Case: A three year, 11 month old girl sustained a right displaced extension supracondylar fracture (ESF) of the humerus with comminution of the lateral column after an indoor fall. At surgery, fracture reduction showed multidirectional instability. Adequate reduction was achieved by applying longitudinal traction of the arm with partial elbow flexion and forearm supination. One percutaneous medial pin, followed by one lateral cross pin, was used to immobilize the fracture. Normal posterolateral new periosteal bone formation was seen on radiograph on the lateral side. At 5-year follow-up, she had full range of asymptomatic and symmetrical elbow motion. Conclusion: This case report shows a displaced ESF with a comminuted lateral humeral column, which contributed to a lack of adequate lateral pin purchase on bone. A modified pin fixation technique first with a medial pin and followed by a lateral pin with both placed through the medial column was used for stable fracture fixation. In addition, this case showed that fracture comminution was a contributory factor to the rare multidirectional instability of the Gartland Type IV fracture.

University of Miami Miller School of Medicine, Miami, FL *See also p. 748. Dr. Abraham has disclosed that he does not have any potential conflicts of interest.

Alveolar macrophages (AM) play a central role in initiation and resolution of lung inflammation, but the integration of these opposing core functions is poorly understood. AM expression of cholesterol 25-hydroxylase (CH25H), the primary biosynthetic enzyme for 25-hydroxycholesterol (25HC), far exceeds the expression of macrophages in other tissues, but no role for CH25H has been defined in lung biology. As 25HC is an agonist for the antiinflammatory nuclear receptor, liver X receptor (LXR), we speculated that CH25H might regulate inflammatory homeostasis in the lung. Here, we show that, of natural oxysterols or sterols, 2SHC is induced in the inflamed lung of mice and humans. Ch25h(-/-) mice fail to induce 25HC and LXR target genes in the lung after LPS inhalation and exhibit delayed resolution of airway neutrophilia, which can be rescued by systemic treatment with either 25HC or synthetic LXR agonists. LXR-null mice also display delayed resolution, suggesting that native oxysterols promote resolution. During resolution, Ch25h is induced in macrophages upon their encounter with apoptotic cells and is required for LXR-dependent prevention of AM lipid overload, induction of Mertk, efferocytic resolution of airway neutrophilia, and induction of TGF-beta. CH25H/2SHC/LXR is, thus, an inducible metabolic axis that programs AMs for efferocytic resolution of inflammation.

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.

Arthrogryposis multiplex congenita involves stiff contracture of joints and weak atrophic muscles presenting at birth. The two most common forms are amyoplasia and distal arthrogryposis. Amyoplasia affects all 4 extremities: internally rotated shoulders, extended fixed elbows, flexed fixed wrists, extended fixed knees, clubfeet, and decreased muscle volume. Distal arthrogryposis is a group of syndromes with a genetic basis. The distal joints are contracted. Clubfeet and congenital vertical talus are the most common foot deformities. A 10-year-old boy presented with distal arthrogryposis with bilateral congenital tali. He reported having deformed and painful feet and difficulty wearing shoes. His rocker-bottom foot deformities caused him to walk with a heel to heel gait. He also had stiff extended knees. His previous foot surgeries included failed open reduction and pin fixation of the talonavicular joints with Achilles tendon lengthening and capsulotomies. The boy underwent bilateral talectomies and releases of contracted joint capsules and lengthening of multiple extrinsic tendons through separate incisions. The talectomy of each foot was performed via a novel medial surgical approach. At 2-year follow-up, he had normal-appearing plantar grade feet. He had a painless gait, could ambulate independently, and was considered to have an excellent result. This is the first detailed report of performing a talectomy via a medial approach for bilateral congenital tali in a patient with arthrogryposis multiplex congenita. [ Orthopedics . 2020; 43(6):e623–e626.]

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.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. HMGB1 induces neutrophil dysfunction in experimental sepsis and in patients who survive septic shock Murielle Grégoire, Jean-Marc Tadié, Fabrice Uhel, Arnaud Gacouin, Caroline Piau, Nathaniel Bone, Yves Le Tulzo, Edward Abraham, Karin Tarte, Jaroslaw W. Zmijewski

In the version of this article originally published, a grant was omitted from the Acknowledgements section. The following sentence should have been included: "R.B.M. was supported by a Department of Veterans Affairs Merit Award (5I01BX003272)." The error has been corrected in the HTML and PDF versions of this article.

