Hvidovre Hospital

BACKGROUND: Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease (COPD), but their effect on survival is unknown. METHODS: We conducted a randomized, double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily (combination regimen), administered with a single inhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination regimen and placebo; the frequency of exacerbations, health status, and spirometric values were also assessed. RESULTS: Of 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P=0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P<0.001 for comparisons between these treatments and placebo). CONCLUSIONS: The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients. (ClinicalTrials.gov number, NCT00268216 [ClinicalTrials.gov].).

OBJECTIVES: WGS-based antimicrobial susceptibility testing (AST) is as reliable as phenotypic AST for several antimicrobial/bacterial species combinations. However, routine use of WGS-based AST is hindered by the need for bioinformatics skills and knowledge of antimicrobial resistance (AMR) determinants to operate the vast majority of tools developed to date. By leveraging on ResFinder and PointFinder, two freely accessible tools that can also assist users without bioinformatics skills, we aimed at increasing their speed and providing an easily interpretable antibiogram as output. METHODS: The ResFinder code was re-written to process raw reads and use Kmer-based alignment. The existing ResFinder and PointFinder databases were revised and expanded. Additional databases were developed including a genotype-to-phenotype key associating each AMR determinant with a phenotype at the antimicrobial compound level, and species-specific panels for in silico antibiograms. ResFinder 4.0 was validated using Escherichia coli (n = 584), Salmonella spp. (n = 1081), Campylobacter jejuni (n = 239), Enterococcus faecium (n = 106), Enterococcus faecalis (n = 50) and Staphylococcus aureus (n = 163) exhibiting different AST profiles, and from different human and animal sources and geographical origins. RESULTS: Genotype-phenotype concordance was ≥95% for 46/51 and 25/32 of the antimicrobial/species combinations evaluated for Gram-negative and Gram-positive bacteria, respectively. When genotype-phenotype concordance was <95%, discrepancies were mainly linked to criteria for interpretation of phenotypic tests and suboptimal sequence quality, and not to ResFinder 4.0 performance. CONCLUSIONS: WGS-based AST using ResFinder 4.0 provides in silico antibiograms as reliable as those obtained by phenotypic AST at least for the bacterial species/antimicrobial agents of major public health relevance considered.

Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.

BACKGROUND: Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. METHODS: We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. RESULTS: Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. CONCLUSIONS: Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)

Stereology is a set of simple and efficient methods for quantitation of three-dimensional microscopic structures which is specifically tuned to provide reliable data from sections. Within the last few years, a number of new methods has been developed which are of special interest to pathologists. Methods for estimating the volume, surface area and length of any structure are described in this review. The principles on which stereology is based and the necessary sampling procedures are described and illustrated with examples. The necessary equipment, the measurements, and the calculations are invariably simple and easy.

The new stereological methods for correct and efficient sampling and sizing of cells and other particles are reviewed. There is a hierarchy of methods starting from the simplest where even the microscopic magnification may be unknown to the most complex where typically both section thickness and the magnification must be known. Optical sections in suitably modified microscopes can be used to improve the ease and speed with which even the most demanding of these methods are performed. The methods are illustrated by practical examples of applications to a wide range of histological entities including synapses, neurons and cancer cells, glomerular corpuscles and ovarian follicles.

OBJECTIVE: To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression. METHODS: The clinical and serologic features of APS (Sapporo preliminary criteria) in 1,000 patients from 13 European countries were analyzed using a computerized database. RESULTS: The cohort consisted of 820 female patients (82.0%) and 180 male patients (18.0%) with a mean +/- SD age of 42 +/- 14 years at study entry. "Primary" APS was present in 53.1% of the patients; APS was associated with systemic lupus erythematosus (SLE) in 36.2%, with lupus-like syndrome in 5.0%, and with other diseases in 5.9%. A variety of thrombotic manifestations affecting the majority of organs were recorded. A catastrophic APS occurred in 0.8% of the patients. Patients with APS associated with SLE had more episodes of arthritis and livedo reticularis, and more frequently exhibited thrombocytopenia and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis, and migraine. Male patients had a higher frequency of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. In 28 patients (2.8%), disease onset occurred before age 15; these patients had more episodes of chorea and jugular vein thrombosis than the remaining patients. In 127 patients (12.7%), disease onset occurred after age 50; most of these patients were men. These patients had a higher frequency of stroke and angina pectoris, but a lower frequency of livedo reticularis, than the remaining patients. CONCLUSION: APS may affect any organ of the body and display a broad spectrum of manifestations. An association with SLE, the patient's sex, and the patient's age at disease onset can modify the disease expression and define specific subsets of APS.

Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA1c testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA1c measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies &amp; Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.

BACKGROUND: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].).

BACKGROUND: The results of case-control studies and anecdotal reports suggest that pancreatitis may be a risk factor for pancreatic cancer, but there have been no studies of sufficient size and power to assess the magnitude of the relation between these two diseases. METHODS AND RESULTS: We undertook a multicenter historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from clinical centers in six countries. A total of 56 cancers were identified among these patients during a mean (+/-SD) follow-up of 7.4 +/- 6.2 years. The expected number of cases of cancer calculated from country-specific incidence data and adjusted for age and sex was 2.13, yielding a standardized incidence ratio (the ratio of observed to expected cases) of 26.3 (95 percent confidence interval, 19.9 to 34.2). For subjects with a minimum of two or five years of follow-up, the respective standardized incidence ratios were 16.5 (95 percent confidence interval, 11.1 to 23.7) and 14.4 (95 percent confidence interval, 8.5 to 22.8). The cumulative risk of pancreatic cancer in subjects who were followed for at least 2 years increased steadily, and 10 and 20 years after the diagnosis of pancreatitis, it was 1.8 percent (95 percent confidence interval, 1.0 to 2.6 percent) and 4.0 percent (95 percent confidence interval, 2.0 to 5.9 percent), respectively. CONCLUSIONS: The risk of pancreatic cancer is significantly elevated in subjects with chronic pancreatitis and appears to be independent of sex, country, and type of pancreatitis.

Renal sodium and water retention and plasma volume expansion have been shown to precede ascites formation in experimental cirrhosis. The classical "underfilling" theory, in which ascites formation causes hypovolemia and initiates secondary renal sodium and water retention, thus seems unlikely. While the occurrence of primary renal sodium and water retention and plasma volume expansion prior to ascites formation favors the "overflow" hypothesis, the stimulation of the renin-angiotensin-aldosterone system, vasopressin release and sympathetic nervous system associated with cirrhosis is not consonant with primary volume expansion. In this present article, the "Peripheral Arterial Vasodilation Hypothesis" is proposed as the initiator of sodium and water retention in cirrhosis. Peripheral arterial vasodilation is one of the earliest observations in the cirrhotic patient and experimental animals with cirrhosis. Arterial vasodilators and arteriovenous fistula are other examples in which renal sodium and water retention occur secondary to a decreased filling of the arterial vascular tree. An increase in cardiac output and hormonal stimulation are common features of cirrhosis, arteriovenous fistula and drug-induced peripheral arterial vasodilation. However, a predilection for the retained sodium and water to transudate into the abdominal cavity occurs with cirrhosis because of the presence of portal hypertension. The Peripheral Arterial Vasodilation Hypothesis also explains the continuum from compensated to decompensated cirrhosis to the hepatorenal syndrome.

The European Hernia Society (EHS) is proud to present the EHS Guidelines for the Treatment of Inguinal Hernia in Adult Patients. The Guidelines contain recommendations for the treatment of inguinal hernia from diagnosis till aftercare. They have been developed by a Working Group consisting of expert surgeons with representatives of 14 country members of the EHS. They are evidence-based and, when necessary, a consensus was reached among all members. The Guidelines have been reviewed by a Steering Committee. Before finalisation, feedback from different national hernia societies was obtained. The Appraisal of Guidelines for REsearch and Evaluation (AGREE) instrument was used by the Cochrane Association to validate the Guidelines. The Guidelines can be used to adjust local protocols, for training purposes and quality control. They will be revised in 2012 in order to keep them updated. In between revisions, it is the intention of the Working Group to provide every year, during the EHS annual congress, a short update of new high-level evidence (randomised controlled trials [RCTs] and meta-analyses). Developing guidelines leads to questions that remain to be answered by specific research. Therefore, we provide recommendations for further research that can be performed to raise the level of evidence concerning certain aspects of inguinal hernia treatment. In addition, a short summary, specifically for the general practitioner, is given. In order to increase the practical use of the Guidelines by consultants and residents, more details on the most important surgical techniques, local infiltration anaesthesia and a patient information sheet is provided. The most important challenge now will be the implementation of the Guidelines in daily surgical practice. This remains an important task for the EHS. The establishment of an EHS school for teaching inguinal hernia repair surgical techniques, including tips and tricks from experts to overcome the learning curve (especially in endoscopic repair), will be the next step. Working together on this project was a great learning experience, and it was worthwhile and fun. Cultural differences between members were easily overcome by educating each other, respecting different views and always coming back to the principles of evidence-based medicine. The members of the Working Group would like to thank the EHS board for their support and especially Ethicon for sponsoring the many meetings that were needed to finalise such an ambitious project.

