 2017 13 http://www.pcbs.gov.ps/portals/_pcbs/PressRelease/Press_En_10-8-2017-youth-en.pdf (accessed 07 14 March 2018). 15 26. A. Ferguson, B Richie, M.Gomez. Psychological factors after traumatic amputation in landmine survivors: The bridge between physical healing and full recovery. Disability and Rehabilitation 16 2004;26:931–938 17 27. Marie M, Hannigan B, Jones A. Mental health needs and services in the West Bank, Palestine. Int J 18 Ment HealthFor Syst 2016; peer10:23. review only 19 28. Giacaman, R. et al. Mental health, social distress and political oppression: The case of the occupied 20 Palestinian territory. Global public health 2011;6(5)547-559. 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 Table 1. Characteristics of study participants a (N = 254) BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 Demographics Patients (N) Statistics 8 (%) 9 10 11 Palestinian 254 100 12 13 Male 234 92 14 15 Children 43 17 16 17 Female 20 8 18 For peer review only 19 Refugee statusb 154 57 20 21 Age –Inclusion, years 28 [10]* 22 23 24 Age-Injury, years 23 [9]* 25 26 Family income, NIS 27 28 < 700 76 30 29 30 800-1600 105 42 31 32 >1700 50 28 33 34 35 Employment 36 http://bmjopen.bmj.com/ 37 Unemployed 191 75 38 39 Unemployed due to amputation 112 44 40 41 ≥ 3 unemployed family members 152 61 42 43 ≥ 3 persons economically dependent on amputee 160 64 44 on September 25, 2021 by guest. Protected copyright. 45 a Number of participants: 254, from 0-2 % of the participants had missing data on any variable. 46 b Refugee = patient is from a family who has formal UN refugee status as of 1948 47 48 NIS= New Israeli Shekel. 1 NIS equals 0,26 US Dollar. 49 * median and interquartile range, otherwise percentage. 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Table 2. Psychological distress 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 GHQ total score GHQ total score 6 7 8 β 95 % CI P β 95 % CI P 9 10 Unemployment due to trauma 0.308 0.071 to 0.545 0.011 0.329 0.093 to 0.564 0.006 11 12 13 14 Pain 0.306 0.112 to 0.499 0.002 0.320 0.125 to 0.515 0.001 15 16 Severity of injury -0.035 -0.130 to 0.060 0.32 17 18 For peer review only 19 Family income -0.040 -0.216 to 0.135 0.65 20 21 Loss of family members 0.054 -0.208 to 0.317 0.68 22 23 24 25 26 27 Abbreviations: β, regression coefficient beta; CI, confidence interval; GHQ, General Health Questionnaire 28 a Crude model: Logistic regression adjusted for age and gender, with GHQ > 3 points as the dependent variable. 29 b Adjusted model: severity of injury, pain frequency and severity of injury added to the model described in a 30 * p-value < 0.05 31 32 33 34 Table 3. Pain after amputation 35 36 Pain severity Pain severity http://bmjopen.bmj.com/ 37 38 OR 95 % CI P OR 95 % CI P 39 40 41 Family income 0.535 0.359 to 0.797 0.002 0.551 0.346 to 0.876 0.012 42 43 44 Psychological distress 2.395 1.476 to 3.388 0.000 2.386 1.417 to 4.017 0.001 on September 25, 2021 by guest. Protected copyright. 45 46 Severity of injury 0.242 0.257 to 1.408 0.134 47 48 49 Unemployment due to trauma 0.913 0.441 to 1.892 0.808 50 51 Loss of family members 1.489 0.725 to 3.057 0.277 52 53 54 55 56 57 Abbreviations: β, regression coefficient beta; CI, confidence interval. 58 a Crude model: Ordinal logistic regression adjusted for age and gender, with Pain as the dependent variable. 59 b Adjusted model: severity of injury, psychological distress and severity of injury added to the model described 60 in a

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1 2 3 * p-value < 0.05 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Figure 1. Frequency of pain after amputation trauma 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 8 9 10 Number of participants: 249. Five (1,96 % ) participants had missing data. 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 http://bmjopen.bmj.com/ 5 6 7 For peer review only 8 9 10 11 12 on September 25, 2021 by guest. Protected copyright. 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from

Does pain, psychological distress and deteriorated family economy follow traumatic amputation among war casualties? A retrospective, cross-sectional study from Gaza.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-029892.R1

Article Type: Research

Date Submitted by the 15-Apr-2019 Author:

Complete List of Authors: Heszlein-Lossius, Hanne; The Arctic University of Norway, Tromsø, Norway, Institute of Clinical Medicine Al-Borno, Yahya; Al-Shifa Hospital Shaqqoura, Samar; Al-Shifa Hospital Skaik, Nashwa; Al-Shifa Hospital Giil, Lasse; Haraldsplass Diakonale Sykehus AS Gilbert, Mads; The Arctic University of Norway, Tromsø, Norway, Clinic of Emergency Medicine

Primary Subject Global health

Heading: http://bmjopen.bmj.com/

Secondary Subject Heading: Emergency medicine, Global health, Mental health, Surgery

Keywords: GHQ-12, military, amputation, pain, unemployment, Gaza

on September 25, 2021 by guest. Protected copyright.

