Validity of Ultra-Short-Term Heart Rate Variability Derived from Femoral Arterial Pulse Waveform in a British Military Cohort.

Various non-electrocardiogram (ECG) based methods are considered reliable sources of heart rate variability (HRV) measurement. However, the ultra-short recording of a femoral arterial waveform has never been validated against the gold-standard ECG-based 300s HRV and was the aim of this study.A validity study was conducted using a sample from the first follow-up of the longitudinal ADVANCE study UK. The participants were adult servicemen (n = 100); similar in age, rank, and deployment period (Afghanistan 2003-2014). The femoral arterial waveforms (14s) from the pulse wave velocity (PWV) assessment, and ECG (300s) were recorded at rest in the supine position using the Vicorder™ and Bittium Faros™ devices, respectively, in the same session. HRV analysis was performed using Kubios Premium. Resting heart rate (HR) and root mean square of successive differences (RMSSD) were reported. The Bland-Altman %plots were constructed to explore the PWV-ECG agreement in HRV measurement. A further exploratory analysis was conducted across methods and durations.The participants' mean age was 38.0 ± 5.3 years. Both PWV-derived HR (r = 0.85) and RMSSD (rs=0.84) showed strong correlations with their 300s-ECG counterparts (p < 0.001). Mean HR was significantly higher with ECG than PWV (mean bias: -12.71 ± 7.73%, 95%CI: -14.25%, -11.18%). In contrast, the difference in RMSSD between the two methods was non-significant [mean bias: -2.90 ± 37.82% (95%CI: -10.40%, 4.60%)] indicating good agreement. An exploratory analysis of 14s ECG-vs-300s ECG measurement revealed strong agreement in both RMSSD and HR.The 14s PWV-derived RMSSD strongly agrees with the gold-standard (300s-ECG-based) RMSSD at rest. Conversely, HR appears method sensitive.

Upper Limb Function in People With Upper and Lower Limb Loss 8 Years Postinjury: The Armed Services Trauma Outcome Study (ADVANCE) Cohort Study.

OBJECTIVE: Upper limb (UL) disability in people with UL amputation/s is well reported in the literature, less so for people with lower limb amputation/s. This study aimed to compare UL disability in injured (major trauma) and uninjured UK military personnel, with particular focus on people with upper and lower limb amputation/s. METHODS: A volunteer sample of injured (n = 579) and uninjured (n = 566) UK military personnel who served in a combat role in the Afghanistan war were frequency matched on age, sex, service, rank, regiment, role, and deployment period and recruited to the Armed Services Trauma Rehabilitation Outcome (ADVANCE) longitudinal cohort study. Participants completed the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire, scored from 0 (no disability) to 100 (maximum disability) 8 years postinjury. Mann-Whitney U and Kruskal Wallis tests were used to compared DASH scores between groups. An ordinal model was used to assess the effect of injury and amputation on DASH scores. RESULTS: DASH scores were higher in the group with injuries compared to the group without injuries (3.33 vs 0.00) and higher in people with lower limb loss compared to the group without injuries (0.83 vs 0.00), although this was not statistically significant. In the adjusted ordinal model, the odds of having a higher DASH score was 1.70 (95% CI = 1.18-2.47) times higher for people with lower limb loss compared to the group without injuries. DASH score was not significantly different between people with major and partial UL loss (15.42 vs 12.92). The odds of having a higher DASH score was 8.30 (95% CI = 5.07-13.60) times higher for people with UL loss compared to the uninjured group. CONCLUSION: People with lower limb loss have increased odds of having more UL disability than the uninjured population 8 years postinjury. People with major and partial UL loss have similar UL disability. The ADVANCE study will continue to follow this population for the next 20 years. IMPACT: For the first time, potential for greater upper limb disability has been shown in people with lower limb loss long-term, likely resulting from daily biomechanical compensations such as weight-bearing, balance, and power generation. This population may benefit from prophylactic upper limb rehabilitation, strength, and technique.

The relationship between ambulatory arterial stiffness index and incident atrial fibrillation.

