Pennsylvania Hospital

BACKGROUND: The volume of primary total joint arthroplasty (TJA) procedures has risen in recent decades. However, recent procedure growth has not been at previously projected exponential rates. To anticipate the future expense of TJA, updated models are necessary to predict TJA volume in the U.S. METHODS: Retrospective review using the National Inpatient Sample, a representative sample of all hospital discharges within the U.S., was employed to determine the volume of primary TJA procedures performed from 2000 to 2014. Over 116 million discharge records were reviewed and weighted to determine the simulated annual TJA volume. The annual incidence rate of each procedure was determined by combining procedure volume with annual census data among the overall population and in subpopulations defined by sex and age. Linear and Poisson regression analyses were performed to determine the projected future volume of TJA procedures. Subanalysis with linear regression estimates based on 2000 to 2008 and 2008 to 2014 growth rates was performed. RESULTS: On the basis of 2000-to-2014 data, primary total hip arthroplasty (THA) is projected to grow 71%, to 635,000 procedures, by 2030 and primary total knee arthroplasty (TKA) is projected to grow 85%, to 1.26 million procedures, by 2030. However, TKA procedure growth rate has been slowing over recent years, and models based on 2008-to-2014 data projected growth to only approximately 935,000 procedures by 2030. CONCLUSIONS: Previously anticipated exponential TJA growth is inconsistent with the most recent trends. An updated projection based on 2000-to-2014 data is provided to project the growth of primary TJA procedures to the year 2030. These data will help guide health-care economic policy and allocation of future resources in order to optimize the delivery of patient care.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with reported prevalence in the United States of 1 in 59 children (approximately 1.7%). Core deficits are identified in 2 domains: social communication/interaction and restrictive, repetitive patterns of behavior. Children and youth with ASD have service needs in behavioral, educational, health, leisure, family support, and other areas. Standardized screening for ASD at 18 and 24 months of age with ongoing developmental surveillance continues to be recommended in primary care (although it may be performed in other settings), because ASD is common, can be diagnosed as young as 18 months of age, and has evidenced-based interventions that may improve function. More accurate and culturally sensitive screening approaches are needed. Primary care providers should be familiar with the diagnostic criteria for ASD, appropriate etiologic evaluation, and co-occurring medical and behavioral conditions (such as disorders of sleep and feeding, gastrointestinal tract symptoms, obesity, seizures, attention-deficit/hyperactivity disorder, anxiety, and wandering) that affect the child's function and quality of life. There is an increasing evidence base to support behavioral and other interventions to address specific skills and symptoms. Shared decision making calls for collaboration with families in evaluation and choice of interventions. This single clinical report updates the 2007 American Academy of Pediatrics clinical reports on the evaluation and treatment of ASD in one publication with an online table of contents and section view available through the American Academy of Pediatrics Gateway to help the reader identify topic areas within the report.

