Spondyloarthritis encompasses a group of common inflammatory diseases thought to be driven by IL-17A-secreting type-17 lymphocytes. Here we show increased numbers of GM-CSF-producing CD4 and CD8 ...lymphocytes in the blood and joints of patients with spondyloarthritis, and increased numbers of IL-17A
GM-CSF
double-producing CD4, CD8, γδ and NK cells. GM-CSF production in CD4 T cells occurs both independently and in combination with classical Th1 and Th17 cytokines. Type 3 innate lymphoid cells producing predominantly GM-CSF are expanded in synovial tissues from patients with spondyloarthritis. GM-CSF
CD4
cells, isolated using a triple cytokine capture approach, have a specific transcriptional signature. Both GM-CSF
and IL-17A
GM-CSF
double-producing CD4 T cells express increased levels of GPR65, a proton-sensing receptor associated with spondyloarthritis in genome-wide association studies and pathogenicity in murine inflammatory disease models. Silencing GPR65 in primary CD4 T cells reduces GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis.
Spinal cord injury (SCI) frequently results in motor, sensory, and autonomic dysfunction for which there is currently no cure. Recent pre-clinical and clinical research has led to promising advances ...in treatment; however, therapeutics indicating promise in rodents have not translated successfully in human trials, likely due, in part, to gross anatomical and physiological differences between the species. Therefore, large animal models of SCI may facilitate the study of secondary injury processes that are influenced by scale, and may assist the translation of potential therapeutic interventions. The aim of this study was to characterize two severities of thoracic contusion SCI in female domestic pigs, measuring motor function and spinal cord lesion characteristics, over 2 weeks post-SCI. A custom-instrumented weight-drop injury device was used to release a 50 g impactor from 10 cm (
= 3) or 20 cm (
= 7) onto the exposed dura, to induce a contusion at the T10 thoracic spinal level. Hind limb motor function was assessed at 8 and 13 days post-SCI using a 10-point scale. Volume and extent of lesion-associated signal hyperintensity in T2-weighted magnetic resonance (MR) images were assessed at 3, 7, and 14 days post-injury. Animals were transcardially perfused at 14 days post-SCI and spinal cord tissue was harvested for histological analysis. Bowel function was retained in all animals and transient urinary retention occurred in one animal after catheter removal. All animals displayed hind limb motor deficits. Animals in the 10-cm group demonstrated some stepping and weight-bearing and scored a median 2-3 points higher on the 10-point motor function scale at 8 and 13 days post-SCI, than did the 20-cm group. Histological lesion volume was 20% greater, and 30% less white matter was spared, in the 20-cm group than in the 10-cm group. The MR signal hyperintensity in the 20-cm injury group had a median cranial-caudal extent approximately 1.5 times greater than the 10-cm injury group at all three time-points, and median volumes 1.8, 2.5, and 4.5 times greater at day 3, 7, and 14 post-injury, respectively. Regional differences in axonal injury were observed between groups, with amyloid precursor protein immunoreactivity greatest in the 20-cm group in spinal cord sections adjacent to the injury epicenter. This study demonstrated graded injuries in a domestic pig strain, with outcome measures comparable to miniature pig models of contusion SCI. The model provides a vehicle for the study of SCI and potential treatments, particularly where miniature pig strains are not available and/or where small animal models are not appropriate for the research question.
The results of recent large-scale clinical trials have led us to review our understanding of the metabolic response to stress and the most appropriate means of managing nutrition in critically ill ...patients. This review presents an update in this field, identifying and discussing a number of areas for which consensus has been reached and others where controversy remains and presenting areas for future research. We discuss optimal calorie and protein intake, the incidence and management of re-feeding syndrome, the role of gastric residual volume monitoring, the place of supplemental parenteral nutrition when enteral feeding is deemed insufficient, the role of indirect calorimetry, and potential indications for several pharmaconutrients.
Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or ...develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS.
The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO
/FiO
ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 10
/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 .
Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 SD 31·6 vs 48·7 35·7; difference 4·9 95% CI -4·8 to 14·5; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine 15% of 62 patients vs 21 30% of 71 patients; hazard ratio 0·46 95% CI 0·22 to 0·98; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 -0·26 to -0·02; p=0·0215), similar day 60 mortality (23 18% of 127 patients vs 18 15% of 123 patients; odds ratio OR 1·29 95% CI 0·66 to 2·53; p=0·46), and more day 60 survivors at home (86 87% of 99 patients vs 73 73% of 100 patients; OR 2·45 1·18 to 5·08; p=0·0165). A similar number of serious adverse events occurred in each group (seven 5% of 128 patients in the heparin group vs three 2% of 124 patients in the placebo group; OR 2·33 0·59 to 9·24; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group).
