Loma Linda University Medical Center

Introduction Periprosthetic joint infection (PJI) is one of the most challenging and frequent complications after lower-extremity joint (hip and knee) arthroplasty. However, there is no single accepted set of diagnostic criteria for PJI. Various definitions have been proposed; however, none have been widely adopted. Furthermore, some of these definitions disagree with each other [14]. Therefore, a workgroup convened by the Musculoskeletal Infection Society (MSIS) analyzed the available evidence to propose a new definition for PJI. A summary of recommendations of those in attendance at a premeeting workshop of the 21st Annual Meeting of the MSIS on August 4, 2011, pertaining to the definition of PJI is outlined below. Existing published data on the definition of PJI was discussed by e-mail in the preceding 6 months by the executive members of the MSIS and a group of experts with known interest in this field. The intention of this proposal is to have a “gold standard” definition for PJI that can be universally adopted by all physicians, surveillance authorities (including the Centers for Disease Control, medical and surgical journals, the medicolegal community), and all involved in management of PJI. The panel acknowledged, in certain low-grade infections (ie, Propionibacterium acnes), several of these criteria may not be routinely met despite the presence of PJI. Using this definition, clinicians can be confident in their diagnosis and therefore provide appropriate treatment. Additionally, adoption of this definition for research purposes will allow for consistency between studies and potential improvement of the quality of the published body of evidence. Definition of Periprosthetic Joint Infection Based on the proposed criteria, definite PJI exists when: There is a sinus tract communicating with the prosthesis; or A pathogen is isolated by culture from at least two separate tissue or fluid samples obtained from the affected prosthetic joint; or Four of the following six criteria exist: Elevated serum erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) concentration, Elevated synovial leukocyte count, Elevated synovial neutrophil percentage (PMN%), Presence of purulence in the affected joint, Isolation of a microorganism in one culture of periprosthetic tissue or fluid, or Greater than five neutrophils per high-power field in five high-power fields observed from histologic analysis of periprosthetic tissue at ×400 magnification. PJI may be present if fewer than four of these criteria are met. Considerations Microbiologic Testing It is imperative that tissue for culture be obtained from representative periprosthetic tissue or fluid. To limit the risk of contamination, each sample should be taken with separate, sterile instruments. The definition of phenotypically identical organisms should be based on phenotypic similarities and in vitro antimicrobial susceptibility testing since confirmation of genetic identity is not routinely performed on clinical isolates. We recommend that at least three and no more than five periprosthetic specimen culture samples are taken and incubated in an aerobic and anaerobic environment. Fungal and mycobacterial cultures should not be performed routinely and reserved to higher-risk scenarios. The time of culture incubation has not been standardized yet. Isolation of a single low-virulence pathogen such as coagulase-negative Staphylococcus, P. acnes, or Corynebacteria in the absence of other criteria is not believed to represent a definite infection. Isolation of a single virulent organism such as S. aureus may represent a PJI. Furthermore, recent evidence has identified that certain tests, such as Gram stain, of periprosthetic tissue or fluid are not sensitive in diagnosing PJI [7]. Serum Tests Based on previous publications, an ESR of greater than 30 mm/hour and a CRP of greater than 10 mg/L would represent elevated levels [11, 15]. However, it is important to note there are variations in measuring these markers between laboratories. Furthermore, the level of these serum markers is affected by age, sex, and medical comorbidities of the patient. It has also been reported these markers can be elevated for approximately 30 to 60 days in the immediate postoperative period [3, 9]. Synovial Tests Multiple studies have provided thresholds for synovial leukocyte count and PMN% in the differential. In the chronically infected knee arthroplasty, these values have been reported from 1100 to 4000 cells/μL and 64% to 69%, respectively [5, 8, 16]. In patients with acute infections, the levels of synovial cell count and PMN% are much higher (approximately 20,000 cells/μL and 89%, respectively). Acute infections are defined as less than 3 months from index surgery or from the onset of symptoms [1]. The levels of synovial cell count and PMN% in the infected hip arthroplasty are not well delineated. A sole study has provided a threshold of 3000 cells/μL for leukocytes and 80% for PMN% for the infected hip arthroplasty [15]. None of these studies have included patients with underlying inflammatory arthropathies and related diseases. Current research is proceeding to provide more definitive thresholds for all patients. Histology Examination of periprosthetic tissues for evidence of neutrophils has been traditionally conducted by specially trained musculoskeletal pathologists. Histologic examination consequently may be operator dependent. It is therefore incumbent on surgeons to ensure their pathologists are in agreement with the diagnostic criteria for PJI. When examining for the presence of neutrophils, the histopathologist should disregard neutrophils entrapped in superficial fibrin or adherent to endothelium or small veins. Also, caution should be exercised in analyzing this test in cases where elevated neutrophil count might be expected, such as recent periprosthetic fractures or inflammatory arthropathy. Future Developments This proposed definition was based on current evidence supporting the role of various tests in diagnosis of PJI that are available in the literature. We recognize there are numerous other tests currently being evaluated, including measurement of CRP from the synovial fluid [12], synovial leukocyte esterase [13], sonication of explanted prosthetics [17], and molecular techniques such as PCR [10] and other molecular markers such as IL-6 [2, 4, 6]. As these or other techniques become validated and widely available, the currently proposed definition may require modification. Acknowledgments We thank the following individuals for their involvement and invaluable input throughout the development of this document: Robert Barrack MD, Keith Berend MD, Sandra Berrios-Torres (from Centers for Disease Control and Prevention), Kevin Bozic MD, John Esterhai MD, Ryan Fagan (from Centers for Disease Control and Prevention), Thomas Fehring MD, Terry Gioe MD, Teresa Horan (from Centers for Disease Control and Prevention), Steven Kurtz PhD, Bas Masri MD, Arvind Nana MD, Douglas Osmon MD, John Segreti MD, and Mark Spangehl MD.