OBJECTIVE: This update of a 2007 guideline from the American Academy of Otolaryngology--Head and Neck Surgery Foundation provides evidence-based recommendations to manage adult rhinosinusitis, defined as symptomatic inflammation of the paranasal sinuses and nasal cavity. Changes from the prior guideline include a consumer added to the update group, evidence from 42 new systematic reviews, enhanced information on patient education and counseling, a new algorithm to clarify action statement relationships, expanded opportunities for watchful waiting (without antibiotic therapy) as initial therapy of acute bacterial rhinosinusitis (ABRS), and 3 new recommendations for managing chronic rhinosinusitis (CRS). PURPOSE: The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing adult rhinosinusitis and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to improve diagnostic accuracy for adult rhinosinusitis, promote appropriate use of ancillary tests to confirm diagnosis and guide management, and promote judicious use of systemic and topical therapy, which includes radiography, nasal endoscopy, computed tomography, and testing for allergy and immune function. Emphasis was also placed on identifying multiple chronic conditions that would modify management of rhinosinusitis, including asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia. ACTION STATEMENTS: The update group made strong recommendations that clinicians (1) should distinguish presumed ABRS from acute rhinosinusitis (ARS) caused by viral upper respiratory infections and noninfectious conditions and (2) should confirm a clinical diagnosis of CRS with objective documentation of sinonasal inflammation, which may be accomplished using anterior rhinoscopy, nasal endoscopy, or computed tomography. The update group made recommendations that clinicians (1) should either offer watchful waiting (without antibiotics) or prescribe initial antibiotic therapy for adults with uncomplicated ABRS; (2) should prescribe amoxicillin with or without clavulanate as first-line therapy for 5 to 10 days (if a decision is made to treat ABRS with an antibiotic); (3) should reassess the patient to confirm ABRS, exclude other causes of illness, and detect complications if the patient worsens or fails to improve with the initial management option by 7 days after diagnosis or worsens during the initial management; (4) should distinguish CRS and recurrent ARS from isolated episodes of ABRS and other causes of sinonasal symptoms; (5) should assess the patient with CRS or recurrent ARS for multiple chronic conditions that would modify management, such as asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia; (6) should confirm the presence or absence of nasal polyps in a patient with CRS; and (7) should recommend saline nasal irrigation, topical intranasal corticosteroids, or both for symptom relief of CRS. The update group stated as options that clinicians may (1) recommend analgesics, topical intranasal steroids, and/or nasal saline irrigation for symptomatic relief of viral rhinosinusitis; (2) recommend analgesics, topical intranasal steroids, and/or nasal saline irrigation) for symptomatic relief of ABRS; and (3) obtain testing for allergy and immune function in evaluating a patient with CRS or recurrent ARS. The update group made recommendations that clinicians (1) should not obtain radiographic imaging for patients who meet diagnostic criteria for ARS, unless a complication or alternative diagnosis is suspected, and (2) should not prescribe topical or systemic antifungal therapy for patients with CRS.

BACKGROUND: Treatments for non-ST-segment-elevation myocardial infarction (NSTEMI) reduce ischemic events but increase bleeding. Baseline prediction of bleeding risk can complement ischemic risk prediction for optimization of NSTEMI care; however, existing models are not well suited for this purpose. METHODS AND RESULTS: We developed (n=71 277) and validated (n=17 857) a model that identifies 8 independent baseline predictors of in-hospital major bleeding among community-treated NSTEMI patients enrolled in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) Quality Improvement Initiative. Model performance was tested by c statistics in the derivation and validation cohorts and according to postadmission treatment (ie, invasive and antithrombotic therapy). The CRUSADE bleeding score (range 1 to 100 points) was created by assignment of weighted integers that corresponded to the coefficient of each variable. The rate of major bleeding increased by bleeding risk score quintiles: 3.1% for those at very low risk (score < or = 20); 5.5% for those at low risk (score 21-30); 8.6% for those at moderate risk (score 31-40); 11.9% for those at high risk (score 41-50); and 19.5% for those at very high risk (score >50; P(trend) <0.001). The c statistics for the major bleeding model (derivation=0.72 and validation=0.71) and risk score (derivation=0.71 and validation=0.70) were similar. The c statistics for the model among treatment subgroups were as follows: > or = 2 antithrombotics=0.72; <2 antithrombotics=0.73; invasive approach=0.73; conservative approach=0.68. CONCLUSIONS: The CRUSADE bleeding score quantifies risk for in-hospital major bleeding across all postadmission treatments, which enhances baseline risk assessment for NSTEMI care.