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1 2 3 Does pain, psychological distress and deteriorated family economy follow traumatic 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 amputation among war casualties? A retrospective, cross-sectional study from Gaza. 6 7 8 Hanne Heszlein-Lossius, MD1*, Yahya Al-Borno, MD2, Samar Shaqqoura MD2, Nashwa Skaik, MD2, Lasse 9 Maelvaer Giil, MD3, Mads Gilbert, MD, PhD 1,4 10 11 12 13 1 The Anaesthesia and Critical Care Research Group, Institute of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway 14 15 2 Al-Shifa Medical Centre, Gaza Strip, occupied Palestinian territory 16 3 Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway 17 18 4 Clinic of Emergency Medicine,For University peer Hospital of North review Norway, Tromsø, Norway only 19 20 21 22 *Corresponding author 23 Hanne Heszlein-Lossius 24 25 UiT The Arctic University of Norway 26 Tromsø, Norway 27 E-mail: [email protected] 28 29 30 31 32 Keywords: amputees; Gaza; GHQ-12; poverty; Israel; military incursion; Palestine; rehabilitation; trauma; 33 unemployment, global health 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 ABSTRACT 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 Objectives: The aim of this study was to explore determinants of psychosocial distress and 7 8 pain in patients who have survived severe extremity amputation in Gaza. 9 10 11 Setting: This study was conducted in a secondary care rehabilitation center in Gaza, 12 13 Palestine. The clinic is Gaza’s sole provider of artificial limbs. 14 15 16 Participants: We included 254 civilian Palestinians who had survived but lost one or more 17 18 limb(s) during militaryFor incursions peer from 2006-2016. review We included only patients with surgically 19 20 treated amputation injuries who attended physical rehabilitation at a specialist prosthesis 21 22 center in Gaza. Amputees with injuries prior to 2006 or non-military related injuries were 23 excluded. 24 25 We assessed their pain and psychological stress using the General Health Questionnaire 26 27 (GHQ-12). We used income, amputation severity scored by proximity to torso, current 28 employment status, loss of family-members and loss of home as independent variables. 29 30 31 32 Results: The amputees median age was 23 years at the time of trauma, while a median of 4.3 33 34 years had passed from trauma to study inclusion. Nine of ten were male, while 43 were 35 children when they were amputated (17 % ≤ 18 years). One hundred and ninety-one (75 %) 36 http://bmjopen.bmj.com/ 37 were unemployed and 112 (44 %) reported unemployment caused by being amputated. Pain 38 39 was the most frequent complaint, and 80 amputees (32 %) reported to suffer from daily pain. 40 41 Family income was significantly correlated with the physical pain (Odds ratio (OR) = 0.54, 42 CI = 0.36 to 0.80, p= 0.002). Psychological distress was higher among unemployed amputees 43 44

(OR= 1,36, CI 1.07 to 1.72, p = 0.011). We found no association between psychological on September 25, 2021 by guest. Protected copyright. 45 46 distress (GHQ-scores) and the extent of the initial amputation. 47 48 49 Conclusion: Pain and psychological distress following war-related extremity amputation of 50 51 one or more limbs correlated stronger with deteriorated family economy and being 52 53 unemployed than with the anatomical and medical severity of extremity amputations. 54 55 56 57 58 59 60

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 Summary box 7 8 Strengths and limitations of this study 9 10  The use of self-reported reasons for unemployment is a potential weakness in this 11 12 study. 13 14  The lack of longitudinal data also poses limitations. The most recent cases we 15 included were in an early stage of treatment and rehabilitation and would probably be 16 17 more unlikely to be able to work. 18 For peer review only 19  We also have a potential risk of selection bias as some amputees sustained fatal 20 21 injuries while others with minor injuries (like finger/toe amputations) may not have 22 been referred for rehabilitation. 23 24  Strengths of this study include a representative sample of the patients attending 25 26 rehabilitation in Gaza, a response rate of 99 %, the close cooperation with the local 27 28 staff and the conduction of the study in Arabic. 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 BACKGROUND 6 7 During the last decade Gaza has experienced four large scale military incursions, leaving 8 thousands of Palestinians injured, disabled and displaced. The number of civilians surviving 9 10 with traumatic war-related amputations are increasing. The traumatic injuries from the 11 12 recurrent military incursions on Gaza are aggravated by a siege enforced by military blockade 13 14 since 2007, a shattered local economy, and high unemployment rates. According to the 15 Palestinian Central Bureau of Statistics (PCBS), 10369 Palestinians have been killed from 16 17 2000 to 2016.1 18 For peer review only 19 Limb loss is associated with a number of secondary conditions, including psychological 20 distress and pain, which may affect the long term outcome for the patients.2 21 22 The risk factors for such complications among traumatic amputees in Gaza are relatively 23 24 unknown, and has to our knowledge, not been studied before. To understand and establish 25 26 knowledge of common complications like pain and psychological distress, and the risk factors 27 for these complications, is important and may result in better outcomes for the amputees in 28 29 Gaza. 30 31 Poverty is known to follow physical war injuries and further amplifies the burden of trauma 32 2 33 for victims and families. The public health problems posed from war and conflict injuries are 34 more common in low and middle-income countries (LMIC), such as Palestine.3-5 35 36 Limb loss due to military attacks is a sudden, brutal life changing event for both amputees and http://bmjopen.bmj.com/ 37 38 families. As stated by Clasper and colleagues: Traumatic amputations remain one of the most 39 emotionally disturbing wounds of conflict.6 These wounds may be followed not only by pain 40 41 and loss of function, but also poverty if the ability to carry on with everyday work is lost,7-8 42 43 and poverty predicts poorer outcomes after trauma-related amputations.7, 9-10 The negative 44 on September 25, 2021 by guest. Protected copyright. 45 impact of traumatic life events, such as war, are more severe among Palestinians in Gaza with 46 a low family income.11 Life satisfaction following traumatic limb amputation is closely related 47 48 both to the ability to return to work and to adequate rehabilitation. 12-13 49 50 51 We wanted to find out whether psychosocial factors (family income, unemployment) were 52 53 significant predictors of the level of psychological distress and of the presence or absence of 54 55 pain in Palestinian patients who had suffered traumatic extremity amputations and were 56 57 attending rehabilitation in Gaza. 58 59 60 MATERIAL AND METHODS