In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS.
Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.
To compare health service utilization of patients interacting with a mobile integrated health care program consisting of advanced care paramedics delivering community paramedic care to people ...experiencing homelessness before and after their initial visit.
ED visits, physician claims, and pharmaceutical dispensations were compared in the year prior to and in the year following the initial community paramedic visit. Administrative databases were linked and utilization rates were calculated and analyzed between periods in this pre-post cohort study.
The 1360 community paramedic patients included in this study had no significant change in ED visits (IRR: 1.02) following their initial visit. There were 17,699 ED visits in the pre-period and 18,398 visits in the post-period. There was an observed increase in rates of primary care physician claims (IRR 1.22) and pharmaceutical dispensations from community pharmacies (IRR 1.04). Patients who did not have pharmaceutical dispensations and those without physician claims in the pre-period were significantly less likely to not access these services in the post-period.
In the year following the initial community paramedic visit there were small but significant increases in community-based care utilization of people experiencing homelessness. These data suggest that the continued development and implementation of paramedics as part of an interdisciplinary care team can increase access to care for a traditionally underserved population with complex health needs. Patients would likely benefit from the integration of community paramedics in community-based management that aim to improve access to care following ED visits.
Objective: Linking emergency medical services (EMS) data to hospital outcomes is important for quality assurance and research initiatives. However, non-linkage due to missing or incomplete patient ...information may increase the risk of bias and distort findings. The purpose of this study was to explore if an optimization strategy, in addition to an existing linkage process, improved the linkage rate and reduced selection and information bias. Methods: 4,150 transported patients in a metropolitan EMS system in Alberta, Canada from 2016/17 were linked to two Emergency Department (ED) databases by a standard strategy using a unique health care number, date/time of ED arrival, and hospital name. An optimized strategy added additional linkage steps incorporating last name, year of birth, and a manual search. The strategies were compared to assess the rate of linkage, and to describe event and patient-level characteristics of unlinked records. Results: The standard strategy resulted in 3,650 out of 4,150 (88.0%) linked records (95% CI 86.9%-88.9%). Of the 500 non-linked records, an additional 381 were linked by the optimized strategy (n = 4,031/4,150 97.1%; 95% CI: 96.6%-97.6%). There were no false positive linkages. The highest linkage failure was in 25 to 34 year-old patients (n = 93/478, 19.5%), males (n = 236/1975, 12.0%), Echo level events (n = 15/77, 19.5%), and emergency transport (45/231, 19.5%). The optimized strategy improved linkage in these groups by 68.8% (64/93), 79.2% (187/236), 40.0% (6/15), and 51.1% (23/45) respectively. For dispatch card, the highest linkage failure occurred in Card 24-Pregnancy/Childbirth/Miscarriage (n = 30/44, 68.2%), Card 27-Stab/Gunshot/Penetrating Trauma (n = 6/17, 35.3%), and Card 9-Cardiac/Respiratory Arrest/Death (n = 12/46, 26.1%). The optimized strategy improved linkage by 10.0% (3/30), 83.3% (5/6), and 41.7% (5/12) respectively. For the 119 unlinked records, 71 (59.7%) had sufficient information for linkage, but no appropriately matching records could be found. Conclusion: An optimized sequential deterministic strategy linking EMS data to ED outcomes improved the linkage rate without increasing the number of false positive links, and reduced the potential for bias. Even with adequate information, some records were not linked to their ED visit. This study underscores the importance of understanding how data are linked to hospital outcomes in EMS research and the potential for bias.
In this large trial, elderly, high-risk patients were randomly assigned before surgery to goal-directed therapy guided by a pulmonary-artery catheter or to standard care without the use of such a ...catheter. There was no significant difference between the groups in mortality in the hospital or at 6 or 12 months. Pulmonary embolism was more frequent in the catheter group.
These findings argue against the routine use of this catheter during and after surgery.
The clinical value of data obtained from pulmonary-artery catheters remains unproven. The light, flexible, balloon-tipped, flow-directed pulmonary-artery catheter was introduced clinically three decades ago,
1
and its use has continued without definitive evidence of decreased morbidity or mortality.
2
More than 1.5 million pulmonary-artery catheters are inserted into medical and surgical patients in North America annually,
3
despite calls for a moratorium
4
,
5
on the use of this invasive technology because observational studies have suggested an association with increased mortality.
6
–
8
Proponents argue that physiological measurements provided by the use of a pulmonary-artery catheter permit refinements of treatment that improve patients' outcomes. This . . .
The optimal prehospital fluid for the treatment of hypotension is unknown. Hypertonic fluids may increase circulatory volume and mute the pro-inflammatory response of the body to injury and illness. ...The purpose of this systematic review is to determine whether in patients presenting with hypotension in the prehospital setting (population), the administration of hypertonic saline (intervention), compared to an isotonic fluid (control), improves survival to hospital discharge (outcome).
