University of Colorado Hospital

We study recently developed nonparametric methods for estimating the number of missing studies that might exist in a meta-analysis and the effect that these studies might have had on its outcome. These are simple rank-based data augmentation techniques, which formalize the use of funnel plots. We show that they provide effective and relatively powerful tests for evaluating the existence of such publication bias. After adjusting for missing studies, we find that the point estimate of the overall effect size is approximately correct and coverage of the effect size confidence intervals is substantially improved, in many cases recovering the nominal confidence levels entirely. We illustrate the trim and fill method on existing meta-analyses of studies in clinical trials and psychometrics.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is thatthere is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the completeprocess including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increasedautophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in manycases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as forreviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multipleassays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagyrelated protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

BACKGROUND: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer. METHODS: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. RESULTS: Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. CONCLUSIONS: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

BACKGROUND: Among patients with heart failure who have mitral regurgitation due to left ventricular dysfunction, the prognosis is poor. Transcatheter mitral-valve repair may improve their clinical outcomes. METHODS: At 78 sites in the United States and Canada, we enrolled patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy. Patients were randomly assigned to transcatheter mitral-valve repair plus medical therapy (device group) or medical therapy alone (control group). The primary effectiveness end point was all hospitalizations for heart failure within 24 months of follow-up. The primary safety end point was freedom from device-related complications at 12 months; the rate for this end point was compared with a prespecified objective performance goal of 88.0%. RESULTS: Of the 614 patients who were enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of all hospitalizations for heart failure within 24 months was 35.8% per patient-year in the device group as compared with 67.9% per patient-year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.40 to 0.70; P<0.001). The rate of freedom from device-related complications at 12 months was 96.6% (lower 95% confidence limit, 94.8%; P<0.001 for comparison with the performance goal). Death from any cause within 24 months occurred in 29.1% of the patients in the device group as compared with 46.1% in the control group (hazard ratio, 0.62; 95% CI, 0.46 to 0.82; P<0.001). CONCLUSIONS: Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy, transcatheter mitral-valve repair resulted in a lower rate of hospitalization for heart failure and lower all-cause mortality within 24 months of follow-up than medical therapy alone. The rate of freedom from device-related complications exceeded a prespecified safety threshold. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079 .).

These guidelines were developed jointly by the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Surgical Infection Society (SIS), and the Society for Healthcare Epidemiology of America (SHEA). This work represents an update to the previously published ASHP Therapeutic Guidelines on Antimicrobial Prophylaxis in Surgery,1 as well as guidelines from IDSA and SIS.2,3 The guidelines are intended to provide practitioners with a standardized approach to the rational, safe, and effective use of antimicrobial agents for the prevention of surgical-site infections (SSIs) based on currently available clinical evidence and emerging issues. Prophylaxis refers to the prevention of an infection and can be characterized as primary prophylaxis, secondary prophylaxis, or eradication. Primary prophylaxis refers to the prevention of an initial infection. Secondary prophylaxis refers to the prevention of recurrence or reactivation of a preexisting infection. Eradication refers to the elimination of a...

Criteria for the classification of giant cell (temporal) arteritis were developed by comparing 214 patients who had this disease with 593 patients with other forms of vasculitis. For the traditional format classification, 5 criteria were selected: age greater than or equal to 50 years at disease onset, new onset of localized headache, temporal artery tenderness or decreased temporal artery pulse, elevated erythrocyte sedimentation rate (Westergren) greater than or equal to 50 mm/hour, and biopsy sample including an artery, showing necrotizing arteritis, characterized by a predominance of mononuclear cell infiltrates or a granulomatous process with multinucleated giant cells. The presence of 3 or more of these 5 criteria was associated with a sensitivity of 93.5% and a specificity of 91.2%. A classification tree was also constructed using 6 criteria. These criteria were the same as for the traditional format, except that elevated erythrocyte sedimentation rate was excluded, and 2 other variables were included: scalp tenderness and claudication of the jaw or tongue or on deglutition. The classification tree was associated with a sensitivity of 95.3% and specificity of 90.7%.

BACKGROUND: The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less. METHODS: Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years. RESULTS: Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per milliliter, 17.0 percent among those with values of 1.1 to 2.0 ng per milliliter, 23.9 percent among those with values of 2.1 to 3.0 ng per milliliter, and 26.9 percent among those with values of 3.1 to 4.0 ng per milliliter. The prevalence of high-grade cancers increased from 12.5 percent of cancers associated with a PSA level of 0.5 ng per milliliter or less to 25.0 percent of cancers associated with a PSA level of 3.1 to 4.0 ng per milliliter. CONCLUSIONS: Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less--levels generally thought to be in the normal range.

