Practice Variation between Salaried and Fee-for-Service Surgeons for Lumbar Surgery.

OBJECTIVE: To examine differences in surgical practices between salaried and fee-for-service (FFS) surgeons for two common degenerative spine conditions. Surgeons may offer different treatments for similar conditions on the basis of their compensation mechanism. METHODS: The study assessed the practices of 63 spine surgeons across eight Canadian provinces (39 FFS surgeons and 24 salaried) who performed surgery for two lumbar conditions: stable spinal stenosis and degenerative spondylolisthesis. The study included a multicenter, ambispective review of consecutive spine surgery patients enrolled in the Canadian Spine Outcomes and Research Network registry between October 2012 and July 2018. The primary outcome was the difference in type of procedures performed between the two groups. Secondary study variables included surgical characteristics, baseline patient factors, and patient-reported outcome. RESULTS: For stable spinal stenosis (n = 2234), salaried surgeons performed statistically fewer uninstrumented fusion (p < 0.05) than FFS surgeons. For degenerative spondylolisthesis (n = 1292), salaried surgeons performed significantly more instrumentation plus interbody fusions (p < 0.05). There were no statistical differences in patient-reported outcomes between the two groups. CONCLUSIONS: Surgeon compensation was associated with different approaches to stable lumbar spinal stenosis and degenerative lumbar spondylolisthesis. Salaried surgeons chose a more conservative approach to spinal stenosis and a more aggressive approach to degenerative spondylolisthesis, which highlights that remuneration is likely a minor determinant in the differences in practice of spinal surgery in Canada. Further research is needed to further elucidate which variables, other than patient demographics and financial incentives, influence surgical decision-making.

Temporal analysis of complication rates of cervical spine surgery for degenerative spine disease between younger and older cohorts using the CSORN registry: Is age just a number?

STUDY DESIGN: An ambispective review of consecutive cervical spine surgery patients enrolled in the Canadian Spine Outcomes and Research Network (CSORN) between January 2015 and September 2019. PURPOSE: To compare complication rates of degenerative cervical spine surgery over time between older (> 65) and younger age groups (< 65). More elderly people are having spinal surgery. Few studies have examined the temporal nature of complications of cervical spine surgery by patient age groups. METHODS: Adverse events were collected prospectively using adverse event forms. Binary logistic regression analysis was utilized to assess associations between risk modifiers and adverse events at the intra-, peri-operative and 3 months post-surgery. RESULTS: Of the 761 patients studied (age < 65, n = 581 (76.3%) and 65 + n = 180 (23.7%), the intra-op adverse events were not significantly different; < 65 = 19 (3.3%) vs 65 + = 11 (6.1%), p < 0.087. Peri-operatively, the < 65 group had significantly lower percentage of adverse events (65yrs (11.2%) vs. 65 + = (26.1%), p < 0.001). There were no differences in rates of adverse events at 3 months post-surgery (< 65 = 39 (6.7%) vs. 65 + = 12 (6.7%), p < 0.983). Less blood loss (OR = 0.99, p < 0.010) and shorter length of hospital stay (OR = 0.97, p < 0.025) were associated with not having intra-op adverse events. Peri-operatively, > 1 operated level (OR = 1.77, p < 0.041), shorter length of hospital stay (OR = 0.86, p < 0.001) and being younger than 65 years (OR = 2.11, p < 0.006) were associated with not having adverse events. CONCLUSION: Following degenerative cervical spine surgery, the older and younger age groups had significantly different complication rates at peri-operative time points, and the intra-operative and 3-month post-operative complication rates were similar in the groups.

The Ulnar Olecranon-Coronoid Notch Angle Affects Terminal Elbow Extension in Children and Adolescents.