Searches were conducted in Medline, Embase, CINAHL, and CENTRAL from the date of database inception to November, 2016, and included all languages. Two reviewers independently selected randomized control trials of hypotensive human participants administered hypertonic saline in the prehospital setting. The comparison was isotonic fluid, which included normal saline, and near isotonic fluids such as Ringer's Lactate. Assessment of study quality was done using the Cochrane Collaborations' risk of bias tool and a fixed effect meta-analysis was conducted to determine the pooled relative risk of survival to hospital discharge. Secondary outcomes were reported for fluid requirements, multi-organ failure, adverse events, length of hospital stay, long term survival and disability.
Of the 1160 non-duplicate citations screened, thirty-eight articles underwent full-text review, and five trials were included in the systematic review. All studies administered a fixed 250 ml dose of 7.5% hypertonic saline, except one that administered 300 ml. Two studies used normal saline, two Ringer's Lactate, and one Ringer's Acetate as control. Routine care co-interventions included isotonic fluids and colloids. Five studies were included in the meta-analysis (n = 1162 injured patients) with minimal statistical heterogeneity (I
= 0%). The pooled relative risk of survival to hospital discharge with hypertonic saline was 1.02 times that of patients who received isotonic fluids (95% Confidence Interval: 0.95, 1.10). There were no consistent statistically significant differences in secondary outcomes.
There was no significant difference in important clinical outcomes for hypotensive injured patients administered hypertonic saline compared to isotonic fluid in the prehospital setting. Hypertonic saline cannot be recommended for use in prehospital clinical practice for the management of hypotensive injured patients based on the available data. PROSPERO registration # CRD42016053385 .
Severe acute renal failure (sARF) is associated with considerable morbidity, mortality and use of healthcare resources; however, its precise epidemiology and long-term outcomes have not been well ...described in a non-specified population.
Population-based surveillance was conducted among all adult residents of the Calgary Health Region (population 1 million) admitted to multidisciplinary and cardiovascular surgical intensive care units between May 1 1999 and April 30 2002. Clinical records were reviewed and outcome at 1 year was assessed.
sARF occurred in 240 patients (11.0 per 100,000 population/year). Rates were highest in males and older patients (> or = 65 years of age). Risk factors for development of sARF included previous heart disease, stroke, pulmonary disease, diabetes mellitus, cancer, connective tissue disease, chronic renal dysfunction, and alcoholism. The annual mortality rate was 7.3 per 100,000 population with rates highest in males and those > or = 65 years. The 28-day, 90-day, and 1-year case-fatality rates were 51%, 60%, and 64%, respectively. Increased Charlson co-morbidity index, presence of liver disease, higher APACHE II score, septic shock, and need for continuous renal replacement therapy were independently associated with death at 1 year. Renal recovery occurred in 78% (68/87) of survivors at 1 year.
sARF is common and males, older patients, and those with underlying medical conditions are at greatest risk. Although the majority of patients with sARF will die, most survivors will become independent from renal replacement therapy within a year.
We conducted a prospective, observational cohort study designed to compare intestinal permeability (IP) and development of multiple organ dysfunction syndrome (MODS) in a subset of critically ill ...patients in an intensive care unit (ICU). All patients with an expected ICU stay of 72 h or more were entered into the study, and IP was determined on a daily basis whenever possible from the urinary fractional excretion of orally administered lactulose and mannitol (LMR). Forty-seven consecutive patients were studied, and 28 developed MODS either at the time of admission or during their ICU course. These patients, as a group, had significantly worse IP at admission than did a non-MODS cohort (LnLMR: -2.10 +/- 1.10 versus -3.26 +/- 0.83). Those patients who developed MODS following admission also had a significantly greater admission IP than did the non-MODS group (-2.51 +/- 0.85). Differences in IP between cohorts could not be explained by differences in the incidence of systemic inflammatory response syndrome (SIRS)/sepsis or shock. With multivariate regression analysis, the only parameter present on admission that was predictive of subsequent MODS was IP. Differences in IP and the severity of organ dysfunction were also present (MODS severity mild: -3.01 +/- 0.72; moderate: -1.97 +/- 0.69; and severe: -1.12 +/- 0.96). Patients who developed MODS had a persistently abnormal IP during their ICU stay, and a significantly delayed improvement in their IP compared with the non-MODS cohort. We conclude that the development of MODS is associated with an abnormal and severe derangement of IP that is detectable prior to the onset of the syndrome. This observation lends credence to the premise that gastrointestinal (GI) dysfunction may be causally associated with the development of MODS in the critically ill patient.
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