Expert consensus guidance on respiratory physiotherapy and rehabilitation of patients with rib fractures: An international, multidisciplinary e-Delphi study.

BACKGROUND: There is limited research supporting optimal respiratory physiotherapy or physical rehabilitation strategies for patients with rib fractures. The aim of this study was to develop key recommendations for the physiotherapy management of patients with rib fractures. METHODS: A three-round modified e-Delphi survey design, using an international Delphi panel including physiotherapy clinicians, researchers and lecturers, physician associates, trauma surgeons, and intensivists, was used in this study. The draft recommendations were developed by the Steering Group, based on available research. Over three rounds, panelists rated their agreement (using a Likert scale) with regard to recommendation for physiotherapists delivering respiratory physiotherapy and physical rehabilitation to patients following rib fractures. Recommendations were retained if they achieved consensus (defined as ≥70% of panelists ≥5/7) at the end of each round. RESULTS: A total of 121 participants from 18 countries registered to participate in the study, with 87 (72%), 77 (64%), and 79 (65%) registrants completing the three rounds, respectively. The final guidance document included 18 respiratory physiotherapy and rehabilitation recommendations, mapped over seven clinical scenarios for patients (1) not requiring mechanical ventilation, (2) requiring mechanical ventilation, (3) with no concurrent fracture of the shoulder girdle complex, (4) with a concurrent fracture of the shoulder girdle complex, (5) with/without concurrent upper limb orthopedic injuries, (6) undergoing surgical stabilization of rib fractures, and (7) at hospital discharge. CONCLUSION: This guidance provides key recommendations for respiratory physiotherapy and physical rehabilitation of patients with rib fractures. It could also be used to inform future research priorities in the field. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Imaging of Light-Enhanced Extracellular Vesicle-Mediated Delivery of Oxaliplatin to Colorectal Cancer Cells via Laser Ablation, Inductively Coupled Plasma Mass Spectrometry.

Extracellular vesicles (EVs) are lipid bilayer structures released by all cells that mediate cell-to-cell communication via the transfer of bioactive cargo. Because of the natural origin of EVs, their efficient uptake by recipient cells, capacity to stabilize and transport biomolecules and their potential for cell/tissue targeting and preferential uptake by cancer cells, they have enormous potential for bioengineering into improved and targeted drug delivery systems. In this work, we investigated the use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) as a tool to measure the loading of platinum-based chemotherapeutic agents. The EV loading of oxaliplatin via co-incubation was demonstrated, and LA-ICP-MS imaging showed greater efficiency of delivery to colorectal cancer cells compared to free oxaliplatin, leading to enhanced cytotoxic effect. Further, the impact of EV co-loading with a porphyrin (C5SHU, known as 'C5') photosensitizer on oxaliplatin delivery was assessed. Fluorescence analysis using nano-flow cytometry showed dose-dependent EV loading as well as a trend towards the loading of larger particles. Exposure of OXA-C5-EV-treated colorectal cancer cells to light indicated that delivery was enhanced by both light exposure and porphyrins, with a synergistic effect on cell viability observed between oxaliplatin, EVs and light exposure after the delivery of the co-loaded EVs. In summary, this work demonstrates the utility of LA-ICP-MS and mass spectrometry imaging in assessing the loading efficiency and cellular delivery of platinum-based therapeutics, which would also be suitable for agents containing other elements, confirms that EVs are more efficient at delivery compared to free drugs, and describes the use of light exposure in optimizing delivery and therapeutic effects of EV-mediated drug delivery both in combination and independently of porphyrin-based photosensitizers.

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium.

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. CONCLUSIONS/INTERPRETATION: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.

Specific physical activities, sedentary behaviours and sleep as long-term predictors of accelerometer-measured physical activity in 91,648 adults: a prospective cohort study.