BACKGROUND: Limitations to terminal elbow extension (TEE) in pediatric populations have been commonly associated with the degree of ligamentous laxity and not bony factors. Ligamentous laxity, quantified through the Beighton score, is criticized for unreliably assessing joint mobility. This study aims to show that the olecranon-coronoid notch angle (OCNA) affects TEE in healthy children and adolescents. METHODS: A retrospective study of 711 pediatric patients treated for upper extremity and shoulder injuries was cross-sectionally studied at 2 tertiary centers from 2014 to 2021. Radiographs were used to measure the OCNA, humerocondylar angle, proximal anterior ulnar angle, and the presence of secondary centers of ossification. A 2-axis goniometer measured clinical TEE to a firm endpoint. The statistical analysis studied the relationships between OCNA and TEE and the effect that age and sex have on these measurements. RESULTS: Increased TEE was associated with increased OCNA (P<0.001) when accounting for age and sex. The average OCNA was 30.0 degrees (7.5 degrees), and the average TEE was 5.6 degrees (8.0 degrees). There was a difference in OCNA between subjects who had elbow hypoextension, normal TEE, and elbow hyperextension (P<0.001). The most common injuries were distal radius fractures (182, 26%), elbow sprains and contusions (111, 16%), distal both bone forearm fractures (95, 14%), single or both bone shaft fractures (77, 11%), and supracondylar fractures (74, 11%). CONCLUSION: These results show that the orientation of the opening of the olecranon-coronoid notch influences the arc of TEE motion in a healthy pediatric population. The notch restrains TEE by activating the bony block mechanism between the olecranon apophysis and the olecranon fossa. The measurement of the OCNA can serve as a reproducible and quantitative method to predict hypomobility to hypermobility of TEE motion. LEVEL OF EVIDENCE: Prognostic study: Level II.

Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2.

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593-596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251-262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.

Variation in surgical treatment of degenerative spondylolisthesis in Canada: surgeon assessment of stability and impact on treatment.

INTRODUCTION: Controversy exists regarding the optimal surgical treatment of degenerative lumbar spondylolisthesis (DS). Not all DS patients are the same, and the degree to which inherent stability may dictate treatment is unknown. The purpose of this study was to determine the variability in surgical approach relative to surgeon classified stability. The secondary objective was to compare patient-reported outcomes (PROs) across different surgical techniques and grades of stability. METHODS: Patients prospectively enrolled from eleven tertiary care institutions and followed from 2015 to 2019. The surgical technique was at the surgeon's discretion. Surgeons were asked to grade the degree of instability based on the degenerative spondylolisthesis instability classification system (DSIC). DSIC categorizes three different types (I-stable, II-potentially unstable, and III-unstable). One-year changes in PROs were compared between each group. Multivariable regression was used to identify any characteristics that explained variability in treatment. RESULTS: There were 323 patients enrolled in this study. Surgeons' stability classification versus procedure [decompression alone (D)/decompression and posterolateral fusion (D-PL)/and decompression with posterior/transforaminal lumbar interbody fusion (D-PLIF/TLIF)] were as follows: type I (n = 91): D-41%/D-PL-13%/D-PLIF/TLIF-46%; type II (n = 175): D-23%/D-PL-17%/D-PLIF/TLIF-60%; and type III (n = 57):(D-0%/D-PL-14%/D-PLIF/TLIF-86%). Type I patients undergoing D-PL had some improvements in EQ-5D and NRS versus those undergoing D-PLIF/TLIF but otherwise there were no other significant differences between groups. Regression analysis demonstrated advanced age (OR = 1.06, CI 1.02-10.12) and type I (OR = 2.61, CI 1.17-5.81) were associated with receiving decompression surgery alone. CONCLUSIONS: There exists considerable variation in surgical management of DS in Canada. Given similar PROs in two of the three groups, there is potential to tailor surgical intervention and improve resource utilization.

A novel method for predicting superior gluteal nerve safe zones in the lateral approach to the hip.

INTRODUCTION: The superior gluteal nerve (SGN) is at risk for laceration during lateral approach total hip arthroplasty (THA). The purpose of this study is to assess the accuracy of the trochanter-to-iliac crest distance (TCD) and the nerve-to-trochanter distance (NTD) ratio in determining a reproducible safe zone around the SGN independent of height. MATERIALS AND METHODS: Eighteen hemipelvises were dissected and the SGNs were exposed. The distance (NTD) from greater trochanter (GT) to the most inferior branch of the SGN encountered in each of the three approaches (Bauer et al., 1979) was measured. A reference distance (TCD) was measured from the GT to the highest point on the iliac crest. The NTD was divided by the TCD to generate standardized ratios. Coefficient of variation CV = (SD/mean) × 100 was calculated for each distance and ratio to measure relative variability. RESULTS: The standardized ratios (and CV) were determined for the nerve branches in three different surgical approaches: Hardinge 0.464 (0.9%), Bauer 0.406 (1.7%), and Frndak 0.338 (4.1%). There was a strong correlation of the individual NTDs with the TCD: NTD for Hardinge (r = 0.996, p < .001), NTD for Bauer (r = 0.984, p < .001), and NTD for Frndak (r = 0.932, p < .001). CONCLUSION: By measuring the TCD preoperatively and using the respective standardized ratios, surgeons can accurately predict the NTD and how proximal to the GT each SGN branch can be expected to be encountered during lateral approach to the hip. This will allow surgeons to work with a more precise safe zone around the SGN and minimize the possibility for a nerve injury.