OBJECTIVE: Serial lactate concentrations can be used to examine disease severity in the intensive care unit. This study examines the clinical utility of the lactate clearance before intensive care unit admission (during the most proximal period of disease presentation) as an indicator of outcome in severe sepsis and septic shock. We hypothesize that a high lactate clearance in 6 hrs is associated with decreased mortality rate. DESIGN: Prospective observational study. SETTING: An urban emergency department and intensive care unit over a 1-yr period. PATIENTS: A convenience cohort of patients with severe sepsis or septic shock. INTERVENTIONS: Therapy was initiated in the emergency department and continued in the intensive care unit, including central venous and arterial catheterization, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, and inotropes when appropriate. MEASUREMENTS AND MAIN RESULTS: Vital signs, laboratory values, and Acute Physiology and Chronic Health Evaluation (APACHE) II score were obtained at hour 0 (emergency department presentation), hour 6, and over the first 72 hrs of hospitalization. Therapy given in the emergency department and intensive care unit was recorded. Lactate clearance was defined as the percent decrease in lactate from emergency department presentation to hour 6. Logistic regression analysis was performed to determine independent variables associated with mortality. One hundred and eleven patients were enrolled with mean age 64.9 +/- 16.7 yrs, emergency department length of stay 6.3 +/- 3.2 hrs, and overall in-hospital mortality rate 42.3%. Baseline APACHE II score was 20.2 +/- 6.8 and lactate 6.9 +/- 4.6 mmol/L. Survivors compared with nonsurvivors had a lactate clearance of 38.1 +/- 34.6 vs. 12.0 +/- 51.6%, respectively (p =.005). Multivariate logistic regression analysis of statistically significant univariate variables showed lactate clearance to have a significant inverse relationship with mortality (p =.04). There was an approximately 11% decrease likelihood of mortality for each 10% increase in lactate clearance. Patients with a lactate clearance> or =10%, relative to patients with a lactate clearance <10%, had a greater decrease in APACHE II score over the 72-hr study period and a lower 60-day mortality rate (p =.007). CONCLUSIONS: Lactate clearance early in the hospital course may indicate a resolution of global tissue hypoxia and is associated with decreased mortality rate. Patients with higher lactate clearance after 6 hrs of emergency department intervention have improved outcome compared with those with lower lactate clearance.