BACKGROUND:Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. METHODS:We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. RESULTS:Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment. CONCLUSIONS:This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.

The Editor-in-Chief of Critical Care Medicine thanks the following physicians and healthcare professionals for contributing their time and expertise to the review of the manuscripts submitted to Critical Care Medicine from the previous year. Peer review is one of the most important cornerstones assuring the publication of the highest quality science and medical research. We sincerely appreciate the enormous amount of time and effort expended in 2011 by our outstanding reviewers.

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.

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-β1-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.

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.

Sepsis is accompanied by the initial activation of proinflammatory pathways and long-lasting immunosuppression that appears to contribute to late-occurring mortality. Although high-mobility group box 1 (HMGB1) is involved in many aspects of inflammation, its role in sepsis-induced immune suppression remains unclear. In this study, we examined HMGB1's contribution to neutrophil NADPH oxidase activity dysfunction and associated neutrophil-dependent bacterial clearance in mice subjected to sepsis and in patients who survive septic shock. Using a murine model of polymicrobial septic peritonitis, we demonstrated that treatment with anti-HMGB1 Ab significantly diminished sepsis-induced dysfunction of neutrophil NADPH oxidase activity. In a subsequent set of experiments, we found that blocking HMGB1 preserved the ability of neutrophils from patients recovering from septic shock to activate NADPH oxidase. Taken together, our data suggest that HMGB1 accumulation in the late phase of sepsis plays a specific role in the development of postsepsis immunosuppression and specifically affects neutrophil-dependent antibacterial defense mechanisms. Thus, blocking HMGB1 may be a promising therapeutic intervention to diminish the adverse effects of sepsis-induced immunosuppression.