Opioid use trends in patients undergoing elective thoracic and lumbar spine surgery.

Background: Opioid use in North America has increased rapidly in recent years. Preoperative opioid use is associated with several negative outcomes. Our objectives were to assess patterns of opioid use over time in Canadian patients who undergo spine surgery and to determine the effect of spine surgery on 1-year postoperative opioid use. Methods: A retrospective analysis was performed on prospectively collected data from the Canadian Spine Outcomes and Research Network for patients undergoing elective thoracic and lumbar surgery. Self-reported opioid use at baseline, before surgery and at 1 year after surgery was compared. Baseline opioid use was compared by age, sex, radiologic diagnosis and presenting complaint. All patients meeting eligibility criteria from 2008 to 2017 were included. Results: A total of 3134 patients provided baseline opioid use data. No significant change in the proportion of patients taking daily (range 32.3%-38.2%) or intermittent (range 13.7%-22.5%) opioids was found from pre-2014 to 2017. Among patients who waited more than 6 weeks for surgery, the frequency of opioid use did not differ significantly between the baseline and preoperative time points. Significantly more patients using opioids had a chief complaint of back pain or radiculopathy than neurogenic claudication (p < 0.001), and significantly more were under 65 years of age than aged 65 years or older (p < 0.001). Approximately 41% of patients on daily opioids at baseline remained so at 1 year after surgery. Conclusion: These data suggest that additional opioid reduction strategies are needed in the population of patients undergoing elective thoracic and lumbar spine surgery. Spine surgeons can be involved in identifying patients taking opioids preoperatively, emphasizing the risks of continued opioid use and referring patients to appropriate evidence-based treatment programs.

Contexte: En Amérique du Nord, l'utilisation d'opioïdes a augmenté rapidement dans les dernières années. La prise d'opioïdes en période préopératoire est associée à plusieurs issues négatives. Cette étude visait à évaluer l'évolution des tendances dans l'utilisation d'opioïdes des patients canadiens ayant subi une chirurgie spinale, et de déterminer les effets de la chirurgie sur leur utilisation 1 an après l'opération. Méthodes: Une analyse rétrospective a été réalisée à partir de données recueillies de manière prospective par le Canadian Spine Outcomes and Research Network pour les patients ayant subi une chirurgie thoracique ou une chirurgie spinale élective. On a comparé l'utilisation autodéclarée d'opioïdes au début du suivi, avant la chirurgie et 1 an après la chirurgie. L'utilisation d'opioïdes au départ a été comparée selon le sexe, l'âge, le diagnostic radiologique et le motif de consultation. Entre 2008 et 2017, tous les patients satisfaisant aux critères d'admissibilités ont été inclus dans l'étude. Résultats: Au total, 3134 patients ont fourni des données sur leur prise d'opioïdes au début du suivi. Il n'y avait pas de changement significatif dans la proportion de patients utilisant quotidiennement (32,3 % à 38,2 %) ou occasionnellement (13,7 % à 22,5 %) des opioïdes entre les patients à l'étude avant 2014 et ceux à l'étude de 2014 à 2017. Parmi les patients qui ont attendu plus de 6 semaines avant la chirurgie, la fréquence de la prise d'opioïdes n'a pas changé de manière significative entre le début du suivi et la rencontre préopératoire. Une proportion significativement plus grande de patients qui utilisaient des opioïdes consultaient principalement pour des douleurs au dos ou une radiculopathie que pour une claudication neurogène (p < 0,001), et il y avait une proportion significativement plus grande de patients de moins de 65 ans qui utilisaient des opioïdes que de patients de 65 ans ou plus (p < 0,001). Environ 41 % des patients qui prenaient quotidiennement des opioïdes au départ le faisaient aussi 1 an après la chirurgie. Conclusion: Ces données suggèrent que des stratégies supplémentaires de réduction de l'utilisation d'opioïdes sont nécessaires pour les patients qui subissent une chirurgie thoracique ou une chirurgie spinale élective. Il est possible de demander aux chirurgiens spécialisés dans ce domaine de repérer les patients qui prennent des opioïdes avant l'opération, puisque l'utilisation prolongée comporte des risques, et de les aiguiller vers un programme de traitement adéquat et fondé sur des données probantes.