OBJECTIVES: Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery. This study was undertaken to determine the efficacy and safety of using micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled asymptomatic women with a singleton pregnancy and a sonographic short cervix (10-20 mm) at 19 + 0 to 23 + 6 weeks of gestation. Women were allocated randomly to receive vaginal progesterone gel or placebo daily starting from 20 to 23 + 6 weeks until 36 + 6 weeks, rupture of membranes or delivery, whichever occurred first. Randomization sequence was stratified by center and history of a previous preterm birth. The primary endpoint was preterm birth before 33 weeks of gestation. Analysis was by intention to treat. RESULTS: Of 465 women randomized, seven were lost to follow-up and 458 (vaginal progesterone gel, n=235; placebo, n=223) were included in the analysis. Women allocated to receive vaginal progesterone had a lower rate of preterm birth before 33 weeks than did those allocated to placebo (8.9% (n=21) vs 16.1% (n=36); relative risk (RR), 0.55; 95% CI, 0.33-0.92; P=0.02). The effect remained significant after adjustment for covariables (adjusted RR, 0.52; 95% CI, 0.31-0.91; P=0.02). Vaginal progesterone was also associated with a significant reduction in the rate of preterm birth before 28 weeks (5.1% vs 10.3%; RR, 0.50; 95% CI, 0.25-0.97; P=0.04) and 35 weeks (14.5% vs 23.3%; RR, 0.62; 95% CI, 0.42-0.92; P=0.02), respiratory distress syndrome (3.0% vs 7.6%; RR, 0.39; 95% CI, 0.17-0.92; P=0.03), any neonatal morbidity or mortality event (7.7% vs 13.5%; RR, 0.57; 95% CI, 0.33-0.99; P=0.04) and birth weight < 1500 g (6.4% (15/234) vs 13.6% (30/220); RR, 0.47; 95% CI, 0.26-0.85; P=0.01). There were no differences in the incidence of treatment-related adverse events between the groups. CONCLUSIONS: The administration of vaginal progesterone gel to women with a sonographic short cervix in the mid-trimester is associated with a 45% reduction in the rate of preterm birth before 33 weeks of gestation and with improved neonatal outcome.

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

International cancer registries make real-world genomic and clinical data available, but their joint analysis remains a challenge. AACR Project GENIE, an international cancer registry collecting data from 19 cancer centers, makes data from >130,000 patients publicly available through the cBioPortal for Cancer Genomics (https://genie.cbioportal.org). For 25,000 patients, additional real-world longitudinal clinical data, including treatment and outcome data, are being collected by the AACR Project GENIE Biopharma Collaborative using the PRISSMM data curation model. Several thousand of these cases are now also available in cBioPortal. We have significantly enhanced the functionalities of cBioPortal to support the visualization and analysis of this rich clinico-genomic linked dataset, as well as datasets generated by other centers and consortia. Examples of these enhancements include (i) visualization of the longitudinal clinical and genomic data at the patient level, including timelines for diagnoses, treatments, and outcomes; (ii) the ability to select samples based on treatment status, facilitating a comparison of molecular and clinical attributes between samples before and after a specific treatment; and (iii) survival analysis estimates based on individual treatment regimens received. Together, these features provide cBioPortal users with a toolkit to interactively investigate complex clinico-genomic data to generate hypotheses and make discoveries about the impact of specific genomic variants on prognosis and therapeutic sensitivities in cancer. SIGNIFICANCE: Enhanced cBioPortal features allow clinicians and researchers to effectively investigate longitudinal clinico-genomic data from patients with cancer, which will improve exploration of data from the AACR Project GENIE Biopharma Collaborative and similar datasets.

Autogenous bone grafts from the ilium are frequently harvested for purposes of bone union and/or stability. Although some donor site complications may be unavoidable, awareness of the anatomy and complications may aid in planning the approach and minimizing the risks. Documented donor site complications include pain, nerve and arterial injury, peritoneal perforation, sacroiliac joint instability, and herniation of abdominal contents through defects in the ilium. Strict observation of relevant anatomic considerations will help in avoiding these complications.

OBJECTIVE: Disagreement exists concerning the appropriate delivery room management of the airway of vigorous meconium-stained infants. Some suggest a universal approach to intubation and suctioning of the airway in all such neonates, whereas others advocate a selective approach. We performed this investigation: 1) to assess whether intubation and suctioning of apparently vigorous, meconium-stained neonates would reduce the incidence of meconium aspiration syndrome (MAS); and 2) to determine the frequency of complications from delivery room intubation and suctioning of such infants. METHODS: Inclusion criteria included: 1) gestational age >/=37 weeks; 2) birth through meconium-stained amniotic fluid of any consistency; and 3) apparent vigor immediately after birth. Subjects were randomized to be intubated and suctioned (INT) or to expectant management (EXP). Primary outcome measures included: 1) the incidence of respiratory distress, including MAS, and 2) the incidence of complications from intubation. RESULTS: A total of 2094 neonates were enrolled from 12 participating centers (1051 INT and 1043 EXP). Meconium-stained amniotic fluid consistency was similar in both groups. Of the 149 (7.1%) infants that subsequently demonstrated respiratory distress, 62 (3.0%) had MAS and 87 (4.2%) had findings attributed to other disorders. There were no significant differences between groups in the occurrence of MAS (INT = 3.2%; EXP = 2.7%) or in the development of other respiratory disorders (INT = 3.8%; EXP = 4.5%). Of 1098 successfully intubated infants, 42 (3.8%) had a total of 51 complications of the procedure. In all cases, the complications were mild and transient in nature. CONCLUSIONS: Compared with expectant management, intubation and suctioning of the apparently vigorous meconium-stained infant does not result in a decreased incidence of MAS or other respiratory disorders. Complications of intubation are infrequent and short-lived.