BACKGROUND: The evidence for the prospective relationships between specific physical activities (PA), sedentary behaviours (SB) and sleep on subsequent total PA levels is scarce. The purpose of this study was to examine prospective associations of self-reported PA, SB and sleep, and changes in these with subsequent accelerometer-measured PA. METHODS: A sub-sample of 91,648 UK Biobank participants reported moderate-to-vigorous PA (MVPA), lifestyle activities, TV viewing, computer use and sleep through screen-based questionnaires at baseline (2006-2010), and provided valid accelerometry data (dominant wrist-worn for 7 days between 2013 and 2015). A further sub-sample of 7709 participants repeated the screen-based questionnaires between 2012 and 2013. RESULTS: In both women (n = 51,545) and men (n = 40,103), positive associations were observed between all self-reported measures of PA at baseline (MVPA, lifestyle/job-related activities, active transporting modes) and accelerometer-measured PA levels at follow-up (median 5.7 years); an exception was 'walking/standing at work' in women. Sedentary time at work, TV viewing and computer use were inversely associated with PA at follow-up. Sleeping either more or less than 7 h/day at baseline was associated with lower PA at follow-up (except for ≤6 h/day in men). In the repeat self-report sub-sample (median 4.3 years), relatively higher physical activity at follow-up was observed in those who maintained or achieved favourable levels of MVPA, walking for pleasure, strenuous sports, other exercises, heavy DIY (in women), heavy physical work, and walking/standing at work (in women), sedentary time at work, getting about methods (in women), commuting methods (in women), TV viewing, computer use or sleep. CONCLUSIONS: Initial levels of PA, SB and sleep, and changes in these variables were generally associated with subsequent accelerometer-measured PA in the expected directions, suggesting these specific behaviours all contribute to the total volume of physical activity over time and could thus be targets for intervention.

Characteristics of hardware failure in patients undergoing surgical stabilization of rib fractures: A Chest Wall Injury Society multicenter study.

BACKGROUND: Surgical stabilization of rib fractures (SSRF) is increasingly used for severe rib fractures/flail chest. There are no reports discussing mechanisms of failure of implanted hardware, its clinical presentation, or consequences. The purpose of this study was to evaluate the incidence, presenting signs, and clinical sequela of hardware failure after SSRF. METHODS: A multicenter, retrospective study was performed by a group of surgeons with a large SSRF case volume. All cases with known hardware failure from January 1, 2010, to December 31, 2017, were included. The surgeon's experience at the time of hardware implantation, specific implant used, number of failures the surgeon had experienced with the same system, and time from implantation to hardware failure were recorded. Additionally, patient demographics, including age, comorbid conditions, and number and location of rib fractures were recorded. Symptomatology associated with hardware failure and need for explant and/or reimplantation of hardware was also recorded. Nonparametric statistical tests were used to compare cohorts. RESULTS: Of 1,224 patients who underwent SSRF, 38 patients with 233 rib fractures and 279 fracture segments experienced hardware failure and were enrolled in the study. Twelve patients presented more than 3 months following injury. Median age was 54 years old and 34% were active smokers. One hundred forty-four plates were implanted with a median of four plates per patient. Median number of SSRF cases by each surgeon was 100 (range, 1-280). Fractures and hardware failure were most frequent in the anterolateral/lateral region. Hardware failure was mostly due to screw migration and plate fracture. Hardware failure was asymptomatic in 40% and presented as pain in 42% of cases. Fifty-five percent of the cases required explantation of hardware, and only 10% required SSRF again. There was no difference between the acute and chronic fracture cohorts. CONCLUSION: Hardware failure after SSRF is rare and often asymptomatic. When present, it rarely requires redo SSRF. LEVEL OF EVIDENCE: Therapeutic, level V.

Descriptive epidemiology of changes in objectively measured sedentary behaviour and physical activity: six-year follow-up of the EPIC-Norfolk cohort.

BACKGROUND: Sedentary time increases and total physical activity decreases with age. The magnitude and correlates of changes in sedentary time, light-intensity physical activity (LPA), moderate-to-vigorous intensity physical activity (MVPA), and overall physical activity remain unclear. We quantified these changes and identified their individual and sociodemographic correlates. METHODS: We used data from 1259 adults (67.8 ± 6.9 years; 41.9% women) who participated in the EPIC-Norfolk Study. Activity was assessed at baseline (2004-2011) and follow-up (2012-2016) for 7 days using accelerometers. Potential correlates of change were specified a priori. We used unadjusted and adjusted sex-stratified linear regressions to identify correlates of change. RESULTS: Only 3.7% of adults met the current MVPA recommendations. Sedentary time increased by 3.0 min/day/year (SD = 12.3). LPA, MVPA, and overall PA decreased by 1.7 min/day/year (SD = 5.4), 3.0 min/day/year (SD = 6.0), and 8.8 cpm/year (SD = 18.8), respectively. Correlates of greater rates of increase in sedentary time included older age and higher BMI in men, and older age, higher BMI, smoking, and urban dwelling in women. Correlates of greater rates of decrease in physical activity included older age, higher BMI, living alone, depression, car use, and/or fair/poor self-rated health in men, and older age, higher BMI, depression, smoking, and/or urban dwelling in women (e.g. depressed women had a 1.0 min/day/year greater rate of decline in MVPA than non-depressed women, 95% CI -1.8, - 0.2). CONCLUSIONS: Most (> 95%) adults are insufficiently active. Sedentary time increases and LPA, MVPA and overall physical activity decreases over time, with more pronounced rates of change observed in specific sub-groups (e.g. among older and depressed adults). To promote active living, the correlates of these changes should be considered in future interventions.