New Single-stage Double Osteotomy for Late-presenting Infantile Tibia Vara: A Comprehensive Approach.

BACKGROUND: Successful surgical treatment of late-presenting infantile tibia vara (ITV) patient requires the correction of oblique deformities. The purpose of this study was to report on a new comprehensive approach to correct and prevent recurrence of these deformities with a single procedure. METHODS: Medical records of 23 consecutive children (7 to 18 y) with advanced ITV (29 knees) were retrospectively reviewed after a mean of 7.3 years postoperatively (range, 2 to 22 y). Indications for the corrective surgery were any child 7 year or older with a varus mechanical axis angle ≥10 degrees or a varus anatomic axis angle ≥11 degrees and a medial tibial angle (MTA) slope <60 degrees. The deformities were corrected with a dome-shaped osteotomy proximal to the tibial tubercle with a midline vertical extension to the subchondral region of the joint and a lateral hemi-epiphysiodesis. RESULTS: At latest follow-up, means and medians of each tibial radiographic axis measurement improved significantly from preoperative values (P<0.001): mechanical axis angle from 23 degrees to 4 degrees varus, anatomic axis angle from 25 degrees varus to 1 degree valgus, MTA downward slope from 30 to 78 degrees, posterior MTA from 59 to 80 degrees. In total, 79% and 74% had good to excellent results based on radiographic criteria and clinical questionnaire for satisfaction, pain and function, respectively. Two abnormal medial tibial plateau types were described. CONCLUSIONS: This is the first study to use a single-stage double osteotomy performed proximal to the tibial tubercle for the late-presenting ITV for children 7 years of age or older. In addition to the effective correction of the 4 major tibial deformities, a lateral proximal tibial hemi-epiphysiodesis minimizes recurrence of tibia vara. A contralateral proximal tibial epiphysiodesis is recommended for treated skeletally immature patients with unilateral disease. LEVEL OF EVIDENCE: Therapeutic level IV. See instructions for authors for a complete description of levels of evidence.

Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis.

Metabolic reprogramming has been intrinsically linked to macrophage activation. Alveolar macrophages are known to play an important role in the pathogenesis of pulmonary fibrosis. However, systematic characterization of expression profile in these cells is still lacking. Furthermore, main metabolic programs and their regulation of cellular phenotype are completely unknown. In this study, we comprehensively analyzed the expression profile and main metabolic programs in alveolar macrophages from mice with or without experimental pulmonary fibrosis. We found that alveolar macrophages from both bleomycin and active TGF-ß1-induced fibrotic mouse lungs demonstrated a primarily profibrotic M2-like profile that was distinct from the well-defined M1 or any of the M2 subtypes. More importantly, we found that fibrotic lung alveolar macrophages assumed augmented glycolysis, which was likely attributed to enhanced expression of multiple key glycolytic mediators. We also found that fatty acid oxidation was upregulated in these cells. However, the profibrotic M2-like profile of fibrotic lung alveolar macrophages was not dependent on fatty acid oxidation and synthesis or lipolysis, but instead on glycolysis, in contrast to the typical IL-4-induced macrophages M(IL-4). Additionally, glutaminolysis, a key metabolic program that has been implicated in numerous pathologies, was not required for the profibrotic M2-like phenotype of these macrophages. In summary, our study identifies a unique expression and metabolic profile in alveolar macrophages from fibrotic lungs and suggests glycolytic inhibition as an effective antifibrotic strategy in treating lung fibrosis.

Alternative pre-mRNA splicing of Toll-like receptor signaling components in peripheral blood mononuclear cells from patients with ARDS.