This guideline has been approved by the AASLD and represents the position of the Association. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently-published world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the author's decades of experience caring for patients with cirrhosis and ascites. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines3).4 These guidelines were developed for the care of adult patients with clinically detectable ascites. Although the general approach may be applicable to children, the pediatric database is much smaller and there may be unanticipated differences between adults and children. Patients with ascites detected only by imaging modalities but not yet clinically evident are excluded because of the lack of published information regarding the natural history of this entity. A Medline search from 1966 through 2007 was performed; search terms included ascites, hepatorenal syndrome, diet therapy, drug therapy, radiotherapy, surgery, and therapy. The search involved only articles published in English and involving humans. A manual search of the author's files and recent abstracts was also performed. The search yielded 2115 articles including 153 published since a similar search was performed in 2002 in preparation for writing the previous guideline on ascites. AASLD, American Association for the Study of Liver Diseases; LDH, lactate dehydrogenase; PMN, polymorphonuclear leukocyte; SAAG, serum-ascites albumin gradient; SBP, spontaneous bacterial peritonitis; TIPS, transjugular intrahepatic portasystemic stent-shunt. Cirrhosis was the twelfth leading cause of death in the United States, according to a 2006 Vital Statistics Report in which data were collected through 2004.5 Ascites is the most common of the three major complications of cirrhosis; the other complications are hepatic encephalopathy and variceal hemorrhage.6 Approximately 50% of patients with “compensated” cirrhosis, i.e., without having developed one of these complications, develop ascites during 10 years of observation.6 Ascites is the most common complication of cirrhosis that leads to hospital admission.7 The pathophysiology of ascites and hepatorenal syndrome have been reviewed elsewhere.8 Development of fluid retention in the setting of cirrhosis is an important landmark in the natural history of chronic liver disease: of patients with ascites in and in patients are for liver of ascites. patients with ascites in the United have cirrhosis (Table of patients with ascites, there is a cause of fluid is on an of the cause of not to therapy. 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PURPOSE To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes. PATIENTS AND METHODS Men with T1b-T2b prostate cancer and prostate-specific antigen </= 15 ng/mL were randomly assigned to a total dose of either 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high). No patient received androgen suppression therapy with radiation. Local failure (LF), biochemical failure (BF), and overall survival (OS) were outcomes. Results A total of 393 men were randomly assigned, and median follow-up was 8.9 years. Men receiving high-dose radiation therapy were significantly less likely to have LF, with a hazard ratio of 0.57. The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4% for conventional-dose and 16.7% for high-dose radiation therapy (P < .0001). This difference held when only those with low-risk disease (n = 227; 58% of total) were examined: 28.2% for conventional and 7.1% for high dose (P < .0001). There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1% v 30.4%, P = .06). Eleven percent of patients subsequently required androgen deprivation for recurrence after conventional dose compared with 6% after high dose (P = .047). There remains no difference in OS rates between the treatment arms (78.4% v 83.4%; P = .41). Two percent of patients in both arms experienced late grade >/= 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade >/= 3 GI toxicity. CONCLUSION This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade >/= 3 late urinary or rectal morbidity.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a rare multisystemic fibrosing disorder that principally affects the skin but may affect other organs of patients with renal insufficiency. The purpose of our study was to identify any common risk factors and determine whether i.v. gadodiamide is associated with the development of NSF. MATERIALS AND METHODS: A retrospective chart review was performed for all 12 patients diagnosed with NSF at our institution between 2000 and 2006 to identify the clinical manifestations, timing, and dose of gadodiamide administration; dialysis records; concurrent medications; comorbid conditions and surgeries; laboratory findings; imaging findings; and clinical outcome. A review of the dialysis and MR records between 2000 and 2006 showed 559 MRI examinations on 168 dialysis patients (including 301 contrast-enhanced examinations). RESULTS: NSF was diagnosed by clinical findings and tissue diagnosis. All 12 patients had renal insufficiency--eight with dialysis-dependent chronic renal insufficiency and four with acute hepatorenal syndrome. All 12 patients developed skin fibrosis within 2-11 weeks after gadodiamide administration. The odds ratio for development of NSF after gadodiamide exposure was 22.3. No other common event or exposure could be found. Four patients had abnormal scintigraphic bone scans with skin and muscle uptake and lower-extremity MRI finding of edema in the muscles, intermuscular fascia, and skin. Despite the fact that 10 patients were dialyzed within 2 days of gadodiamide administration, this did not prevent the development of NSF. CONCLUSION: Development of NSF was strongly associated with gadodiamide administration in the setting of either acute hepatorenal syndrome or dialysis-dependent chronic renal insufficiency.

Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.