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 Study participants 6 7 This study was conducted in the Gaza Strip which has seen four major military incursions 8 since 2006 (Operation Summer Rain 2006, Operation Cast Lead 2008-09, Operation Pillar of 9 10 Defense 2012, Operation Protective Edge 2014).14-16 11 12 We included 254 extremity civilian amputees from Gaza in a cross-sectional study. Inclusion 13 14 criteria were one or several extremity amputations during 2006-2016 due to a military attack 15 and being a Palestinian resident above the age of 16 years at the time of inclusion. We 16 17 screened 1170 patient records and excluded 915 amputees whose amputations were not 18 For peer review only 19 related to war or was sustained before 2006. The study was conducted at The Artificial Limb 20 and Polio Center (ALPC) in Gaza City which is the sole place in the Gaza Strip where limb 21 22 prostheses are tailored and fitted.17 There were no major differentiation between the patients. 23 24 We conducted a pilot study from June-Nov in 2014 where the first 90 patients who met the 25 26 inclusion criteria participated. The pilot study response rate was 99 %, and we followed up by 27 including all registered patients from ALPC who met the inclusion criteria. This pilot was 28 29 followed by an in-depth descriptive study 18 The decision to use ALPC as a study center had 30 31 numerous advantages: It is located in central Gaza City, has good facilities with running water 32 33 and generators supplying electricity during the daily power outages. It is a relatively safe 34 place where the researchers and patients could meet without travelling to other areas of Gaza 35 36 during ongoing military incursions. The center provides gratis services for the amputation http://bmjopen.bmj.com/ 37 38 patients, which was an important asset and prevented recruitment of patients from being 39 biased by patients’ financial situation. 40 41 Patients’ medical history was taken the patient filled in a printed questionnaire in Arabic. 42 43 Questionnaires were designed for yes/no or Likert-scale graded answers. Illiterate patients had 44 on September 25, 2021 by guest. Protected copyright. 45 the questions read out loud in Arabic. We used 12-question General Health Quality survey 46 (GHQ-12), a well validated questionnaire to assess mental health.19-20 The questionnaires were 47 48 completed before each included patient underwent a detailed clinical medical examination by 49 50 an experienced physician. 51 52 53 Level of amputation and severity of injury 54 55 We classified the amputations with the commonly used orthopaedic terms: above or below the 56 57 extremity joints (reference). Every amputation was pictured by hand by the examiner on an 58 anatomical sketch in addition to being photographed. The amputations were classified in an 59 60 ordinal scale by an increasing order of severity based on proximity to the torso and number of

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1 2 3 affected limbs. The ordinal scale was as follows: 1 = finger/toes/hands/feet; 2 = below knee or 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 below elbow; 3 = above knee or elbow; and 4 = bilateral amputation or amputation in both 6 7 lower and upper extremities or unilateral amputation at hip-level/shoulder-level. Various 8 weapon deliverers had caused the amputations in all cases. 21 9 10 11 12 Pain 13 14 The patients provided details on the frequency of their pain during an average week. The 15 ordinal scale was as follows: 0= never pain, 1= pain one day a week or less, 2= pain two-three 16 17 days a week, 3= pain four-six days a week, and 4= pain every day. 18 For peer review only 19 20 Mental health 21 22 To assess mental wellbeing, we were advised by local Palestinian psychologists at the Gaza 23 24 Community Mental Health Center (GCMHC) to use the validated questionnaire GHQ-12. The 25 26 questionnaire is a 12-questions screening tool in Arabic commonly used to assess mental 27 distress in the general population in a community. It is self-administrated and easy to 28 29 complete. The Arabic version has been validated for use in Arab-speaking patients, and has 30 31 been used in previous studies in Gaza.19-20,22 Scoring methods for GHQ-12 were bi-modal (0- 32 33 0-1-1). We used a cutoff of 3 when we scored the GHQ-scores in accordance with a previous 34 study conducted in Gaza by the World Health Organization (WHO) 22. Cronbach’s alfa was 35 36 0.72 for the GHQ-items 1 through 12. The use of a cut-off value is only relevant if the http://bmjopen.bmj.com/ 37 23 38 investigators are screening for “caseness”, which was our intention in this study . 39 40 41 42 43 Family income 44 on September 25, 2021 by guest. Protected copyright. 45 We recorded family income from each patient’s self-reported questionnaires which included 46 the following alternatives: a total family income per month 0 = less than 700 New Israeli 47 48 Shekels* (NIS) 1 = 800-1600 NIS 2 = 1700-2500 NIS 3= 2600-3400 NIS, and 4 = more than 49 50 3500 NIS. 51 52 * (100 NIS= 32 USD) 53 54 55 Employment status 56 57 The self-reported employment status and patients perceived reason(s) for unemployment 58 (employed, no available job, student/housewife, unemployed due to injury) were documented. 59 60