A key physiological feature of acute respiratory distress syndrome (ARDS) is inflammation. Toll-like receptor (TLR) signaling is required to combat the infection that underlies many ARDS cases but also contributes to pathological inflammation. Several TLR signaling pathway genes encoding positive effectors of inflammation also produce alternatively spliced mRNAs encoding negative regulators of inflammation. An imbalance between these isoforms could contribute to pathological inflammation and disease severity. To determine whether splicing in TLR pathways is altered in patients with ARDS, we monitored alternative splicing of MyD88 and IRAK1, two genes that function in multiple TLR pathways. The MyD88 and IRAK1 genes produce long proinflammatory mRNAs (MyD88L and IRAK1) and shorter anti-inflammatory mRNAs (MyD88S and IRAK1c). We quantified mRNA encoding inflammatory cytokines and MyD88 and IRAK1 isoforms in peripheral blood mononuclear cells (PBMCs) from 104 patients with ARDS and 30 healthy control subjects. We found that MyD88 pre-mRNA splicing is altered in patients with ARDS in a proinflammatory direction. We also observed altered MyD88 isoform levels in a second critically ill patient cohort, suggesting that these changes may not be unique to ARDS. Early in ARDS, PBMC IRAK1c levels were associated with patient survival. Despite the similarities in MyD88 and IRAK1 alternative splicing observed in previous in vitro studies, there were differences in how MyD88 and IRAK1 alternative splicing was altered in patients with ARDS. We conclude that pre-mRNA splicing of TLR signaling genes is altered in patients with ARDS, and further investigation of altered splicing may lead to novel prognostic and therapeutic approaches.

Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism.

The M1 and M2 polarized phenotypes dictate distinctive roles for macrophages as they participate in inflammatory disorders. There has been growing interest in the role of cellular metabolism in macrophage polarization. However, it is currently unclear whether different aspects of a specific metabolic program coordinately regulate this cellular process. In this study, we found that pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, plays an important role in the differential activation of macrophages. Knockdown of PDK1 diminished M1, whereas it enhanced M2 activation of macrophages. Mechanistically, PDK1 knockdown led to diminished aerobic glycolysis in M1 macrophages, which likely accounts for the attenuated inflammatory response in these cells. Furthermore, we found that mitochondrial respiration is enhanced during and required by the early activation of M2 macrophages. Suppression of glucose oxidation, but not that of fatty acids, inhibits this process. Consistent with its inhibitory role in early M2 activation, knockdown of PDK1 enhanced mitochondrial respiration in macrophages. Our data suggest that two arms of the glucose metabolism synergistically regulate the differential activation of macrophages. Our findings also highlight the central role of PDK1 in this event via controlling glycolysis and glucose oxidation.

Biopsychosocial factors predict quality of life in thoracolumbar spine surgery.

PURPOSE: Surgical intervention is a treatment option for various spinal pathology but many patients report no improvement or even an exacerbation of symptoms like pain. This study examined the association of preoperative (pre-op) biopsychosocial risk factors with poor quality of life at 2 and 6 months using hierarchical models controlling demographic and medical variables. METHOD: Participants undergoing thoracolumbar spine surgery (N = 214) were provided with questionnaire packages to complete pre-op, at 2 and at 6-month postoperative clinical follow-ups (i.e., demographics, psychosocial measures, SF-12, medical, and clinical measures). The surgeon recorded surgical measures. RESULTS: Examining the pre-op period only, greater age and medication use (for back symptoms) were associated with poorer physical quality of life [physical component summary score (PCS)], while greater catastrophizing, depression, and lower social support were associated with poorer mental QoL [mental component summary score (MCS)]. Lower preoperative PCS, social support, and greater kinesiophobia were associated with diminished PCS at 2-month. Higher pre-op MCS and higher social support was associated with better MCS at 2-month. Poorer PCS at 6-month was associated with older age and low social support, while diminished MCS was associated with lower pre-op social support, MCS, and longer time in the operation room. Preoperative kinesiophobia partially mediated the relationship between pre-op PCS and 2-month PCS. Age partially mediated the relationship between pre-op PCS and at 6-month. For MCS, social support was the lone partial mediator of baseline MCS and both 2 and 6-month MCS. CONCLUSION: These results show that preoperative psychosocial variables are significantly associated with poorer postoperative health-related QoL outcomes following spinal surgeries, supporting a biopsychosocial pre-op care map.