OBJECT: Local tumor control, patient survival, and treatment failure outcomes were analyzed to assess treatment efficacy in 58 patients in whom fractionated proton radiation therapy (RT) was administered for skull base chordomas and chondrosarcomas. METHODS: Between March 1992 and January 1998, a total of 58 patients who could be evaluated were treated for skull base tumors, 33 for chordoma and 25 for chondrosarcoma. Following various surgical procedures, residual tumor was detected in 91% of patients; 59% demonstrated brainstem involvement. Target dosages ranged from 64.8 and 79.2 (mean 70.7) Co Gy equivalent. The range of follow up was 7 to 75 months (mean 33 months). In 10 patients (17%) the treatment failed locally, resulting in local control rates of 92% (23 of 25 patients) for chondrosarcomas and 76% (25 of 33 patients) for chordomas. Tumor volume and brainstem involvement influenced control rates. All tumors with volumes of 25 ml or less remained locally controlled, compared with 56% of tumors larger than 25 ml (p = 0.02); 94% of patients without brainstem involvement did not experience recurrence; in patients with brainstem involvement (and dose reduction because of brainstem tolerance constraints) the authors achieved a tumor control rate of 53% (p = 0.04). Three patients died of their disease, and one died of intercurrent disease. Actuarial 5-year survival rates were 100% for patients with chondrosarcoma and 79% for patients with chordoma. Grade 3 and 4 late toxicities were observed in four patients (7%) and were symptomatic in three (5%). CONCLUSIONS: High-dose proton RT offers excellent chances of lasting tumor control and survival, with acceptable risks. In this series all small- and medium-sized tumors with no demonstrable brainstem involvement have been controlled; all such patients are alive. Surgical debulking enhanced delivery of full tumoricidal doses, but even patients with large tumors and disease abutting crucial normal structures benefited.

Ascites is the most common of the major complications of cirrhosis. The development of ascites is an important landmark in the natural history of cirrhosis and has been proposed as an indication for liver transplantation. The initial evaluation of a patient with ascites should include a history, physical evaluation, and abdominal paracentesis with ascitic fluid analysis. Treatment should consist of abstinence from alcohol, sodium restricted diet, and diuretics. This regimen is effective in approximately 90% of patients. The treatment options for the diuretic-resistant patients include serial therapeutic paracenteses, liver transplantation, and peritoneovenous shunting.

BACKGROUND: When challenged with extracellular fluid shear stress, vascular endothelial cells are known to release nitric oxide, an important vasodilator. Here, we show that the ability of cultured endothelial cells to sense a low range of fluid shear depends on apical membrane organelles, called cilia, and that cilia are compartments required for proper localization and function of the mechanosensitive polycystin-1 molecule. METHODS AND RESULTS: Cells with the Pkd1(null/null) or Tg737(orpk/orpk) mutation encoded for polycystin-1 or polaris, respectively, are unable to transmit extracellular shear stress into intracellular calcium signaling and biochemical nitric oxide synthesis. Cytosolic calcium and nitric oxide recordings further show that fluid shear sensing is a cilia-specific mechanism because other mechanical or pharmacological stimulation does not abolish calcium and nitric oxide signaling in polycystin-1 and polaris mutant endothelial cells. Polycystin-1 localized in the basal body of Tg737(orpk/orpk) endothelial cells is insufficient for a fluid shear stress response. Furthermore, the optimal shear stress to which the cells respond best does not alter the apical cilia structure but modifies the responsiveness of cells to higher shear stresses through proteolytic modification of polycystin-1. CONCLUSIONS: We demonstrate for the first time that polycystin-1 (required for cilia function) and polaris (required for cilia structure) are crucial mechanosensitive molecules in endothelial cells. We propose that a distinctive communication with the extracellular microenvironment depends on the proper localization and function of polycystin-1 in cilia.