BACKGROUND: The ambulatory arterial stiffness index (AASI) is an indirect measure of blood pressure variability and arterial stiffness which are atrial fibrillation (AF) risk factors. The relationship between AASI and AF development has not been previously investigated and was the primary aim of this study. METHODS: This was an observational cohort study of adults (aged 18-85 years) in sinus rhythm, who underwent 24-h ambulatory blood pressure monitoring (ABPM) for the diagnosis of hypertension or its control. RESULTS: Eight hundred and twenty-one patients (49% men) aged 58.7 ± 15.3 years were followed up for a median of 4.0 years (3317 patient-years). In total, 75 patients (9.1%) developed ≥1 AF episode during follow-up. The mean AASI was 0.46 ± 0.17 (median 0.46). AASI values (0.52 ± 0.16 vs. 0.45 ± 0.17; p < .001) and the proportion of AASI values above the median (65.3% vs. 48.4%; p = .005) were greater among the patients who developed AF versus those that did not respectively. AASI significantly correlated with age (r = .49; 95% confidence interval: 0.44-0.54: p < .001). On Kaplan-Meier analysis, higher baseline AASI by median, tertiles, and quartiles were all significantly associated with AF development (X2: 10.13; p < .001). On Cox regression analyses, both a 1-standard deviation increase and AASI > median were independent predictors of AF, but this relationship was no longer significant when age was included in the model. CONCLUSIONS: AASI is an independent predictor of AF development. However, this relationship becomes insignificant after adjustment for age which is higher correlated with AASI.

Validity and reliability of outcome measures to assess dysfunctional breathing: a systematic review.

OBJECTIVE: This study aimed to systematically review the psychometric properties of outcome measures that assess dysfunctional breathing (DB) in adults. METHODS: Studies on developing and evaluating measurement properties to assess DB were included. The study investigated the empirical research published between 1990 and February 2022, with an updated search in May 2023 in the Cochrane Library database of systematic reviews and the Cochrane Central Register of Controlled Trials, the Ovid Medline (full), the Ovid Excerta Medica Database, the Ovid allied and complementary medicines database, the Ebscohost Cumulative Index to Nursing and Allied Health Literature and the Physiotherapy Evidence Database. The included studies' methodological quality was assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) risk of bias checklist. Data analysis and synthesis followed the COSMIN methodology for reviews of outcome measurement instruments. RESULTS: Sixteen studies met the inclusion criteria, and 10 outcome measures were identified. The psychometric properties of these outcome measures were evaluated using COSMIN. The Nijmegen Questionnaire (NQ) is the only outcome measure with 'sufficient' ratings for content validity, internal consistency, reliability and construct validity. All other outcome measures did not report characteristics of content validity in the patients' group. DISCUSSION: The NQ showed high-quality evidence for validity and reliability in assessing DB. Our review suggests that using NQ to evaluate DB in people with bronchial asthma and hyperventilation syndrome is helpful. Further evaluation of the psychometric properties is needed for the remaining outcome measures before considering them for clinical use. PROSPERO REGISTRATION NUMBER: CRD42021274960.

The underlying mechanisms by which Post-Traumatic Growth is associated with cardiovascular health in male UK military personnel: The ADVANCE cohort study.

Post-Traumatic Growth (PTG) is associated with good cardiovascular health, but the mechanisms of this are poorly understood. This cross-sectional analysis assessed whether factors of PTG (Appreciation of Life (AOL), New Possibilities (NP), Personal Strength (PS), Relating to Others (RTO) and Spiritual Change (SC)) are associated with cardiovascular health in a cohort of 1006 male UK military personnel (median age 34). The findings suggest AOL, PS and RTO are associated with better cardiovascular health through cardiometabolic effects (lower levels of triglycerides, and total cholesterol) and haemodynamic functioning (lower diastolic blood pressure), but not inflammation. However, NP and SC were associated with poorer cardiovascular health through cardiometabolic effects (lower levels of high-density lipoproteins and higher levels of total cholesterol) and AOL had a non-linear association with low-density lipoproteins. These findings suggest that the relationship between PTG and cardiovascular functioning is complex and in need of further scrutiny.

Exploratory analysis of spontaneous versus paced breathing on heart rate variability in veterans with combat-related traumatic injury.