Criteria for the classification of Takayasu arteritis were developed by comparing 63 patients who had this disease with 744 control patients with other forms of vasculitis. Six criteria were selected for the traditional format classification: onset at age less than or equal to 40 years, claudication of an extremity, decreased brachial artery pulse, greater than 10 mm Hg difference in systolic blood pressure between arms, a bruit over the subclavian arteries or the aorta, and arteriographic evidence of narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities. The presence of 3 or more of these 6 criteria demonstrated a sensitivity of 90.5% and a specificity of 97.8%. A classification tree also was constructed with 5 of these 6 criteria, omitting claudication of an extremity. The classification tree demonstrated a sensitivity of 92.1% and a specificity of 97.0%.

Criteria for the classification of Churg-Strauss syndrome (CSS) were developed by comparing 20 patients who had this diagnosis with 787 control patients with other forms of vasculitis. For the traditional format classification, 6 criteria were selected: asthma, eosinophilia greater than 10% on differential white blood cell count, mononeuropathy (including multiplex) or polyneuropathy, non-fixed pulmonary infiltrates on roentgenography, paranasal sinus abnormality, and biopsy containing a blood vessel with extravascular eosinophils. The presence of 4 or more of these 6 criteria yielded a sensitivity of 85% and a specificity of 99.7%. A classification tree was also constructed with 3 selected criteria: asthma, eosinophilia greater than 10% on differential white blood cell count, and history of documented allergy other than asthma or drug sensitivity. If a subject has eosinophilia and a documented history of either asthma or allergy, then that subject is classified as having CSS. For the tree classification, the sensitivity was 95% and the specificity was 99.2%. Advantages of the traditional format compared with the classification tree format, when applied to patients with systemic vasculitis, and their comparison with earlier work on CSS are discussed.

Criteria for the classification of Wegener's granulomatosis (WG) were developed by comparing 85 patients who had this disease with 722 control patients with other forms of vasculitis. For the traditional format classification, 4 criteria were selected: abnormal urinary sediment (red cell casts or greater than 5 red blood cells per high power field), abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates), oral ulcers or nasal discharge, and granulomatous inflammation on biopsy. The presence of 2 or more of these 4 criteria was associated with a sensitivity of 88.2% and a specificity of 92.0%. A classification tree was also constructed with 5 criteria being selected. These criteria were the same as for the traditional format, but included hemoptysis. The classification tree was associated with a sensitivity of 87.1% and a specificity of 93.6%. We describe criteria which distinguish patients with WG from patients with other forms of vasculitis with a high level of sensitivity and specificity. This distinction is important because WG requires cyclophosphamide therapy, whereas many other forms of vasculitis can be treated with corticosteroids alone.

BACKGROUND: Obesity in childhood is associated with increased cardiovascular risk. It is uncertain whether this risk is attenuated in persons who are overweight or obese as children but not obese as adults. METHODS: We analyzed data from four prospective cohort studies that measured childhood and adult body-mass index (BMI, the weight in kilograms divided by the square of the height in meters). The mean length of follow-up was 23 years. To define high adiposity status, international age-specific and sex-specific BMI cutoff points for overweight and obesity were used for children, and a BMI cutoff point of 30 was used for adults. RESULTS: Data were available for 6328 subjects. Subjects with consistently high adiposity status from childhood to adulthood, as compared with persons who had a normal BMI as children and were nonobese as adults, had an increased risk of type 2 diabetes (relative risk, 5.4; 95% confidence interval [CI], 3.4 to 8.5), hypertension (relative risk, 2.7; 95% CI, 2.2 to 3.3), elevated low-density lipoprotein cholesterol levels (relative risk, 1.8; 95% CI, 1.4 to 2.3), reduced high-density lipoprotein cholesterol levels (relative risk, 2.1; 95% CI, 1.8 to 2.5), elevated triglyceride levels (relative risk, 3.0; 95% CI, 2.4 to 3.8), and carotid-artery atherosclerosis (increased intima-media thickness of the carotid artery) (relative risk, 1.7; 95% CI, 1.4 to 2.2) (P ≤ 0.002 for all comparisons). Persons who were overweight or obese during childhood but were nonobese as adults had risks of the outcomes that were similar to those of persons who had a normal BMI consistently from childhood to adulthood (P>0.20 for all comparisons). CONCLUSIONS: Overweight or obese children who were obese as adults had increased risks of type 2 diabetes, hypertension, dyslipidemia, and carotid-artery atherosclerosis. The risks of these outcomes among overweight or obese children who became nonobese by adulthood were similar to those among persons who were never obese. (Funded by the Academy of Finland and others.).

A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.