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1 2 3 Ethics, consent and permission 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 We chose the ALPC as our local study base in agreement with the local health authorities, the 6 7 board of Gaza`s main hospital, Al-Shifa Hospital (Gaza’s trauma center), and the Director of 8 the ALPC. All patient completed written consent prior to participating. The study was 9 10 approved by the Regional Ethical Committee (approval number: 2016/1265/REK Nord) in 11 12 Norway and the Regional Ethics Committee in Gaza, named Helsinki approval, from the local 13 14 Health authorities in Gaza. We reimbursed all participants’ roundtrip travel expenses to 15 ALPC. 16 17 18 For peer review only 19 Statistics 20 Descriptive statistics are reported as mean and standard deviation (SD) for parametric data, 21 22 median and interquartile range (IQR) for non-parametric data. We consider a p-value <0·05 23 24 statistically significant. Frequencies are reported as percentage of the total study population 25 26 for groups and subgroups. Logistic regression was used to assess association with a binary 27 categorization of the GHQ-12 score (bimodal 0-0-1-1), as described by WHO 22. Ordinal 28 29 regressions was used for multivariate analysis with pain, a scale described above of increasing 30 31 pain frequency from 0 till 4, as the outcome. Both models were first assessed with age gender 32 33 and the independent variable of interest, before adjusting for additional variables. 34 Data analysis is conducted in SPSS Statistics version 22.0 (SPSS Inc., Chicago, IL, USA) and 35 36 STATA 15 (StataCorp. 2015. Stata Statistical Software: Release 15. College Station, TX: http://bmjopen.bmj.com/ 37 38 StataCorp LP). 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 RESULTS 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 Patient demographics 8 Two-hundred and fifty-four patients participated in the study. Most of them were males in 9 10 their 20-ies, all Palestinians from Gaza. All participants were registered as patient at the 11 12 ALPC and had sustained one or more traumatic extremity amputations. Nearly nine of ten 13 14 patients had major amputations (n = 216, with 85 % above wrist or ankle). Seventeen percent 15 (n = 43) had been hit and sustained amputation(s) during childhood (aged 18 years or 16 17 younger, Seventy-five percent (191) of the amputees were unemployed at the time of 18 For peer review only 19 inclusion in the study. 20 Thirty per cent of the amputees (76/254) were surviving on less than 700 New Israeli Shekel 21 22 monthly at the time of inclusion. 23 24 Table 1 summarizes the patient characteristics. 25 26 27 Psychological distress and unemployment 28 29 Among the 191 (75 %) unemployed patients, 112 (44 %) reported that their unemployment 30 31 was a direct result of the amputation injury. More than half of the amputees (55 %, n = 135) 32 33 had GHQ-scores above the cut-off of 3 points indicative of psychological distress. 34 We found psychological distress to be higher among amputees who considered themselves 35 36 unemployed due to the injury (OR= 1,36, CI 1.07 to 1.72, p = 0.011). In contrast, we did not http://bmjopen.bmj.com/ 37 38 find any association between the level of extremity amputation and level of psychological 39 distress as assessed by GHQ-scores (Table 2). 40 41 42 43 Pain and poverty 44 on September 25, 2021 by guest. Protected copyright. 45 Every third amputee (n = 80, 32%) studied reported that they suffered from daily pain. 46 The frequency of physical pain correlated with low family income, also when adjusted for the 47 48 severity of the injury (OR = 0.54, CI = 0.36 to 0.80, p = 0.002, see Table 3 and Figure 1). 49 50 51 Psychological distress and pain 52 53 The frequency of pain was significantly associated with the level of psychological distress 54 55 (GHQ) among the participants. GHQ 12 scores increased among patients with frequent pain 56 57 (OR = 1.35, CI = 1.12 to 1.65, p = 0.002). Also, self-reported pain increased among patients 58 with higher levels of psychological distress (OR = 2.40, CI = 1.48 to 3.39, p < 0.001 ). 59 60