BACKGROUND: The National Cardiogenic Shock Initiative is a single-arm, prospective, multicenter study to assess outcomes associated with early mechanical circulatory support (MCS) in patients presenting with acute myocardial infarction and cardiogenic shock (AMICS) treated with percutaneous coronary intervention (PCI). METHODS: Between July 2016 and February 2019, 35 sites participated and enrolled into the study. All centers agreed to treat patients with AMICS using a standard protocol emphasizing invasive hemodynamic monitoring and rapid initiation of MCS. Inclusion and exclusion criteria mimicked those of the "SHOCK" trial with an additional exclusion criteria of intra-aortic balloon pump counter-pulsation prior to MCS. RESULTS: A total of 171 consecutive patients were enrolled. Patients had an average age of 63 years, 77% were male, and 68% were admitted with AMICS. About 83% of patients were on vasopressors or inotropes, 20% had a witnessed out of hospital cardiac arrest, 29% had in-hospital cardiac arrest, and 10% were under active cardiopulmonary resuscitation during MCS implantation. In accordance with the protocol, 74% of patients had MCS implanted prior to PCI. Right heart catheterization was performed in 92%. About 78% of patients presented with ST-elevation myocardial infarction with average door to support times of 85 ± 63 min and door to balloon times of 87 ± 58 min. Survival to discharge was 72%. Creatinine ≥2, lactate >4, cardiac power output (CPO) <0.6 W, and age ≥ 70 years were predictors of mortality. Lactate and CPO measurements at 12-24 hr reliably predicted overall mortality postindex procedure. CONCLUSION: In contemporary practice, use of a shock protocol emphasizing best practices is associated with improved outcomes.

PURPOSE: To compare the effectiveness of a high-spatial-resolution susceptibility-weighted (SW) magnetic resonance (MR) imaging technique with that of a conventional gradient-recalled-echo (GRE) MR imaging technique for detection of hemorrhage in children and adolescents with diffuse axonal injury (DAI). MATERIALS AND METHODS: Seven young patients with a mean Glasgow Coma Scale score of 7 +/- 4 (SD) at admission were imaged a mean of 5 days +/- 3 after injury. High-spatial-resolution three-dimensional GRE imaging performed with postprocessing by using a normalized phase mask was compared with conventional GRE MR imaging. The total and mean values of lesion number and apparent hemorrhage volume load determined with both examinations were compared. Mean values were compared by using paired t test analysis. Differences were considered to be significant at P < or =.05. RESULTS: Hemorrhagic lesions were much more visible on SW MR images than on conventional GRE MR images. SW MR imaging depicted 1,038 hemorrhagic DAI lesions with an apparent total hemorrhage volume of 57,946 mm3. GRE MR imaging depicted 162 lesions with an apparent total hemorrhage volume of 28,893 mm3. SW MR imaging depicted a significantly higher mean number of lesions in all patients than did GRE MR imaging, according to results of visual (P =.004) and computer (P =.004) counting analyses. The mean hemorrhage volume load for all patients also was significantly greater (P =.014) by using SW MR imaging according to computer analysis. SW MR imaging appeared to depict much smaller hemorrhagic lesions than GRE MR imaging. The majority (59%) of individual hemorrhagic DAI lesions seen on SW MR images were small in area (<10 mm(2)), whereas the majority (43%) of lesions seen on GRE images were larger in area (10-20 mm(2)). CONCLUSION: SW MR imaging depicts significantly more small hemorrhagic lesions than does conventional GRE MR imaging and therefore has the potential to improve diagnosis of DAI.

OBJECTIVE: Delayed cerebral vasospasm has long been recognized as an important cause of poor outcome after an otherwise successful treatment of a ruptured intracranial aneurysm, but it remains a pathophysiological enigma despite intensive research for more than half a century. METHOD: Summarized in this review are highlights of research from North America, Europe and Asia reflecting recent advances in the understanding of delayed ischemic deficit. RESULT: It will focus on current accepted mechanisms and on new frontiers in vasospasm research. CONCLUSION: A key issue is the recognition of events other than arterial narrowing such as early brain injury and cortical spreading depression and of their contribution to overall mortality and morbidity.