The diagnosis of sepsis is not a new concern. Indeed, as early as 700 BCE, the Greeks recognized Σήψις (sepsis), referring to decomposition or rot, as a life-threatening condition associated with infection and high riskofdeath.Theprimarycriterion for sepsis has historically been progressive organ system dysfunction resulting frominfection.Because theonlyavailable therapies for this condition, antimicrobials and supportive care, are not specific, therewas little concern about developingmore detailed standards for diagnosis. Over the past 30 years, 2 major factors have led to a perceived need for better definitions. In particular, the increasing sophistication, at least in high-income countries, of modalities available for organ support in critical care units, including ventilators and dialysis, has resulted in growing numbers of patients with sepsis receiving care in intensive care units (ICUs) and enhanced awareness of the frequency and high costs associated with this condition. In addition, greater understanding of the underlying pathophysiologic mechanisms responsible for cellular dysfunction in experimental models and in patients with severe infection has accelerated the need for better entry criteria in clinical trials using therapies specifically directed toward molecular events thought to contribute to sepsis-associated morbidity and mortality. In this issue of JAMA, the Sepsis Definitions Task Force presents 3 articles: the updated definitions for sepsis and sepsis shock1 and 2 supporting reports with evidence for derivation and validation of these new definitions.2,3 In their Special Communication, Singer and colleagues1 describe the importance, process used, issues addressed, key findings from the evidence, and synthesis to develop the third iteration of consensus conference definitions for sepsis and septic shock and present the new definitions in detail. Previous versions of these definitions date from 1992 and 2003.4,5 A major underpinning for the present effort was the use of analyses in large cohorts to provide quantitative information in support of the revised criteria. The accompanying report by Seymour and colleagues2 assesses the predictive validity of the Sequential [Sepsisrelated] Organ Failure Assessment score (SOFA), systemic inflammatory response syndrome (SIRS) criteria, and the Logistic Organ Dysfunction System (LODS) score and derived a new score called quickSOFA (qSOFA) in a primary cohort that included 148907 patient encounters with suspected sepsis and a confirmatory analysis that included 706399 out-ofhospital and hospital patient encounters at 165 US and non-US hospitals. The investigators found that among ICU encounters with suspected infection (n = 7932), the predictive validity for in-hospital mortality of SOFA (area under the receiver operating characteristic curve [AUROC], 0.74 [95% CI, 0.73-0.76]) was not significantly different than that derived from the more complex LODS (AUROC, 0.75 [95% CI, 0.73-0.76]) but was superior to that from SIRS (AUROC, 0.64 [95% CI, 0.62-0.66]), supporting use of SOFA in clinical criteria for sepsis. Among patient encounters with suspected infection outside the ICU (n = 66522), qSOFA had high predictive validity for in-hospital mortality (AUROC, 0.81 [95% CI, 0.80-0.82]) that was statistically greater than that for SIRS (AUROC, 0.76 [95% CI, 0.75-0.77]), suggesting that it may have utility as a prompt to consider possible sepsis. In the other accompanying report, Shankar-Hari and colleagues3 describe the process of developing a new definition and clinical criteria for identifying septic shock in adults. The authors conducted a systematic review and meta-analysis of 92 studies informing a Delphi process that created the new definition, then tested the variables identified by the Delphi process in cohort studies (Surviving Sepsis Campaign [n = 28 150; University of Pittsburgh Medical Center [n = 1 309025], and Kaiser Permanente Northern California [n = 1847 165]). According to the new definitions, sepsis is now defined as evidence of infection plus life-threatening organ dysfunction, clinically characterized by an acute change of 2 points or greater in the SOFA score. The new clinical criteria for septic shock include sepsis with fluid-unresponsive hypotension, serum lactate level greater than 2 mmol/L, and the need for vasopressors to maintain mean arterial pressure of 65 mmHg or greater. A major change in the new definitions is the elimination of mention of SIRS. Components of SIRS include tachycardia, tachypnea, hyperthermia or hypothermia, and abnormalities in peripheral white blood cell count. Many studies have shown that the presence of SIRS is nearly ubiquitous in hospitalized patients and occurs in many benign conditions, both related and not related to infection, and thus is not adequately specific for the diagnosis of sepsis.6 It is a strength of the consensus definition that it no longer includes SIRS. Patients with infections and organ dysfunction are exceptionally heterogeneous in terms of demographic characteristics, underlying conditions, microbiology, and other clinically relevant factors.7 The updated definition for sepsis, Related articles pages 762, 775 and 801 Opinion

Acute Respiratory Distress Syndrome (ARDS) severity may be influenced by heterogeneity of neutrophil activation. Interferon-stimulated genes (ISG) are a broad gene family induced by Type I interferons, often as a response to viral infections, which evokes extensive immunomodulation. We tested the hypothesis that over- or under-expression of immunomodulatory ISG by neutrophils is associated with worse clinical outcomes in patients with ARDS. Genome-wide transcriptional profiles of circulating neutrophils isolated from patients with sepsis-induced ARDS (n = 31) and healthy controls (n = 19) were used to characterize ISG expression. Hierarchical clustering of expression identified 3 distinct subject groups with Low, Mid and High ISG expression. ISG accounting for the greatest variability in expression were identified (MX1, IFIT1, and ISG15) and used to analyze a prospective cohort at the Colorado ARDS Network site. One hundred twenty ARDS patients from four urban hospitals were enrolled within 72 hours of initiation of mechanical ventilation. Circulating neutrophils were isolated from patients and expression of ISG determined by PCR. Samples were stratified by standard deviation from the mean into High (n = 21), Mid, (n = 82) or Low (n = 17) ISG expression. Clinical outcomes were compared between patients with High or Low ISG expression to those with Mid-range expression. At enrollment, there were no differences in age, gender, co-existing medical conditions, or type of physiologic injury between cohorts. After adjusting for age, race, gender and BMI, patients with either High or Low ISG expression had significantly worse clinical outcomes than those in the Mid for number of 28-day ventilator- and ICU-free days (P = 0.0006 and 0.0004), as well as 90-day mortality and 90-day home with unassisted breathing (P = 0.02 and 0.004). These findings suggest extremes of ISG expression by circulating neutrophils from ARDS patients recovered early in the syndrome are associated with poorer clinical outcomes.