BACKGROUND: Respiration is a crucial determinant of autonomic balance and heart rate variability (HRV). The comparative effect of spontaneous versus paced breathing on HRV has been almost exclusively explored in healthy adults and never been investigated in an injured military cohort. OBJECTIVE: To examine the effect of spontaneous versus paced breathing on HRV in veterans with combat-related traumatic injury (CRTI). DESIGN: Observational cohort study. SETTING: ArmeD serVices trAuma rehabilitatioN outComE (ADVANCE) study, Stanford Hall, UK. PARTICIPANTS: The sample consisted of 100 randomly selected participants who sustained CRTI (eg, amputation) during their deployment (Afghanistan 2003-2014) and were recruited into the ongoing ADVANCE prospective cohort study. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: HRV was recorded using a single-lead ECG. HRV data were acquired during a sequential protocol of 5-minute spontaneous breathing followed immediately by 5 minutes of paced breathing (six cycles/minute) among fully rested and supine participants. HRV was reported using time domain (root mean square of successive differences), frequency domain (low frequency and high frequency) and nonlinear (sample entropy) measures. The agreement between HRV during spontaneous versus paced breathing was examined using the Bland-Altman analysis. RESULTS: The mean age of participants was 36.5 ± 4.6 years. Resting respiratory rate was significantly higher with spontaneous versus paced breathing (13.4 ± 3.4 vs. 7.6 ± 2.0 breaths/minute; p < .001), respectively. Resting mean heart rate and root mean square of successive differences were significantly higher with paced breathing than spontaneous breathing (p < .001). Paced breathing significantly increased median low frequency power than spontaneous breathing (p < .001). No significant difference was found in the absolute power of high frequency between the two breathing protocols. The Bland-Altman analysis revealed poor agreement between HRV values during spontaneous and paced breathing conditions with wide limits of agreement. CONCLUSION: Slow-paced breathing leads to higher HRV than spontaneous breathing and could overestimate resting "natural-state" HRV.

Pain after combat injury in male UK military personnel deployed to Afghanistan.

BACKGROUND: Chronic pain after injury poses a serious health burden. As a result of advances in medical technology, ever more military personnel survive severe combat injuries, but long-term pain outcomes are unknown. We aimed to assess rates of pain in a representative sample of UK military personnel with and without combat injuries. METHODS: We used data from the ADVANCE cohort study (ISRCTN57285353). Individuals deployed as UK armed forces to Afghanistan were recruited to include those with physical combat injuries, and a frequency-matched uninjured comparison group. Participants completed self-reported questionnaires, including 'overall' pain intensity and self-assessment of post-traumatic stress disorder, anxiety, and depression. RESULTS: A total of 579 participants with combat injury, including 161 with amputations, and 565 uninjured participants were included in the analysis (median 8 yr since injury/deployment). Frequency of moderate or severe pain was 18% (n=202), and was higher in the injured group (n=140, 24%) compared with the uninjured group (n=62, 11%, relative risk: 1.1, 95% confidence interval [CI]: 1.0-1.2, P<0.001), and lower in the amputation injury subgroup (n=31, 19%) compared with the non-amputation injury subgroup (n=109, 26%, relative risk: 0.9, 95% CI: 0.9-1.0, P=0.034). Presence of at least moderate pain was associated with higher rates of post-traumatic stress (RR: 3.7, 95% CI: 2.7-5.0), anxiety (RR: 3.2, 95% CI: 2.4-4.3), and depression (RR: 3.4, 95% CI: 2.7-4.5) after accounting for injury. CONCLUSION: Combat injury, but not amputation, was associated with a higher frequency of moderate to severe pain intensity in this cohort, and pain was associated with adverse mental health outcomes.

Ambulatory arterial stiffness index, mortality, and adverse cardiovascular outcomes; Systematic review and meta-analysis.