The relationship between cardiorespiratory exercise, immune function, and upper respiratory tract infection (URTI) was studied in elderly women utilizing a randomized controlled experimental design with a follow-up of 12 wk. Thirty-two sedentary, elderly Caucasian women, 67-85 yr of age, who met specific selection criteria, were randomized to either a walking or calisthenic group; 30 completed the study. Twelve highly conditioned elderly women, 65-84 yr of age, who were active in endurance competitions, were recruited at baseline for cross-sectional comparisons. Intervention groups exercised 30-40 min, 5 d.wk-1, for 12 wk, with the walking group training at 60% heart rate reserve and the calisthenic group engaging in mild range-of-motion and flexibility movements that kept their heart rates close to resting levels. At baseline, the highly conditioned subjects exhibited superior NK (119 +/- 13 vs 77 +/- 8 lytic units, P < 0.01) and T (33.3 +/- 4.9 vs 21.4 +/- 2.1 cpm x 10(-3) using PHA, P < 0.05) cell function, despite no differences in circulating levels of lymphocyte subpopulations. Twelve weeks of moderate cardiorespiratory exercise improved the VO2max of the sedentary subjects 12.6%, but did not result in any improvement in NK cell activity or T cell function. Incidence of URTI was lowest in the highly conditioned group and highest in the calisthenic control group during the 12-wk study, with the walkers in an intermediate position (chi-square = 6.36, P = 0.042). In conclusion, the highly conditioned elderly women in this study had superior NK and T cell function when compared with their sedentary counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Both the Tanner-Whitehouse-III RUS score, which is based on the radiographic appearance of the epiphyses of the distal part of the radius, the distal part of the ulna, and small bones of the hand, and the digital skeletal age skeletal maturity scoring system, which is based on just the metacarpals and phalanges, correlate highly with the curve acceleration phase in girls with idiopathic scoliosis. However, these systems require an atlas and access to the scoring system, making their use impractical in a busy clinical setting. We sought to develop a simplified system that would correlate highly with scoliosis behavior but that would also be rapid and reliable for clinical practice. METHODS: A simplified staging system involving the use of the Tanner-Whitehouse-III descriptors was developed. It was tested for intraobserver and interobserver reliability by six individuals on thirty skeletal age radiographs. The system was compared with the timing of the curve acceleration phase in a cohort of twenty-two girls with idiopathic scoliosis. RESULTS: The average intraobserver unweighted kappa value was 0.88, and the average weighted kappa value was 0.96. The percentage of exact matches between readings for each rater was 89%, and 100% of the differences were within one unit. The average interobserver unweighted kappa value was 0.71, and the average weighted kappa value was 0.89. The percentage of exact matches between two reviewers was 71%, and 97% of the interobserver differences were within one stage or matched. The agreement was highest between the most experienced raters. Interobserver reliability was not improved by the use of a classification-specific atlas. The correlation of the staging system with the curve acceleration phase was 0.91. CONCLUSIONS: The simplified skeletal maturity scoring system is reliable and correlates more strongly with the behavior of idiopathic scoliosis than the Risser sign or Greulich and Pyle skeletal ages do. The system has a modest learning curve but is easily used in a clinical setting and, in conjunction with curve type and magnitude, appears to be strongly prognostic of future scoliosis curve behavior.

BACKGROUND: Neuroinflammation is an important host defense response to secondary brain injury after intracerebral hemorrhage (ICH). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects by attenuating neuroinflammation in experimental ischemic stroke. Recent studies suggest that apolipoprotein E (apoE) is a novel, high-affinity ligand of TREM2. This study aimed to investigate the effects of TREM2 activation on neuroinflammation and neuronal apoptosis in a mouse model of ICH. METHODS: Adult male CD1 mice (n = 216) were subjected to intrastriatal injection of bacterial collagenase. The TREM2 ligand, apoE-mimetic peptide COG1410 was administered intranasally at 1 h after ICH induction. To elucidate the underlying mechanism, TREM2 small interfering RNA (siRNA) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were administered intracerebroventricularly prior to COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, western blotting, and Fluoro-Jade C- and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. RESULTS: Endogenous TREM2 expression was increased and peaked at 24 h after ICH. TREM2 was expressed on microglia, astrocytes, and neurons. COG1410 improved both short-term and long-term neurological functions, reduced brain edema, inhibited microglia/macrophage activation and neutrophil infiltration, and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Knockdown of endogenous TREM2 by TREM2 siRNA aggravated neurological deficits and decreased the expression of TREM2 in naïve and ICH mice. COG1410 was associated with upregulation of TREM2, PI3K, phosphorylated-Akt, and Bcl-2 and downregulation of TNF-α, IL-1β, and Bax after ICH. The neuroprotective effects of COG1410 were abolished by both TREM2 siRNA and PI3K inhibitor LY294002. CONCLUSIONS: Our finding demonstrated that TREM2 activation improved neurological functions and attenuated neuroinflammation and neuronal apoptosis after ICH, which was, at least in part, mediated by activation of PI3K/Akt signaling pathway. Therefore, activation of TREM2 may be a potential therapeutic strategy for the management of ICH patients.