The coupling of diazotized aryl amines with proteins in alkaline solution yield chromophoric protein derivatives.Digestion of a solution of such azoproteins with proteolytic enzymes results in the formation of colored components soluble in trichloroacetic acid.The intensity of the color in the trichloroacetic acid filtrate of the digested substrate is a function of the proteolytic activity of the enzyme solution and serves as the basis for the method here described.EXPERIMENTAL Preparation of Sulfanilamide-Axocasein--Solution A, 50 gm. of reprecipitated, fat-free casein are dissolved with stirring in 1 liter of water containing 10 gm. of NaHC03.Solution B, 5.0 gm. of sulfanilamide are dissolved in 200 ml. of Hz0 containing 6.0 ml. of 5.0 N NaOH.2.20 gm. of NaNOz are added.To the stirred solution 18.0 ml. of 5 N HCl are added and stirring is continued for 2 minutes.18.0 ml. of 5 N NaOH are then added; the solution is stirred and added at once, with stirring, to Solution A.The azoprotein is precipitated by acidification to pH 4.5, washed with water and alcohol, and air-dried.The azocasein is a red-orange compound with an absorption maximum at 440 mp (Fig. 1).Substrate Solution-A stock solution of the substrate containing 25 mg. of azocasein and 5 mg. of sodium bicarbonate per ml. is prepared by dissolving 2.50 gm. of azoprotein in 50 ml. of 1.0 per cent NaHC03 at 60" with stirring.The pH is adjusted to 8.3 and the solution diluted to 100 ml. with distilled HzO.The stock solution is stored at 0".Duodenal Juice-The specimens are centrifuged at about 1500 R.P.M. for lominutes and the sample taken from the relatively homogeneous middle layer. 1 ml. of sample is diluted to 100 ml. with bicarbonate buffer (5 mg. per ml.), pH 8.3. ProcedureEach determination is set up in duplicate.The flask containing the substrate solution and a rack with the proper number of tubes are placed in a 501

The incidence of rib fractures secondary to trauma has not been clearly reported. Of the 7147 patients seen by our trauma service from January 1987 to June 1992, 711 (10%) had rib fractures. Among the patients with rib fractures, 84 (12%) died, 670 (94%) had associated injuries, 274 (32%) had a hemothorax or pneumothorax, and 187 (26%) had a lung contusion. Fifty-five percent of the patients required an immediate operation or admission to the intensive care unit. Thirty-five percent of the patients required discharge to an extended care facility and 35% developed a pulmonary complication. We conclude that rib fractures are a marker of severe injury in which (1) 12% will die because of their injuries, (2) more than 90% will have associated injuries, (3) one half will require operative and ICU care, (4) one third will develop pulmonary complications, and (5) one third will require discharge to an extended care facility.

PURPOSE: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system. EXPERIMENTAL DESIGN: We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models. RESULTS: , causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3. CONCLUSIONS: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.

BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

Recently, the RTOG and ECOG concluded a joint randomized study on malignant gliomas that was in progress for the past five years. A total of 626 patients entered this protocol. Sixty-seven percent of the 535 evaluable patients have died and thus this represents a preliminary report of a major joint clinical trial. The objective of this study was to evaluate the efficacy after neurosurgery of three new treatment options as compared with control treatment of radiotherapy alone. The four options were: (1) control radiation; 6000 rad/6-7 weeks to whole brain; (2) a higher radiation dose; Control dose plus a booster dose of 1000 rad/1-2 weeks to the tumor; (3) control radiation dose plus BCNU (80 mg/m2/day IV X 3 and repeat BCNU every 8 weeks); (4) Control radiation dose plus combination methyl-CCNU (125 mg/m2/day orally X 1 and repeat methyl-CCNU every 8 weeks), and DTIC (150 mg/m2/day IV X 5 and repeat DTIC every 4 weeks). All pertinent patient characteristics were studied and several important prognostic factors have been identified. Notably, age, histologic type (Astrocytoma with anaplastic foci, versus glioblastoma multiforme), initial performance status, time since first symptoms and presence or absence of seizure. At this time, it appeared that there was no treatment option which was significantly better than the control. The study identified that age was the most important prognostic factor. Patients who were younger than age 40 years had an 18-month survival of 64%, patients who were age 40-60 years had an 18-month survival of 20%, and patients who were older than age 60 had an 18-month survival of 8%. The study also demonstrated that a modified histologic classification of anaplastic astrocytoma versus glioblastoma provided better prognostic information than the astrocytoma grading system of Kernohan. Patients with anaplastic astrocytoma had a median survival of 27 months as compared to 8 months for patients with glioblastoma. In further evaluation of any beneficial effect of chemotherapy, it was identified that only among the 40-60-year-old groups, BCNU treated patients appeared to have significantly increased survival than patients in the control groups (P = 0.01, one-sided). Similarly, methyl-CCNU + DTIC was suggestively better than the control (P = 0.08, one-sided). The higher radiation dose, 7000 rad/8-9 weeks appeared to give no significantly better survival over the control dose option. Both BCNU and methyl-CCNU + DTIC produced some toxicity. The combination of methyl-CCNU + DTIC was more toxic than BCNU, producing severe or worse thrombocytopenia in 23% of the patients as compared to 6% on BCNU.

PURPOSE: To study the efficacy and safety of various dosages of metformin as compared with placebo in patients with type II diabetes mellitus. PATIENTS AND METHODS: A 14-week, multicenter, double-blind, dose-response study was conducted. After a 3-week, single-blind, placebo-controlled washout, 451 patients with fasting plasma glucose levels of at least 180 mg/dL were randomized to receive an 11-week course of placebo or metformin given at 500, 1000, 1500, 2000, or 2500 mg daily. RESULTS: Metformin improved glucose variables as compared with placebo. The adjusted mean changes in fasting plasma glucose from baseline associated with each metformin group at week 7, 11, or at endpoint exceeded those associated with placebo by 19 to 84 mg/dL at dosages of 500 to 2000 mg daily, respectively. The corresponding between-group differences in glycated hemoglobin (HbA1c) ranged from 0.6% to 2.0% at dosages of 500 to 2000 mg daily, respectively. All between-group differences were significant (P < 0.05) for both fasting plasma glucose and HbA1c at week 7, week 11, and endpoint, except for the difference between placebo and metformin 500 mg in fasting plasma glucose at endpoint (P = 0.054). Treatment-related adverse events occurred in 15% of patients in the placebo group and in 28% in the metformin group (P = 0.02); these were primarily manifested as digestive disturbances, such as diarrhea. CONCLUSIONS: Metformin lowered fasting plasma glucose and HbA1c generally in a dose-related manner. Benefits were observed with as little as 500 mg of metformin; maximal benefits were observed at the upper limits of the recommended daily dosage. All dosages were well tolerated. Metformin appears to be a useful therapeutic option for physicians who wish to titrate drug therapy to achieve target glucose concentrations.