The ambulatory arterial stiffness index (AASI) is a novel measure of both blood pressure (BP) variability and arterial stiffness. This systematic review and meta-analysis was designed to evaluate the strength of the association between AASI and mortality and major adverse cardiovascular events (MACE). PubMed, Scopus, CINAHL, Google Scholar. and the Cochrane library were searched for relevant studies to July 31, 2023. Two investigators independently extracted data. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of all included articles. The relationship between baseline AASI and outcomes were examined using relative risk (RR) ratios with 95% confidence intervals (CI) with RevMan web. Thirteen studies were included and representing 28 855 adult patients who were followed up from 2.2 to 15.2 years. A 1-standard deviation (1-SD) increase in AASI was associated with a significant increase in all-cause death (RR 1.12; 95% CI: 0.95-1.32), stroke (RR 1.25; 95% CI: 1.09-1.44), and MACE (RR 1.07; 95% CI: 1.01-1.13; [I2  = 32%]). Higher dichotomized AASI (above vs. below researcher defined cut-offs) was associated with a significant increase in all-cause mortality (RR 1.19; 95% CI: 1.06-1.32), cardiovascular death (RR 1.29; 95% CI: 1.14-1.46), stroke (RR 1.57; 95% CI: 1.33-1.85), and MACE (RR1.29; 95% CI: 1.16-1.44). There was a significant risk of bias in more than 50% of studies with no evidence of significant publication bias. Higher AASI is associated with an increased risk of all-cause and cardiovascular death, stroke, and MACE. Further high-quality studies are warranted to determine reproducible AASI cut-offs to enhance its clinical risk precision.

The Influence of Physical and Mental Health Mediators on the Relationship Between Combat-Related Traumatic Injury and Ultra-Short-Term Heart Rate Variability in a U.K. Military Cohort: A Structural Equation Modeling Approach.

INTRODUCTION: Combat-related traumatic injury (CRTI) adversely affects heart rate variability (HRV). The mediating effect of mental and physical health factors on the relationship between CRTI, its severity and HRV has not been previously studied and investigated. MATERIALS AND METHODS: A cross-sectional mediation analysis of the ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE) prospective cohort study was performed. The sample consisted of injured and uninjured British male servicemen who were frequency-matched based on their age, rank, role-in-theater, and deployment to Afghanistan (2003-2014). CRTI and injury severity (the New Injury Severity Scores [NISS] [NISS < 25 and NISS ≥ 25]) were included as exposure variables. HRV was quantified using the root mean square of successive differences (RMSSD) obtained using pulse waveform analysis. Depression and anxiety mediators were quantified using the Patient Health Questionnaire and Generalized Anxiety Disorder, respectively. Body mass index and the 6-minute walk test (6MWT) represented physical health measures. Two mediation pathways between exposure and outcome variables were examined in comparison with the uninjured group using structural equation modeling. RESULTS: Of 862 servicemen, 428 were injured and 434 were uninjured with the mean age at assessment of 33.9 ± 5.4 (range 23-59) years. Structural equation modeling revealed that depression, anxiety, and body mass index did not significantly mediate the relationship between injury/injury severity and RMSSD. However, the 6MWT significantly mediated the relationship between CRTI and RMSSD (27% mediation). The indirect effect of 6MWT on the relationship between injury severity (NISS ≥ 25 vs. uninjured) and RMSSD was -0.06 (95% CI: -0.12, -0.00, P < .05). CONCLUSIONS: The findings suggest that greater physical function may improve HRV following CRTI. Longitudinal studies are warranted to further validate these findings.

Relationship between combat-related traumatic injury and its severity to predicted cardiovascular disease risk: ADVANCE cohort study.

BACKGROUND: This study investigated the relationship between combat-related traumatic injury (CRTI) and its severity and predicted cardiovascular disease (CVD) risk. MATERIAL AND METHODS: This was an analysis of comparative 10-year predicted CVD risk (myocardial infarction, stroke or CVD-death) using the QRISK®3 scoring-system among adults recruited into the Armed Services Trauma Rehabilitation Outcome (ADVANCE) cohort study. Participants with CRTI were compared to uninjured servicemen frequency-matched by age, sex, rank, deployment (Afghanistan 2003-2014) and role. Injury severity was quantified using the New Injury Severity Score (NISS). RESULTS: One thousand one hundred forty four adult combat veterans were recruited, consisting of 579 injured (161 amputees) and 565 uninjured men of similar age ethnicity and time from deployment/injury. Significant mental illness (8.5% vs 4.4%; p = 0.006) and erectile dysfunction (11.6% vs 5.8%; p < 0.001) was more common, body mass index (28.1 ± 3.9 vs 27.4 ± 3.4 kg/m2; p = 0.001) higher and systolic blood pressure variability (median [IQR]) (1.7 [1.2-3.0] vs 2.1 [1.2-3.5] mmHg; p = 0.008) lower among the injured versus uninjured respectively. The relative risk (RR) of predicted CVD (versus the population expected risk) was higher (RR:1.67 [IQR 1.16-2.48]) among the injured amputees versus the injured non-amputees (RR:1.60 [1.13-2.43]) and uninjured groups (RR:1.52 [1.12-2.34]; overall p = 0.015). After adjustment for confounders CRTI, worsening injury severity (higher NISS, blast and traumatic amputation) were independently associated with QRISK®3 scores. CONCLUSION: CRTI and its worsening severity were independently associated with increased predicted 10-year CVD risk.