An inception cohort of 40 children and adolescents with traumatic brain injury and suspected diffuse axonal injury were studied using a new high-resolution magnetic resonance imaging susceptibility-weighted technique that is very sensitive for hemorrhage. A blinded comparison was performed between the extent of parenchymal hemorrhage and initial clinical variables as well as outcomes measured at 6 to 12 months after injury. Children with lower Glasgow Coma Scale scores (< or =8, n = 30) or prolonged coma (>4 days, n = 20) had a greater average number (p = 0.007) and volume (p = 0.008) of hemorrhagic lesions. Children with normal outcomes or mild disability (n = 30) at 6 to 12 months had, on average, fewer hemorrhagic lesions (p = 0.003) and lower volume (p = 0.003) of lesions than those who were moderately or severely disabled or in a vegetative state. Significant differences also were observed when comparing regional injury to clinical variables. Because susceptibility-weighted imaging is much more sensitive than conventional T2*-weighted gradient-echo sequences in detecting hemorrhagic diffuse axonal injury, more accurate and objective assessment of injury can be obtained early after insult, and may provide better prognostic information regarding duration of coma as well as long-term outcome.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

BACKGROUND: The risk factors affecting aortic stenosis (AS) progression are not clearly defined. Insights into this may allow for its secondary prevention. METHODS AND RESULTS: We investigated predictors of AS progression in 170 consecutive patients with AS who had paired echocardiograms > or =3 months (23+/-11) apart. Various clinical, echocardiographic, and biochemical variables were related to the change in aortic valve area (AVA). The annual rate of reduction in AVA was 0.10+/-0.27 cm(2) or 7+/-18% per year. The reduction in AVA per year was significantly related to initial AVA (r = 0.46, P<0.0001), the mean aortic valve gradient (r = 0.27, P = 0.04), left ventricular (LV) outflow tract velocity (r = 0.26, P = 0.001), and LV end-diastolic diameter (r = 0.20, P = 0.04) and marginally to serum creatinine level (r = 0.15, P = 0.08). Patients with a rate of reduction in AVA faster than the mean had higher serum creatinine (P = 0.04) and calcium (P = 0.08) levels. Those with a serum cholesterol level >200 mg/dL had a rate of AVA reduction roughly twice that of those with a lower cholesterol level (P = 0.04). Stepwise multiple regression analysis identified initial AVA, current smoking, and serum calcium level as the independent predictors of amount of AVA reduction per year. CONCLUSIONS: Absolute and percentage reduction in AVA per year in those with AS is greater in those with milder degrees of stenosis and is accelerated in the presence of smoking, hypercholesterolemia, and elevated serum creatinine and calcium levels. These findings may have important implications in gaining further insights into the mechanism of AS progression and in formulating strategies to retard this process.

Nehlsen-Cannarella, S. L., O. R. Fagoaga, D. C. Nieman, D. A. Henson, D. E. Butterworth, R. L. Schmitt, E. M. Bailey, B. J. Warren, A. Utter, and J. M. Davis. Carbohydrate and the cytokine response to 2.5 h of running. J. Appl. Physiol. 82(5): 1662–1667, 1997.—This randomized, double-blind, placebo-controlled study was designed to determine the influence of 6% carbohydrate (C) vs. placebo (P) beverage ingestion on cytokine responses (5 total samples over 9 h) to 2.5 h of high-intensity running (76.7 ± 0.4% maximal O 2 uptake) by 30 experienced marathon runners. For interleukin-6 (IL-6), a difference in the pattern of change between groups was found, highlighted by a greater increase in P vs. C immediately postrun (753 vs. 421%) and 1.5 h postrun (193 vs. 86%) [ F(4,112) = 3.77, P = 0.006]. For interleukin-1-receptor antagonist (IL-1ra), a difference in the pattern of change between groups was found, highlighted by a greater increase in P vs. C 1.5 h postrun (231 vs. 72%) [ F(2,50) = 6.38, P = 0.003]. No significant interaction effects were seen for bioactive IL-6 or IL-1β. The immediate postrun plasma glucose concentrations correlated negatively with those of plasma cortisol ( r = −0.67, P &lt; 0.001); postrun plasma cortisol ( r = 0.70, P &lt; 0.001) and IL-6 levels ( r = 0.54, P = 0.003) correlated positively with levels of IL-1ra. Taken together, the data indicate that carbohydrate ingestion attenuates cytokine levels in the inflammatory cascade in response to heavy exertion.