The LIPID MAPS Structure Database (LMSD) is a relational database encompassing structures and annotations of biologically relevant lipids. Structures of lipids in the database come from four sources: (i) LIPID MAPS Consortium's core laboratories and partners; (ii) lipids identified by LIPID MAPS experiments; (iii) computationally generated structures for appropriate lipid classes; (iv) biologically relevant lipids manually curated from LIPID BANK, LIPIDAT and other public sources. All the lipid structures in LMSD are drawn in a consistent fashion. In addition to a classification-based retrieval of lipids, users can search LMSD using either text-based or structure-based search options. The text-based search implementation supports data retrieval by any combination of these data fields: LIPID MAPS ID, systematic or common name, mass, formula, category, main class, and subclass data fields. The structure-based search, in conjunction with optional data fields, provides the capability to perform a substructure search or exact match for the structure drawn by the user. Search results, in addition to structure and annotations, also include relevant links to external databases. The LMSD is publicly available at www.lipidmaps.org/data/structure/.

This two-part meta-analysis combined data from eight prospective randomized trials designed to compare the nutritional efficacy of early enteral (TEN) and parenteral (TPN) nutrition in high-risk surgical patients. The combined data gave sufficient patient numbers (TEN, n = 118; TPN, n = 112) to adequately address whether route of substrate delivery affected septic complication incidence. Phase I (dropouts excluded) meta-analysis confirmed data homogeneity across study sites, that TEN and TPN groups were comparable, and that significantly fewer TEN patients experienced septic complications (TEN, 18%; TPN, 35%; p = 0.01). Phase II meta-analysis, an intent-to-treat analysis (dropouts included), confirmed that fewer TEN patients developed septic complications. Further breakdown by patient type showed that all trauma and blunt trauma subgroups had the most significant reduction in septic complications when fed enterally. In conclusion, this meta-analysis attests to the feasibility of early postoperative TEN in high-risk surgical patients and that these patients have reduced septic morbidity rates compared with those administered TPN.

This consensus statement presents a comprehensive and evidence-based set of guidelines for the care of postoperative nausea and vomiting (PONV) in both adult and pediatric populations. The guidelines are established by an international panel of experts under the auspices of the American Society of Enhanced Recovery and Society for Ambulatory Anesthesia based on a comprehensive search and review of literature up to September 2019. The guidelines provide recommendation on identifying high-risk patients, managing baseline PONV risks, choices for prophylaxis, and rescue treatment of PONV as well as recommendations for the institutional implementation of a PONV protocol. In addition, the current guidelines focus on the evidence for newer drugs (eg, second-generation 5-hydroxytryptamine 3 [5-HT3] receptor antagonists, neurokinin 1 (NK1) receptor antagonists, and dopamine antagonists), discussion regarding the use of general multimodal PONV prophylaxis, and PONV management as part of enhanced recovery pathways. This set of guidelines have been endorsed by 23 professional societies and organizations from different disciplines (Appendix 1).Guidelines currently available include the 3 iterations of the consensus guideline we previously published, which was last updated 6 years ago; a guideline published by American Society of Health System Pharmacists in 1999; a brief discussion on PONV management as part of a comprehensive postoperative care guidelines; focused guidelines published by the Society of Obstetricians and Gynecologists of Canada, the Association of Paediatric Anaesthetists of Great Britain & Ireland and the Association of Perianesthesia Nursing; and several guidelines published in other languages.The current guideline was developed to provide perioperative practitioners with a comprehensive and up-to-date, evidence-based guidance on the risk stratification, prevention, and treatment of PONV in both adults and children. The guideline also provides guidance on the management of PONV within enhanced recovery pathways.The previous consensus guideline was published 6 years ago with a literature search updated to October 2011. Several guidelines, which have been published since, are either limited to a specific populations or do not address all aspects of PONV management. The current guideline was developed based on a systematic review of the literature published up through September 2019. This includes recent studies of newer pharmacological agents such as the second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, a dopamine antagonist, neurokinin 1 (NK1) receptor antagonists as well as several novel combination therapies. In addition, it also contains an evidence-based discussion on the management of PONV in enhanced recovery pathways. We have also discussed the implementation of a general multimodal PONV prophylaxis in all at-risk surgical patients based on the consensus of the expert panel.