Reliability of carotid-femoral arterial waveforms for the derivation of ultra-short term heart rate variability in injured British servicemen: An inter-rater reliability study.

In this study, the comparative precision of carotid versus femoral arterial waveforms to measure ultra-short term heart rate variability (HRVUST) following traumatic injury was investigated for the first time. This was an inter-rater reliability study of 50 British servicemen (aged 23-44 years) with non-acute combat-related traumatic injury (CRTI). Paired continuous arterial waveform data for HRVUST analysis, were simultaneously sampled at the carotid and femoral arterial sites (14-16 seconds) during pulse wave velocity (PWV) measurement. HRVUST was reported as the root mean square of the successive differences (RMSSD). Following the determination of the superior sampling site (carotid versus femoral), the blinded inter-rater agreement in RMSSD for the preferred site was quantified using the Intra-class Correlation Coefficient (ICC) and the Bland-Altman plot. The mean age of participants was 34.06±4.88 years. The femoral site was superior to the carotid site with a significantly higher number of reliable signals obtained (Fisher's Exact test; p<0.001). The inter-rater agreement in femoral-derived RMSSD was excellent [ICC 0.99 (95%CI: 0.994-0.997)] with a moderate level of agreement (mean difference [bias]: 0.55; 95% CI: -0.13-1.24 ms). In this study, we demonstrated that the femoral artery is a more reliable site than the carotid artery for HRVUST measurement and post-trauma risk stratification following CRTI.

The relationship between combat-related traumatic amputation and subclinical cardiovascular risk.

BACKGROUND: The relationship between acute combat-related traumatic injury (CRTI) to coronary flow reserve (CFR) and subclinical cardiovascular risk have not been examined and was the primary aim of this study. METHODS AND RESULTS: UK combat veterans from the ADVANCE cohort study (UK-Afghanistan War 2003-14) with traumatic limb amputations were compared to injured non-amputees and to a group of uninjured veterans from the same conflict. Subclinical cardiovascular risk measures included fasted blood atherogenic index of plasma (AIP), triglyceride-glucose index (TyG; insulin resistance), the neutrophil-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein (hs-CRP; vascular inflammation), body mass index (BMI) and visceral fat volume (dual-energy X-ray absorptiometry) and 6-min walk distance (6MWD; physical performance). The subendocardial viability ratio (SEVR), to estimate CFR, was calculated using arterial pulse waveform analysis (Vicorder device). In total 1144 adult male combat veterans were investigated, comprising 579 injured (161 amputees, 418 non-amputees) and 565 uninjured men. AIP, TyG, NLR, hs-CRP, BMI, total body fat and visceral fat volume were significantly higher and the SEVR and 6MWD significantly lower in the amputees versus the injured-non-amputees and uninjured groups. The SEVR was lowest in those with above knee and multiple limb amputations. CRTI (ExpB 0.96; 95% CI 0.94-0.98: p < 0.0001) and amputation (ExpB 0.94: 95% CI 0.91-0.97: p < 0.0001) were independently associated with lower SEVR after adjusting for age, rank, ethnicity and time from injury. CONCLUSION: CRTI, traumatic amputation and its worsening physical deficit are associated with lower coronary flow reserve and heightened subclinical cardiovascular risk.

Association Between Combat-Related Traumatic Injury and Skeletal Health: Bone Mineral Density Loss Is Localized and Correlates With Altered Loading in Amputees: the Armed Services Trauma Rehabilitation Outcome (ADVANCE) Study.