The combination of cardiorespiratory fitness and muscle strength, and mortality risk.

Little is known about the combined associations of cardiorespiratory fitness (CRF) and hand grip strength (GS) with mortality in general adult populations. The purpose of this study was to compare the relative risk of mortality for CRF, GS, and their combination. In UK Biobank, a prospective cohort of > 0.5 million adults aged 40-69 years, CRF was measured through submaximal bike tests; GS was measured using a hand-dynamometer. This analysis is based on data from 70,913 men and women (832 all-cause, 177 cardiovascular and 503 cancer deaths over 5.7-year follow-up) who provided valid CRF and GS data, and with no history of heart attack/stroke/cancer at baseline. Compared with the lowest CRF category, the hazard ratio (HR) for all-cause mortality was 0.76 [95% confidence interval (CI) 0.64-0.89] and 0.65 (95% CI 0.55-0.78) for the middle and highest CRF categories, respectively, after adjustment for confounders and GS. The highest GS category had an HR of 0.79 (95% CI 0.66-0.95) for all-cause mortality compared with the lowest, after adjustment for confounders and CRF. Similar results were found for cardiovascular and cancer mortality. The HRs for the combination of highest CRF and GS were 0.53 (95% CI 0.39-0.72) for all-cause mortality and 0.31 (95% CI 0.14-0.67) for cardiovascular mortality, compared with the reference category of lowest CRF and GS: no significant association for cancer mortality (HR 0.70; 95% CI 0.48-1.02). CRF and GS are both independent predictors of mortality. Improving both CRF and muscle strength, as opposed to either of the two alone, may be the most effective behavioral strategy to reduce all-cause and cardiovascular mortality risk.

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

The prevalence and impact of defensive medicine in the radiographic workup of the trauma patient: a pilot study.

BACKGROUND: Defensive medicine is estimated to cost the United States $210 billion annually. Trauma surgeons are at risk of practicing defensive medicine in the form of reflexively ordering computed tomography (CT) scans. The aim of this study is to quantify the monetary impact and radiation exposure related to the radiographic workup of trauma patients. METHODS: We conducted a prospective, observational study involving 295 trauma patients at Level I trauma center. Physicians were surveyed regarding specific CT scans ordered, likelihood of significant injuries found on scans, and which scans would have been ordered in a hypothetical, litigation-free environment. RESULTS: Four hundred sixteen of 1,097 CT scans (38%) were ordered out of defensive purposes. Nine CT scans (2.2%) that would not have been ordered resulted in a change in management. Defensively ordered CT scans resulted in nearly $120,000 in excess charges and 8.8 mSv of unnecessary radiation per patient. CONCLUSION: Defensively ordered CT scan in the workup of trauma patients is a prevalent and costly practice that exposes patients to potentially unnecessary and harmful radiation.

Weight-based enoxaparin dosing for venous thromboembolism prophylaxis in the obese trauma patient.

BACKGROUND: Limited data exist regarding the efficacy of weight-based dosing of low-molecular weight heparin for venous thromboembolism (VTE) prophylaxis in obese trauma patients. METHODS: Consecutive obese trauma patients were placed on a weight-based protocol for VTE prophylaxis (enoxaparin .5 mg/kg subcutaneously every 12 hours). Peak anti-Xa levels were drawn, and bilateral lower extremity duplex ultrasound was performed. The incidence of VTE and bleeding complications were recorded. RESULTS: Eighty-six patients met the study criteria. Seventy-four patients achieved target prophylactic anti-Xa concentrations, with a mean level of .42 ± .01 IU/mL. Eighteen patients were found to have deep vein thrombosis. However, in 16 of these patients, deep vein thrombosis was diagnosed before weight-based low-molecular weight heparin initiation. No bleeding complications occurred, and no symptomatic pulmonary emboli were identified. CONCLUSIONS: In obese trauma patients, weight-based enoxaparin is an efficacious regimen that provides adequate VTE prophylaxis, as measured by anti-Xa levels, and appears to be safe without bleeding complications.