BACKGROUND: Obesity and obstructive sleep apnea tend to coexist and are associated with inflammation, insulin resistance, dyslipidemia, and high blood pressure, but their causal relation to these abnormalities is unclear. METHODS: We randomly assigned 181 patients with obesity, moderate-to-severe obstructive sleep apnea, and serum levels of C-reactive protein (CRP) greater than 1.0 mg per liter to receive treatment with continuous positive airway pressure (CPAP), a weight-loss intervention, or CPAP plus a weight-loss intervention for 24 weeks. We assessed the incremental effect of the combined interventions over each one alone on the CRP level (the primary end point), insulin sensitivity, lipid levels, and blood pressure. RESULTS: Among the 146 participants for whom there were follow-up data, those assigned to weight loss only and those assigned to the combined interventions had reductions in CRP levels, insulin resistance, and serum triglyceride levels. None of these changes were observed in the group receiving CPAP alone. Blood pressure was reduced in all three groups. No significant incremental effect on CRP levels was found for the combined interventions as compared with either weight loss or CPAP alone. Reductions in insulin resistance and serum triglyceride levels were greater in the combined-intervention group than in the group receiving CPAP only, but there were no significant differences in these values between the combined-intervention group and the weight-loss group. In per-protocol analyses, which included 90 participants who met prespecified criteria for adherence, the combined interventions resulted in a larger reduction in systolic blood pressure and mean arterial pressure than did either CPAP or weight loss alone. CONCLUSIONS: In adults with obesity and obstructive sleep apnea, CPAP combined with a weight-loss intervention did not reduce CRP levels more than either intervention alone. In secondary analyses, weight loss provided an incremental reduction in insulin resistance and serum triglyceride levels when combined with CPAP. In addition, adherence to a regimen of weight loss and CPAP may result in incremental reductions in blood pressure as compared with either intervention alone.

STUDY DESIGN: A prospective, nonblinded, multicenter study of outcomes in patients undergoing single-level anterior lumbar discectomy and interbody fusion with InFUSE Bone Graft. OBJECTIVE: To determine the safety and effectiveness of InFUSE Bone Graft applied to an absorbable collagen sponge in anterior lumbar interbody fusion with threaded cortical allografts. SUMMARY OF BACKGROUND DATA: In primates, InFUSE Bone Graft used with allograft dowels was shown to increase rates of interbody fusion by promoting osteoinduction and enhancing incorporation of the allograft. Recently, in a small series of human patients undergoing anterior lumbar interbody fusion with a tapered cylindrical metal fusion cage, InFUSE Bone Graft has been shown to promote osteoinduction and fusion. METHODS: Forty-six patients underwent a single-level anterior lumbar discectomy and interbody fusion at five investigational sites. They were randomly assigned to one of two groups, and the results in the investigational patients who received threaded cortical allograft dowels with InFUSE Bone Graft were compared with those in the control patients who received threaded allograft dowels with autogenous iliac crest bone graft. Patients' clinical outcomes were assessed using neurologic status, work status, and Oswestry Low Back Pain Disability, Short Form-36, and back and leg pain questionnaires. Anteroposterior, lateral, flexion-extension radiographs, and computed tomography scans were used to evaluate the progression of fusion at 6, 12, and 24 months after surgery. RESULTS: All patients who received InFUSE Bone Graft showed radiographic evidence of bony induction and early incorporation of the cortical allografts. All patients in this group had fusions at 12 months that remained fused at 24 months. At 12 and 24 months, the investigational group showed higher rates of fusion and improved neurologic status and back and leg pain when compared with the control group. There were no unanticipated adverse events related to the use of InFUSE Bone Graft. CONCLUSION: The use of InFUSE Bone Graft is a promising method of facilitating anterior intervertebral spinal fusion, decreasing pain, and improving clinical outcomes in patients who have undergone anterior lumbar fusion surgery with structural threaded cortical allograft bone dowels.

The relationships among attachment classification, psychopathology, and personality traits were examined in a group of 60 psychiatrically hospitalized adolescents. The concordance of attachment classification was examined in 27 adolescent-mother pairs. Both adolescent and maternal attachment status were overwhelmingly insecure and were highly concordant. Adolescents showing a dismissing attachment organization were more likely to have a conduct or substance abuse disorder, narcissistic or antisocial personality disorder, and self-reported narcissistic, antisocial, and paranoid personality traits. Adolescents showing a preoccupied attachment organization were more likely to have an affective disorder, obsessive-compulsive, histrionic, borderline or schizotypal personality disorder, and self-reported avoidant, anxious, and dysthymic personality traits. The results support a model of development of psychopathology based partially on relational experiences with parents.

PURPOSE: To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC. RESULTS: Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC. CONCLUSION: High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC.

CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To provide updated practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: Pathologists involved in the International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS: There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.