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1 2 3 DISCUSSION 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 More than half of the traumatic amputees in this cross-sectional study from Gaza’s main 6 7 rehabilitation clinic reported psychological distress with GHQ-12 scores above the cut-off. 8 Psychological distress was clearly associated with financial deterioration following their loss 9 10 of work due to their extremity amputations. The frequency of pain was also higher among the 11 12 poorest patients, and increased with decreasing family income. On the other hand, the 13 14 anatomical extent and severity of the initial physical amputation trauma did not affect GHQ- 15 scores or the frequency of pain experienced by the amputees. 16 17 18 For peer review only 19 Unemployment due to injury and mental distress 20 The psychological distress increased significantly among the amputees who were unable to 21 22 continue work as a result of their limb loss. This finding is supported by WHOs previous 23 24 findings in Gaza, where GHQ-levels were higher among unemployed.24 25 26 Three out of four patients in this study were unemployed. Close to half of them reported that 27 they currently were unemployed as a consequence of their physical disabilities caused by the 28 29 loss of limb(s). Unemployment was a major risk factor for depression and anxiety in 30 31 Jordanian amputees. 25 The long-term outcomes in 146 traumatic amputees in USA, showed 32 33 that 75 % had sustained change in occupation after amputation with more than half reporting 34 to be less paid in their new positions. 26 35 36 The unemployment among local Palestinian documented in our study is adding up to an http://bmjopen.bmj.com/ 37 27-28 38 already exceptionally high unemployment rate in Gaza, reaching 43·6 % in 2018. 39 The increased poverty that followed after severe extremity amputation injury in this cohort of 40 41 amputees in Gaza, appears to be more important for psychological well-being than the extent 42 43 of the amputation. 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 Pain and low family income 48 49 We also found that low family income was the main predictor to determine how often the 50 51 amputees experienced pain. The frequency of pain increased among amputees who lived in 52 53 families with low income. Surprisingly, neither pain nor psychological distress were affected 54 by the extent of the initial physical trauma. Our findings are supported by the conclusion in 55 56 the study by Husum and colleagues on chronic pain in land mine accident survivors in 57 58 Cambodia and Kurdistan, where patient-related loss of income correlated with the rate of 59 7 60 chronic pain syndrome. Ferguson and colleagues studied the psychological adjustment after

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1 2 3 amputation in landmine victims and found that the amputees recovery and acceptance of limb 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 loss were dependent on the patients economic situation.29 In the context of living with 6 7 disabilities in a society where siege, occupation and recurrent military attacks are part of 8 everyday life, it is also important to acknowledge the effects this may have on fundamental 9 10 psychosocial determinants of pain and psychological distress. 11 12 The most important factor to improve mental health among civilians in Gaza, is end the 13 14 occupation.30 15 16 Social suffering such as unemployment and poverty are effects of the long-lasting siege of 17 18 Gaza which adds burdensFor to thepeer lives of thereview amputees and theironly families. The unemployment 19 20 rate in Palestine was 31 percent in 2018. In Gaza 52 percent of the labor force was 21 unemployed 31. In order for the Palestinian economy to improve, the World Bank stresses the 22 23 need for a political solution allowing the Palestinian economy to expand through access to the 24 25 regional and international markets with export of Palestinian products and services. This 26 requires an immediate end to the siege of Gaza 31. 27 28 To ameliorate the needs of the population of amputees, these issues requires a shift in the 29 30 emphasis from narrow medical indicators, injury and illness to the lack of human security and 31 32 32 human rights violations experienced by ordinary Palestinians. 33 34 35 Limitations and strengths 36 http://bmjopen.bmj.com/ 37 The use of self-reported reasons for unemployment is a potential weakness in this study. 38 39 The lack of longitudinal data also poses limitations. The most recent cases we included were 40 in an early stage of treatment and rehabilitation and would probably be more unlikely to be 41 42 able to work. We also have a potential risk of selection bias as some amputees sustained fatal 43 44 injuries while others with minor injuries (like finger/toe amputations) may not have been on September 25, 2021 by guest. Protected copyright. 45 referred for rehabilitation. However, due to the ongoing conflict, the lack of infrastructure and 46 47 sometimes incomplete medical records, it would be close to impossible to obtain a completely 48 49 representative set of data from the whole population of amputees. 50 51 Strengths of this study include a representative sample of the patients attending rehabilitation 52 at ALPC with a response rate of 99 %, the close cooperation with the local staff and the 53 54 conduction of the study in Arabic. 55 56 57 58 INTERPRETATION 59 60

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1 2 3 More physical pain and decreased mental wellbeing correlated significantly with the more 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 unemployment and less family income (poverty) following traumatic extremity amputations 6 7 among Palestinians in Gaza. Poverty and unemployment after traumatic amputations and 8 disability are heavy, extra burdens adding to the trauma of the physical extremity amputation 9 10 itself. 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3

4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 DECLERATIONS 6 7 8 Ethics, consent and permission 9 10 All patient completed written consent prior to participating. The study was approved by the 11 12 Regional Ethical Committee (approval number: 2016/1265/REK Nord) in Norway and the 13 14 Committee for Helsinki ethics approvals in Gaza. 15 16 17 Consent to publish 18 For peer review only 19 Not applicable. 20 21 22 Availability of data and materials 23 24 The datasets used during the current study are not publicly available as the authors did not 25 26 apply any ethical committees for the permission to share the data. In this particular context, 27 sharing of data could raise safety concerns for the participants in the study and thus 28 29 considered unethical. 30 31 32 33 Patients and Public Involvement 34 This research was done without patient involvement. Patients were not invited to comment 35 36 on the study design and were not consulted to develop patient relevant outcomes or interpret http://bmjopen.bmj.com/ 37 38 the results. Patients were not invited to contribute to the writing or editing of this document 39 for readability or accuracy. 40 41 42 43 Competing interests 44 on September 25, 2021 by guest. Protected copyright. 45 We declare no competing interests. 46 47 48 Funding 49 50 None. 51 52 53 Acknowledgements 54 55 We would like to thank the patients and their families for their time and efforts, Dr. Ali Watti 56 57 MD, Technical Coordinator of ALPC, Mrs. Neveen Alghussien, Data Entry Officer at ALPC, 58 Foaad Hamed, and the other very professional staff at ALPC for their invaluable 59 60 contributions.