The association between combat-related traumatic injury (CRTI) and bone health is uncertain. A disproportionate number of lower limb amputees from the Iraq and Afghanistan conflicts are diagnosed with osteopenia/osteoporosis, increasing lifetime risk of fragility fracture and challenging traditional osteoporosis treatment paradigms. The aim of this study is to test the hypotheses that CRTI results in a systemic reduction in bone mineral density (BMD) and that active traumatic lower limb amputees have localized BMD reduction, which is more prominent with higher level amputations. This is a cross-sectional analysis of the first phase of a cohort study comprising 575 male adult UK military personnel with CRTI (UK-Afghanistan War 2003 to 2014; including 153 lower limb amputees) who were frequency-matched to 562 uninjured men by age, service, rank, regiment, deployment period, and role-in-theatre. BMD was assessed using dual-energy X-ray absorptiometry (DXA) scanning of the hips and lumbar spine. Femoral neck BMD was lower in the CRTI than the uninjured group (T-score -0.08 versus -0.42 p = .000). Subgroup analysis revealed this reduction was significant only at the femoral neck of the amputated limb of amputees (p = 0.000), where the reduction was greater for above knee amputees than below knee amputees (p < 0.001). There were no differences in spine BMD or activity levels between amputees and controls. Changes in bone health in CRTI appear to be mechanically driven rather than systemic and are only evident in those with lower limb amputation. This may arise from altered joint and muscle loading creating a reduced mechanical stimulus to the femur resulting in localized unloading osteopenia. This suggests that interventions to stimulate bone may provide an effective management strategy. © 2023 Crown copyright and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.

ADVANCE-TBI study protocol: traumatic brain injury outcomes in UK military personnel serving in Afghanistan between 2003 and 2014 - a longitudinal cohort study.

INTRODUCTION: Outcomes of traumatic brain injury (TBI) are highly variable, with cognitive and psychiatric problems often present in survivors, including an increased dementia risk in the long term. Military personnel are at an increased occupational risk of TBI, with high rates of complex polytrauma including TBI characterising the UK campaign in Afghanistan. The ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE)-TBI substudy will describe the patterns, associations and long-term outcomes of TBI in the established ADVANCE cohort. METHODS AND ANALYSIS: The ADVANCE cohort comprises 579 military personnel exposed to major battlefield trauma requiring medical evacuation, and 566 matched military personnel without major trauma. TBI exposure has been captured at baseline using a standardised interview and registry data, and will be refined at first follow-up visit with the Ohio State Method TBI interview (a National Institute of Neurological Disorders and Stroke TBI common data element). Participants will undergo blood sampling, MRI and detailed neuropsychological assessment longitudinally as part of their follow-up visits every 3-5 years over a 20-year period. Biomarkers of injury, neuroinflammation and degeneration will be quantified in blood, and polygenic risk scores calculated for neurodegeneration. Age-matched healthy volunteers will be recruited as controls for MRI analyses. We will describe TBI exposure across the cohort, and consider any relationship with advanced biomarkers of injury and clinical outcomes including cognitive performance, neuropsychiatric symptom burden and function. The influence of genotype will be assessed. This research will explore the relationship between military head injury exposure and long-term outcomes, providing insights into underlying disease mechanisms and informing prevention interventions. ETHICS AND DISSEMINATION: The ADVANCE-TBI substudy has received a favourable opinion from the Ministry of Defence Research Ethics Committee (ref: 2126/MODREC/22). Findings will be disseminated via publications in peer-reviewed journals and presentations at conferences.

Association between non-acute Traumatic Injury (TI) and Heart Rate Variability (HRV) in adults: A systematic review and meta-analysis.

Heart rate variability (HRV) is a non-invasive measure of autonomic function. The relationship between unselected long-term traumatic injury (TI) and HRV has not been investigated. This systematic review examines the impact of non-acute TI (>7 days post-injury) on standard HRV indices in adults. Four electronic databases (CINAHL, Medline, Scopus, and Web of Science) were searched. The quality of studies, risk of bias (RoB), and quality of evidence (QoE) were assessed using Axis, RoBANS and GRADE, respectively. Using the random-effects model, mean difference (MD) for root mean square of successive differences (RMSSD) and standard deviation of NN-intervals (SDNN), and standardized mean difference (SMD) for Low-frequency (LF): High-Frequency (HF) were pooled in RevMan guided by the heterogeneity score (I2). 2152 records were screened followed by full-text retrieval of 72 studies. 31 studies were assessed on the inclusion and exclusion criteria. Only four studies met the inclusion criteria. Three studies demonstrated a high RoB (mean RoBANS score 14.5±3.31) with a low QoE. TI was associated with a significantly higher resting heart rate. Meta-analysis of three cross-sectional studies demonstrated a statistically significant reduction in RMSSD (MD -8.45ms, 95%CI-12.78, -4.12, p<0.0001) and SDNN (MD -9.93ms, 95%CI-14.82, -5.03, p<0.0001) (low QoE) in participants with TI relative to the uninjured control. The pooled analysis of four studies showed a higher LF: HF ratio among injured versus uninjured (SMD 0.20, 95%CI 0.01-0.39, p<0.04) (very low QoE). Albeit low QoE, non-acute TI is associated with attenuated HRV indicating autonomic imbalance. The findings might explain greater cardiovascular risk following TI. Trial registration PROSPERO registration number: CRD: CRD42021298530.