PURPOSE: Extraprostatic disease will be manifest in a third of men after radical prostatectomy. We present the long-term followup of a randomized clinical trial of radiotherapy to reduce the risk of subsequent metastatic disease and death. MATERIALS AND METHODS: A total of 431 men with pT3N0M0 prostate cancer were randomized to 60 to 64 Gy adjuvant radiotherapy or observation. The primary study end point was metastasis-free survival. RESULTS: Of 425 eligible men 211 were randomized to observation and 214 to adjuvant radiation. Of those men under observation 70 ultimately received radiotherapy. Metastasis-free survival was significantly greater with radiotherapy (93 of 214 events on the radiotherapy arm vs 114 of 211 events on observation; HR 0.71; 95% CI 0.54, 0.94; p = 0.016). Survival improved significantly with adjuvant radiation (88 deaths of 214 on the radiotherapy arm vs 110 deaths of 211 on observation; HR 0.72; 95% CI 0.55, 0.96; p = 0.023). CONCLUSIONS: Adjuvant radiotherapy after radical prostatectomy for a man with pT3N0M0 prostate cancer significantly reduces the risk of metastasis and increases survival.

Peer Reviewed

BACKGROUND: Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy. METHODS: Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually. RESULTS: After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome. CONCLUSIONS: Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.

The Organ Injury Scaling (OIS) Committee of the American Association for the Surgery of Trauma (AAST) was organized formally in 1987; the fundamental purpose was to devise injury severity scores for individual organs to facilitate clinical investigation and outcomes research. The OIS Committee members were selected on the basis of recognized clinical expertise as well as experience with injury scoring. The Committee was charged to develop a comprehensive set of OISs, monitor their application in the current literature, and recommend modifications when deemed appropriate. The following OISs for spleen and liver represent the first revisions in this long term project. Conceptually, the OIS is a classification scheme based on the anatomic disruption of an individual organ scaled 1 to 6, representing the least to most severe injury. Grades 1 to 5 represent increasingly complex injuries encountered in salvageable patients, while grade 6 is a destructive lesion incompatible with survival. Severity is based on potential threat to the patient's life, and the progressive scale derived from a comprehensive review of the current literature with consensus of the OIS Committee. Finally, the AAST Board of Managers approves all OISs prior to submission for publication. Despite this extensive preparation process, OISs are inherently limited by design as ordinal rather than interval scales. For example, the difference between a grade I versus II injury is generally less significant clinically than a grade IV versus V. The fundamental objective of the OIS, however, is not to assign prognostic value to a specific injury, but rather to provide a clearer description to facilitate comparison of an equivalent injury managed in one fashion versus another. To date, OISs have been developed and published in the Journal of Trauma for spleen, liver, kidney, [1] pancreas, duodenum, small bowel, colon, rectum, [2] chest wall, abdominal vascular, ureter, bladder, urethra, [3] and thoracic vascular, lung, cardiac, diaphragm. [4] While many of these OISs have been employed in clinical research, the individual scaling grades have not been studied independently for scientific accuracy. Nonetheless, with increased clinical testing and constructive review by other investigators, the need for revisions has become apparent. Spleen and liver OISs, first published in 1989, [1] have been applied frequently in the literature over the past five years, and describe two ongoing controversial areas in trauma care. Consequently, it is not surprising that revisions for these two OISs have become necessary. Some of these modifications were straightforward, while others required considerable deliberation of the OIS committee before a consensus could be reached. The significant revisions in the spleen and liver OIS include: 1) global downgrading of hematomas for both spleen and liver, acknowledging their relatively benign course with the advent of widespread CT scanning for blunt abdominal trauma, 2) addition of Couinard's segmental liver anatomy to facilitate quantification of lobar parenchymal disruption, employing internationally familiar terminology, 3) more rigorous criteria for grade IV and V hepatic injuries, recognizing the need to further delineate the operative challenges of these advanced lesions, and 4) restricting the advancement of one grade for multiple injuries within an OIS to grade III. The revised scale for spleen OIS is depicted in Table 1. The specific changes are increased threshold hematoma size to > 5cm for grade III, and elimination of ruptured intraparenchymal hematoma as a grade IV injury. The changes for the revised liver OIS (Table 2) are increased threshold hematoma size to > 10cm for grade III, increased amount of parenchyma involved to > 75% for grade V, and the addition of equivalent Counard segments for grade IV and grade V.Table 1: Spleen injury scale (1994 revision).Table 2: Liver injury scale (1994 revision).We hope these modifications will be helpful to those who employ OISs to improve care of the injured, and look forward to the evaluation of their scientific validity by experienced trauma surgeons.

BACKGROUND: Whether closure of a patent foramen ovale reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown. METHODS: In a multicenter, randomized, open-label trial, with blinded adjudication of end-point events, we randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory. RESULTS: We enrolled 980 patients (mean age, 45.9 years) at 69 sites. Patients were followed for a median of 5.9 years. Treatment exposure in the two groups was unequal (3141 patient-years in the PFO closure group vs. 2669 patient-years in the medical-therapy group), owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval [CI], 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (hazard ratio, 0.38; 95% CI, 0.18 to 0.79; P=0.007). Venous thromboembolism (which comprised events of pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. CONCLUSIONS: Among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270 .).