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1 2 3

4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 Authors' contributions 6 7 Hanne Heszlein-Lossius contributed study design, data collection, data entry, data analysis, 8 interpretation of the results, the primary draft of the manuscript writing, editing the 9 10 manuscript, literature search and final approval of the manuscript. 11 12 13 14 Yahya Al-Borno contributed to study design, patient inclusion, data collection, data transfer, 15 revising the manuscript and final approval of the manuscript. 16 17 18 For peer review only 19 Samar Shaqqoura contributed to study design, patient inclusion, data collection, data transfer, 20 revising the manuscript and final approval of the manuscript. 21 22 23 24 Nashwa Skaik contributed to study design, patient inclusion, data collection, data transfer, 25 26 revising the manuscript and final approval of the manuscript. 27 28 29 Lasse Melvaer Giil contributed to the statistical analysis, interpretation of the results, 30 31 visualization of the data in figures, editing and revising and manuscript, and final approval of 32 33 the manuscript. 34 35 36 Mads Gilbert contributed the original research idea, the study design, interpretation of the http://bmjopen.bmj.com/ 37 38 results, revising and editing the manuscript, and final approval of the manuscript. 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 REFERENCES 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 8 9 10 11 1. Palestinian Central Bureau of Statistics. Killed Palestinians (Martyrs) in Al-Aqsa Uprising 12 (Intifada), by Year 2000- 2016 http://www.pcbs.gov.ps/Portals/_Rainbow/Documents/Mart_3e- 13 2016.htm ((accessed August 29 2018).) 14 2. Pezzin et al. Outcomes of persons with traumatic amputations. Arch Phys Med Rehabil 15 2000;81:292-300 16 3. K .Dalal, L. Svanström 2015 Economic Burden of Disability Adjusted Life Years (DALYs) of 17 Injuries. Health, 7, 487-494. doi: 10.4236/health.2015.74058((accessed Aug 1 2018).) 18 4. C. Murray,For G. King, A.peer Lopez, et al. review2002 Armed Conflict only as a Public Health Problem BMJ 324; 19 346–349. http://j.mp/2oThkHL((accessed Aug 1 2018).) 5. M Mosleh, Dalal. K, Yousef Aljeesh et al. 2018 The Burden of war-injury in the Palestinian helath 20 care sector in Gaza Strip. BMC International Health and Human Rights 21 201818:28https://doi.org/10.1186/s12914-018-0165-3((accessed Aug 1 2018).) 22 6. Clasper, J., & Ramasamy, A. (2013). Traumatic amputations. British journal of pain, 7(2), 67-73. 23 7. Husum H, Resell K, Vorren G, Heng YV, Murad M, Gilbert M, Wisborg T. Chronic pain in land 24 mine accident survivors in Cambodia and Kurdistan. Soc Sci Med. 2002 Nov;55(10):1813-6. 25 8. H. Burger, Č. Marinček (2007) Return to work after lower limb amputation. Disability and 26 Rehabilitation 2007:29(17),1323–1329 27 9. Bosse MJ, MacKenzie EJ, Kellam JF, et al. An Analysis of Outcomes of Reconstruction or 28 Amputation after Leg-Threatening Injuries. New England Journal of Medicine 2002; 347(24):1924– 29 31. 30 10. A. Ferguson, B. Richie, M.Gomez Psychological factors after traumatic amputation in landmine 31 survivors: The bridge between physical healing and full recovery. Disability and Rehabilitation 32 2004; 26:14–15, 931–938 33 11. B. El-Khodary, M. Samara. The effect of exposure to war-traumatic events, stressful life events, and 34 other variables on mental health of Palestinian children and adolescents in the 2012 Gaza war. The 35 Lancet.2018;391,Special issue,S6. 36 12. K. Østlie, P. Magnus, O. Skjeldal, et al. Mental health and satisfaction with life among upper limb http://bmjopen.bmj.com/ 37 amputees: a Norwegian population-based survey comparing adult acquired major upper limb 38 amputees with a control group, Disability and Rehabilitation 2011;33:17–18, 1594–1607 39 13. Z. B. Perkins, H. D. De’Ath, G. Sharp et al. Factors affecting outcome after traumatic limb 40 amputation. British Journal of Surgery 2012; 99:75–86 41 14. B´tsleem Statistics. https://www.btselem.org/statistics ((accessed Aug 1 2017).) 42 15. United Nations Office for the Coordination of Humanitarian Affairs (OCHA). Key figures on the 2014 hostilities. www.ochaopt.org/content/key-figures-2014-hotilities ((accessed Aug 1 2018).) 43 16. United Nations Relief and Work Agency (UNWRA). Emergency appeal progress report July– 44 December 2006. https://www.unwra.org/sites/default/files/2010011814126.pdf ((accessed Aug 1 on September 25, 2021 by guest. Protected copyright. 45 2018).) 46 17. M. Abu Arisheh et al. Amputees The challenge faced by Gaza-strip amputees in seeking medical 47 treatment: A report from Gaza 2016. 48 https://reliefweb.int/sites/reliefweb.int/files/resources/Amputees-report-eng.pdf((accessed Oct 1 49 2018).) 50 18. H. Heszlein-Lossius et al. Life after conflict-related amputation trauma: a clinical study from the 51 Gaza Strip.BMC Int Health Hum Rights2018;18:34 52 19. El-Rufaie O, Daradkeh T. Validation of the Arabic versions of the thirty- and twelve-item General 53 Health Questionnaires in primary care patients. Br J Psychiatry 1996;169:662–4. 54 20. Al Hajjar B. Occupational stress among hospital nurses in Gaza-Palestine. 55 https://www.escholar.manchester.ac.uk/uk-ac-man-scw:189872 ((accessed Aug 10 2017).) 56 21. H.Heszlein-Lossius et al. Traumatic amputations caused by drone attacks in the local population in 57 Gaza: a retrospective cross-sectional study.The Lancet Plan Health 2019;3:1:40-47 58 22. M.Masri et al. Integration of mental helath-care with primary health-care services in the occupied 59 Palestininan territory: a cross-sectional study. The Lancet 2013;382:S9 60