The underlying mechanisms by which PTSD symptoms are associated with cardiovascular health in male UK military personnel: The ADVANCE cohort study.

Post-Traumatic Stress Disorder (PTSD) has been identified as an independent risk factor for cardiovascular disease, but the mechanisms of this relationship are not well understood. This study investigates the associations between PTSD symptom clusters (hyperarousal, intrusive thoughts, avoidance behaviours and emotional numbing) and mechanisms of cardiovascular disease including cardiometabolic effects, inflammation, and haemodynamic functioning. In the ADVANCE study cohort of UK male military personnel, 1111 participants were assessed for PTSD via questionnaire and cardiovascular risk via venous blood sampling, pulse wave analysis and dual energy x-ray absorptiometry between 2015 and 2020. Variable selection procedures were conducted to assess which of the symptom clusters if any were associated with cardiovascular risk outcomes. Associations were confirmed via robust regression modelling. Avoidance behaviours were associated with greater systolic Blood Pressure (BP) (Adjusted Coefficient (AC) 0.640 (95% Confidence Interval (CI) 0.065, 1.149). Emotional numbing was associated with greater estimated glucose disposal rate (AC -0.021 (95%CI -0.036, -0.005). Hyperarousal was associated with greater levels of (log)triglycerides (exponentiated-AC 1.009 (95%CI 1.002, 1.017). Intrusive thoughts were associated with greater visceral adipose tissue (AC 0.574 (95%CI 0.020, 1.250). Nonlinear relationships were observed between emotional numbing with heart rate and intrusive thoughts with systolic BP. Limited evidence is present for symptom associations with lipoproteins and pulse wave velocity. No associations were observed between PTSD symptom clusters and high sensitivity c-reactive protein, diastolic BP, total cholesterol, or haemoglobin fasting glucose. In conclusion, symptom clusters of PTSD were associated with increased cardiovascular risk via cardiometabolic and haemodynamic functioning mechanisms, but not inflammation.

Post-traumatic growth amongst UK armed forces personnel who were deployed to Afghanistan and the role of combat injury, mental health and pain: the ADVANCE cohort study.

BACKGROUND: Post-traumatic growth (PTG) is a positive psychological consequence of trauma. The aims of this study were to investigate whether combat injury was associated with deployment-related PTG in a cohort of UK military personnel who were deployed to Afghanistan, and whether post-traumatic stress disorder (PTSD), depression and pain mediate this relationship. METHODS: 521 physically injured (n = 138 amputation; n = 383 non-amputation injury) and 514 frequency-matched uninjured personnel completed questionnaires including the deployment-related Post-Traumatic Growth Inventory (DPTGI). DPTGI scores were categorised into tertiles of: no/low (score 0-20), moderate (score 21-34) or a large (35-63) degree of deployment-related PTG. Analysis was completed using generalised structural equation modelling. RESULTS: A large degree of PTG was reported by 28.0% (n = 140) of the uninjured group, 36.9% (n = 196) of the overall injured group, 45.4% (n = 62) of amputee and 34.1% (n = 134) of the non-amputee injured subgroups. Combat injury had a direct effect on reporting a large degree of PTG [Relative risk ratio (RRR) 1.59 (95% confidence interval (CI) 1.17-2.17)] compared to sustaining no injury. Amputation injuries also had a significant direct effect [RRR 2.18 (95% CI 1.24-3.75)], but non-amputation injuries did not [RRR 1.35 (95% CI 0.92-1.93)]. PTSD, depression and pain partially mediate this relationship, though mediation differed depending on the injury subtype. PTSD had a curvilinear relationship with PTG, whilst depression had a negative association and pain had a positive association. CONCLUSIONS: Combat injury, in particular injury resulting in traumatic amputation, is associated with reporting a large degree of PTG.