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3ß Modulate the Severity of Sepsis-Induced Lung Injury.

Alterations in metabolic and bioenergetic homeostasis contribute to sepsis-mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3ß signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteria ex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3ß inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicate P. aeruginosa in the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF-1α as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression.

miR-27a regulates inflammatory response of macrophages by targeting IL-10.

Although microRNAs were shown to participate in innate immune responses, it is not completely understood how they regulate negative immunomodulatory events. IL-10 is an important anti-inflammatory mediator that prevents excessive inflammation and associated immunological pathologies. Although the regulation of IL-10 expression has been well studied at both the transcriptional and translational levels, it is less clear how microRNAs control IL-10 expression during inflammation. In this study, we found that miR-27a is downregulated in macrophages following stimulation through TLR2 and TLR4, but not TLR3. Upregulation of miR-27a enhanced the expression of proinflammatory cytokines in TLR2/4-activated macrophages. Conversely, knockdown of miR-27a diminished cytokine expression. Mechanistically, we found that miR-27a negatively regulates IL-10 expression; upregulation of miR-27a decreases, whereas downregulation of miR-27a increases, IL-10 expression in activated macrophages. Likely due to the decreased expression of IL-10, upregulation of miR-27a diminished IL-10-dependent STAT3 phosphorylation in TLR4-activated macrophages. Consistent with IL-10 being a potential mediator for the role of miR-27a in the immune response, blocking IL-10 abolished the enhancing effect of miR-27a on TLR4-activated inflammation. In conclusion, our study identified miR-27a downregulation as a negative-regulatory mechanism that prevents overly exuberant TLR2- and TLR4-driven inflammatory responses.

Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular trap formation and increases severity of acute lung injury.

Although resistin was recently found to modulate insulin resistance in preclinical models of type II diabetes and obesity, recent studies also suggested that resistin has proinflammatory properties. We examined whether the human-specific variant of resistin affects neutrophil activation and the severity of LPS-induced acute lung injury. Because human and mouse resistin have distinct patterns of tissue distribution, experiments were performed using humanized resistin mice that exclusively express human resistin (hRTN(+/-)(/-)) but are deficient in mouse resistin. Enhanced production of TNF-α or MIP-2 was found in LPS-treated hRtn(+/-/-) neutrophils compared with control Rtn(-/-/-) neutrophils. Expression of human resistin inhibited the activation of AMP-activated protein kinase, a major sensor and regulator of cellular bioenergetics that also is implicated in inhibiting inflammatory activity of neutrophils and macrophages. In addition to the ability of resistin to sensitize neutrophils to LPS stimulation, human resistin enhanced neutrophil extracellular trap formation. In LPS-induced acute lung injury, humanized resistin mice demonstrated enhanced production of proinflammatory cytokines, more severe pulmonary edema, increased neutrophil extracellular trap formation, and elevated concentration of the alarmins HMGB1 and histone 3 in the lungs. Our results suggest that human resistin may play an important contributory role in enhancing TLR4-induced inflammatory responses, and it may be a target for future therapies aimed at reducing the severity of acute lung injury and other inflammatory situations in which neutrophils play a major role.

Subsets of airway myeloid-derived regulatory cells distinguish mild asthma from chronic obstructive pulmonary disease.