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1 2 3 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62581-7/fulltext?code=lancet- 4 site (accessed April 4 2019) BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 23. General Health Questionnaire https://www.gl-assessment.co.uk/products/general-health- 6 questionnaire-ghq/ (accessed 06 april 2019) 7 24. United Nations Gaza Strip health assessment-WHO report 2009: The Question of Palestine. 8 https://www.un.org/unispal/document/gaza-strip-health-assessment-who-report/(accessed Oct 21 9 2018). 10 25. Z.Hawamdeh et al. Assessment of anxiety and depression after lower limb amputation in Jordaninan 11 patients. Neuropsychiatr dis treat. 2008;4:627-633 12 26. Pezzin et al. Outcomes of persons with traumatic amputations. Arch Phys Med Rehabil 13 2000;81:292-300 14 27. The World Bank in West Bank and Gaza. 15 http://www.worldbank.org/en/country/westbankandgaza/overview (accessed 09 September 2017). 28. Palestinian Central Bureau of Statistics: International Youth Day 12/08/2017 2017 16 http://www.pcbs.gov.ps/portals/_pcbs/PressRelease/Press_En_10-8-2017-youth-en.pdf (accessed 07 17 March 2018). 18 29. A. Ferguson,For B Richie, peer M.Gomez. Psychological review factors afteronly traumatic amputation in landmine 19 survivors: The bridge between physical healing and full recovery. Disability and Rehabilitation 20 2004;26:931–938 21 30. Marie M, Hannigan B, Jones A. Mental health needs and services in the West Bank, Palestine. Int J 22 Ment Health Syst 2016;10:23. 23 31. The World Bank in West bank and Gaza 24 https://www.worldbank.org/en/country/westbankandgaza/overview#2 (accesed 04 April 2019) 25 32. Giacaman, R. et al. Mental health, social distress and political oppression: The case of the occupied 26 Palestinian territory. Global public health 2011;6(5)547-559. 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 Table 1. Characteristics of study participants a (N = 254) BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 Demographics Patients (N) Statistics 8 (%) 9 10 11 Palestinian 254 100 12 13 Male 234 92 14 15 Childrenb 43 17 16 17 Female 20 8 18 For peer review only 19 Refugee statusc 154 57 20 21 Age –Inclusion, years 28 [10]e 22 23 e 24 Age-Injury, years 23 [9] 25 26 Family income, NIS/US Dollard 27 28 < 700/ 220 76 30 29 30 800-1600/ 252-504 105 42 31 32 >1700/ 535 50 28 33 34 35 Employment 36 http://bmjopen.bmj.com/ 37 Unemployed 191 75 38 39 Unemployed due to amputation 112 44 40 41 ≥ 3 unemployed family members 152 61 42 43 ≥ 3 persons economically dependent on amputee 160 64 44 on September 25, 2021 by guest. Protected copyright. 45 46 a Number of participants: 254, from 0-2 % of the participants had missing data on any variable. 47 b Children refers to participant that were amputated at the age of 18 years old or younger. 48 c Refugee = patient is from a family who has formal UN refugee status as of 1948 49 d NIS= New Israeli Shekel. 1 NIS equals 0,26 US Dollar. 50 e median and interquartile range. 51 52 53 54 55 56 57 58 59 60