Association between non-acute traumatic injury (TI) and heart rate variability (HRV) in adults: A systematic review protocol.

Heart Rate Variability (HRV) is an indirect measure of autonomic function. Attenuated HRV is linked to worsening health outcomes including Major Adverse Cardiovascular Events (MACE). The relationship between traumatic injury (TI) and HRV has been limitedly studied. This research protocol has been designed to conduct a systematic review of the existing evidence on the association between non-acute TI and HRV in adults. Four electronic bibliographic databases (Web of Science, CINAHL, Medline, and Scopus) will be searched. The studies on non-acute (>7 days post injury) TI and HRV in adults will be included, followed by title-abstract screening by two reviewers independently. The quality and risk of bias of the included studies will be assessed using Axis and a six-item Risk of Bias Assessment tool for of Non-randomized Studies (RoBANS) respectively. Grading of Recommendations Assessment, Development and Evaluation (GRADE) will assess the quality of evidence. The extracted data will be synthesized using narrative syntheses and a Forest plot with or without meta-analysis- whichever permitted by the pooled data. This will be the first systematic review to examine the relationship between generalized TI and HRV in adults. Trial registration: (PROPSERO registration number: CRD: CRD42021298530) https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021298530.

Mental health outcomes of male UK military personnel deployed to Afghanistan and the role of combat injury: analysis of baseline data from the ADVANCE cohort study.

BACKGROUND: The long-term psychosocial outcomes of UK armed forces personnel who sustained serious combat injuries during deployment to Afghanistan are largely unknown. We aimed to assess rates of probable post-traumatic stress disorder (PTSD), depression, anxiety, and mental health-associated multimorbidity in a representative sample of serving and ex-serving UK military personnel with combat injuries, compared with rates in a matched sample of uninjured personnel. METHODS: This analysis used baseline data from the ADVANCE cohort study, in which injured individuals were recruited from a sample of UK armed forces personnel who were deployed to Afghanistan and had physical combat injuries, according to records provided by the UK Ministry of Defence. Participants from the uninjured group were frequency-matched by age, rank, regiment, deployment, and role on deployment. Participants were recruited through postal, email, and telephone invitations. Participants completed a comprehensive health assessment, including physical health assessment and self-reported mental health measures (PTSD Checklist, Patient Health Questionnaire-9, and Generalised Anxiety Disorder-7). The mental health outcomes were rates of PTSD, depression, anxiety, and mental health-associated multimorbidity in the injured and uninjured groups. The ADVANCE study is ongoing and is registered with the ISRCTN registry, ISRCTN57285353. FINDINGS: 579 combat-injured participants (161 with amputation injuries and 418 with non-amputation injuries) and 565 uninjured participants were included in the analysis. Participants had a median age of 33 years (IQR 30-37 years) at the time of assessment. 90·3% identified as White and 9·7% were from all other ethnic groups. The rates of PTSD (16·9% [n=89] vs 10·5% [n=53]; adjusted odds ratio [AOR] 1·67 [95% CI 1·16-2·41], depression (23·6% [n=129] vs 16·8% [n=87]; AOR 1·46 [1·08-2·03]), anxiety (20·8% [n=111] vs 13·5% [n=71]; AOR 1·56 [1·13-2·24]) and mental health-associated multimorbidity (15·3% [n=81] vs 9·8% [n=49]; AOR 1·62 [1·12-2·49]) were greater in the injured group than the uninjured group. Minimal differences in odds of reporting any poor mental health outcome were noted between the amputation injury subgroup and the uninjured group (AOR range 0·77-0·97), whereas up to double the odds were noted for the non-amputation injury subgroup compared with the uninjured group (AOR range 1·74-2·02). INTERPRETATION: Serious physical combat injuries were associated with poor mental health outcomes. However, the type of injury sustained influenced this relationship. Regardless of injury, this cohort represents a group who present with greater rates of PTSD than the general population, as well as increased psychological burden from multimorbidity. FUNDING: The ADVANCE Charity.