BACKGROUND: Subsets of myeloid-derived regulatory cells (MDRCs), which are phenotypically similar to the myeloid-derived suppressor cells found in patients with cancer, have recently been appreciated as critical regulators of airway inflammation in mouse models of asthma. OBJECTIVE: We test the hypothesis that subsets of airway MDRCs contribute differentially to the inflammatory milieu in human asthma and chronic obstructive pulmonary disease (COPD). METHODS: We used bronchoalveolar lavage to identify and characterize human airway MDRCs from 10 healthy subjects, 9 patients with mild asthma, and 8 patients with COPD, none of whom were treated with inhaled or systemic corticosteroids. We defined subsets of airway MDRCs using flow cytometry, the molecular mediators they produce, and their abilities to regulate proliferation of polyclonally activated autologous T lymphocytes. RESULTS: We found substantial differences in the functional potential of MDRC subsets in healthy subjects, patients with asthma, and patients with COPD, with these differences regulated by the nitrosative and oxidative free radicals and cytokines they produced. Nitric oxide-producing MDRCs suppressed and superoxide-producing MDRCs enhanced proliferation of polyclonally activated autologous CD4 T cells. HLA-DR(+)CD11b(+)CD11c(+)CD163(-) superoxide-producing MDRCs, which stimulated proliferation of autologous T cells, comprised a high fraction of MDRCs in the airways of patients with mild asthma or COPD but not those of healthy control subjects. CD11b(+)CD14(+)CD16(-)HLA-DR(-) nitric oxide-producing MDRCs, which suppressed T-cell proliferation, were present in high numbers in airways of patients with mild asthma but not patients with COPD or healthy control subjects. CONCLUSION: Subsets of airway MDRCs conclusively discriminate patients with mild asthma, patients with COPD, and healthy subjects from each other. The distinctive activities of these MDRCs in patients with asthma or COPD might provide novel targets for new therapeutics for these common disorders. [Corrected]

Pneumonia prevention to decrease mortality in intensive care unit: a systematic review and meta-analysis.

BACKGROUND: To determine the strategies of prevention of hospital-acquired pneumonia that reduce mortality in intensive care unit (ICU). METHODS: We followed PRISMA (Preferred Reported Items for Systemic Reviews and Meta-Analyses) guidelines. We searched MEDLINE and the Cochrane Controlled Trials Register (through 10 June 2014) as well as reference lists of articles. We included all randomized controlled trials conducted in critically ill adult patients hospitalized in ICUs and evaluating digestive prophylactic methods (selective digestive decontamination [SDD], acidification of gastric content, early enteral feeding, prevention of microinhalation); circuit prophylactic methods (closed suctioning systems, early tracheotomy, aerosolized antibiotics, humidification, lung secretion drainage, silver-coated endotracheal tubes) or oropharyngeal prophylactic methods (selective oropharyngeal decontamination, patient position, sinusitis prophylaxis, subglottic secretion drainage, tracheal cuff monitoring). One reviewer extracted data that were checked by 3 others. The primary outcome was the mortality rate in the ICU. RESULTS: We identified 157 randomized trials to pool in a meta-analysis. The primary outcome was available in 145 studies (n = 37 156). The risk ratio (RR) for death was 0.95 (95% confidence interval [CI], .92-.99; P = .02) in the intervention groups. In subgroup analysis, only SDD significantly decreased mortality compared with control (n = 10 227; RR, 0.84 [95% CI, .76-.92; P < .001]). The RR for in-ICU death was 0.78 (95% CI, .69-.89; P < .001; I(2) = 33%) in trials investigating SDD with systemic antimicrobial therapy and 1.00 (.84-1.21; P = .96; I(2) = 0%) without systemic antimicrobial therapy. CONCLUSIONS: Selective digestive decontamination with systemic antimicrobial therapy reduced mortality and should be considered in critically ill patients at high risk for death.

The human long noncoding RNA lnc-IL7R regulates the inflammatory response.

Long noncoding RNAs (lncRNAs), once thought to be transcriptional noise, have been recently shown to regulate a variety of biological processes. However, there is not much knowledge regarding their roles in the inflammatory response. In this study, we performed human lncRNA microarray assays and identified a number of lncRNAs that demonstrated altered expression in response to LPS stimulation. Of these lncRNAs, lnc-IL7R, which overlaps with the 3'untranslated region (3'UTR) of the human interleukin-7 receptor α-subunit gene (IL7R) gene, was significantly upregulated in LPS-treated cells. Functionally, lnc-IL7R was capable of diminishing the LPS-induced inflammatory response, demonstrated by elevated expression of LPS-induced E-selectin, VCAM-1, IL-6, and IL-8 in lnc-IL7R knockdown cells. Mechanistically, we found that lnc-IL7R knockdown diminished trimethylation of histone H3 at lysine 27 (H3K27me3), a hallmark of silent transcription, at the proximal promoters of the inflammatory mediators. Our data suggest that lnc-IL7R contributes another layer of complexity in regulation of the inflammatory response.