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 Table 2. Psychological distress 6 7 a b 8 Crude model Adjusted model 9 10 OR 95 % CI p OR 95 % CI p 11 12 13 14 Unemployment due to trauma 1.36 1.07 – 1.72 0.011* 1.39 1.10 – 1.76 0.006* 15 16 17 Pain 1.35 1.12 – 1.65 0.002* 1.38 1.13 – 1.67 0.001* 18 For peer review only 19 Severity of injury 0.97 0.88 – 1.06 0.324 20 21 22 Family income 0.96 0.81 – 1.14 0.653 23 24 Loss of family members 1.06 0.80 – 1.37 0.687 25 26 27 Note: Psychological distress indicated by a binary cut-off at a GHQ-score ≥ 3. 28 Abbreviations: CI, confidence interval; GHQ, General Health Questionnaire; OR, odds ratio. 29 30 a Logistic regression adjusted for age and gender, with GHQ > 3 points as the dependent variable. 31 b Severity of injury, pain frequency and severity of injury added to the model described in a 32 * p-value < 0.05 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 Table 3. Pain severity after amputation 6 7 a b 8 Crude model Adjusted model 9 10 OR 95 % CI p OR 95 % CI p 11 12 13 14 Family income 0.54 0.36 - 0.80 0.002* 0.55 0.35 - 0.88 0.012* 15 16 17 Psychological distress 2.40 1.48 - 3.39 <0.001** 2.39 1.42 - 4.02 0.001* 18 For peer review only 19 Severity of injury 0.24 0.26 - 1.41 0.134 20 21 22 Unemployment due to trauma 0.91 0.44 - 1.89 0.808 23 24 25 Loss of family members 1.49 0.73 - 3.06 0.277 26 27 Note: Ordinal weekly pain scale from 0 to 4: never, 1 day a week or less, 2-3 days, 4-6 days and daily. 28 29 Abbreviations: CI, confidence interval; OR, odds ratio. 30 a Crude model: Ordinal logistic regression adjusted for age and gender, with Pain as the dependent variable. 31 b Adjusted model: severity of injury, psychological distress and severity of injury added to the model 32 described in a 33 * p-value < 0.05, ** < 0.001 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Figure 1. Frequency of pain after amputation trauma 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 6 7 8 9 10 Number of participants: 249. Five (1,96 % ) participants had missing data. 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 http://bmjopen.bmj.com/ 5 6 7 For peer review only 8 9 10 11 12 on September 25, 2021 by guest. Protected copyright. 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 21 of 22 BMJ Open

1 2 STROBE Statement—Checklist of items that should be included in reports of cross-sectional studies 3

4 Item BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 No Recommendation 6 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 7 OK Page 1 8 (b) Provide in the abstract an informative and balanced summary of what was done 9 10 and what was found OK page 2 11 Introduction 12 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 13 14 page 4 15 Objectives 3 State specific objectives done in page 4 in background. including any prespecified 16 hypotheses N/A 17 18 Methods For peer review only 19 Study design 4 Present key elements of study design early in the paper ok page 1,4 and 5 20 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 21 exposure, follow-up, and data collection ok page 5 22 23 Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of 24 participants ok page 5 25 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect 26 27 modifiers. Give diagnostic criteria, if applicable page 5-6 28 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 29 measurement assessment (measurement). Describe comparability of assessment methods if there is 30 more than one group ok page 5-6 31 32 Bias 9 Describe any efforts to address potential sources of bias ok page 3 33 Study size 10 Explain how the study size was arrived at ok page 5 34 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 35 describe which groupings were chosen and why ok page 7 36 http://bmjopen.bmj.com/ 37 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 38 page 5 and 7 39 (b) Describe any methods used to examine subgroups and interactions 40 41 (c) Explain how missing data were addressed 42 (d) If applicable, describe analytical methods taking account of sampling strategy 43 (e) Describe any sensitivity analyses 44 on September 25, 2021 by guest. Protected copyright. 45 Results 46 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially 47 eligible, examined for eligibility, confirmed eligible, included in the study, 48 completing follow-up, and analysed ok page 5 49 50 (b) Give reasons for non-participation at each stage ok page 5 51 (c) Consider use of a flow diagram 52 Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and 53 54 information on exposures and potential confounders page 5 and in page 3 55 (b) Indicate number of participants with missing data for each variable of interest ok 56 done in table 1-3. 57 Outcome data 15* Report numbers of outcome events or summary measures done in results 58 59 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and 60 their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included ok

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1 2 (b) Report category boundaries when continuous variables were categorized 3 (c) If relevant, consider translating estimates of relative risk into absolute risk for a 4 BMJ Open: first published as 10.1136/bmjopen-2019-029892 on 18 June 2019. Downloaded from 5 meaningful time period N/A 6 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and 7 sensitivity analyses N/A 8 9 Discussion 10 Key results 18 Summarise key results with reference to study objectives done under discussion 11 page 10. 12 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or 13 14 imprecision. Discuss both direction and magnitude of any potential bias page 1 and 15 11 16 Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, 17 18 Formultiplicity peer of analyses, review results from similaronly studies, and other relevant evidence 19 done in results and discussion and limitations. 20 Generalisability 21 Discuss the generalisability (external validity) of the study results 21 22 Other information 23 Funding 22 Give the source of funding and the role of the funders for the present study and, if 24 applicable, for the original study on which the present article is based ok done in the 25 end of the paper under funding 26 27 28 *Give information separately for exposed and unexposed groups. 29 30 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 31 32 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 33 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 34 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 35 available at www.strobe-statement.org. 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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