Department of Surgical Gastroenterology and Anesthesiology, Hvidovre University Hospital, Hvidovre, Denmark Address correspondence and reprint requests to Henrik Kehlet, MD, PhD, Department of Surgical Gastroenterology, Hvidovre Hospital, 2650-Hvidovre, Denmark. This study was supported by a grant from Alfred Benzon's Fond. Accepted for publication May 14, 1993.

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer. Analyses of fragmentation patterns of cell-free DNA in the blood of patients with cancer and healthy individuals using a machine learning algorithm provide a proof-of principle approach for the early detection and screening of human cancer.

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.

IMPORTANCE: A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex with suppressed HIV-1 RNA viral load for both anal and vaginal sex. OBJECTIVE: To evaluate the rate of within-couple HIV transmission (heterosexual and men who have sex with men [MSM]) during periods of sex without condoms and when the HIV-positive partner had HIV-1 RNA load less than 200 copies/mL. DESIGN, SETTING, AND PARTICIPANTS: The prospective, observational PARTNER (Partners of People on ART-A New Evaluation of the Risks) study was conducted at 75 clinical sites in 14 European countries and enrolled 1166 HIV serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex (September 2010 to May 2014). Eligibility criteria for inclusion of couple-years of follow-up were condomless sex and HIV-1 RNA load less than 200 copies/mL. Anonymized phylogenetic analysis compared couples' HIV-1 polymerase and envelope sequences if an HIV-negative partner became infected to determine phylogenetically linked transmissions. EXPOSURES: Condomless sexual activity with an HIV-positive partner taking virally suppressive ART. MAIN OUTCOMES AND MEASURES: Risk of within-couple HIV transmission to the HIV-negative partner. RESULTS: Among 1166 enrolled couples, 888 (mean age, 42 years [IQR, 35-48]; 548 heterosexual [61.7%] and 340 MSM [38.3%]) provided 1238 eligible couple-years of follow-up (median follow-up, 1.3 years [IQR, 0.8-2.0]). At baseline, couples reported condomless sex for a median of 2 years (IQR, 0.5-6.3). Condomless sex with other partners was reported by 108 HIV-negative MSM (33%) and 21 heterosexuals (4%). During follow-up, couples reported condomless sex a median of 37 times per year (IQR, 15-71), with MSM couples reporting approximately 22,000 condomless sex acts and heterosexuals approximately 36,000. Although 11 HIV-negative partners became HIV-positive (10 MSM; 1 heterosexual; 8 reported condomless sex with other partners), no phylogenetically linked transmissions occurred over eligible couple-years of follow-up, giving a rate of within-couple HIV transmission of zero, with an upper 95% confidence limit of 0.30/100 couple-years of follow-up. The upper 95% confidence limit for condomless anal sex was 0.71 per 100 couple-years of follow-up. CONCLUSIONS AND RELEVANCE: Among serodifferent heterosexual and MSM couples in which the HIV-positive partner was using suppressive ART and who reported condomless sex, during median follow-up of 1.3 years per couple, there were no documented cases of within-couple HIV transmission (upper 95% confidence limit, 0.30/100 couple-years of follow-up). Additional longer-term follow-up is necessary to provide more precise estimates of risk.

BACKGROUND: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. METHODS: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. RESULTS: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. CONCLUSIONS: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

ONE potential adverse outcome from surgery is chronic pain. Analysis of predictive and pathologic factors is important to develop rational strategies to prevent this problem. Additionally, the natural history of patients with and without persistent pain after surgery provides an opportunity to improve the understanding of the physiology and psychology of chronic pain.Ideally, studies of chronic postoperative pain should include (1) sufficient preoperative data (assessment of pain, physiologic and psychologic risk factors for chronic pain); (2) detailed descriptions of the operative approaches used (location and length of incisions, handling of nerves and muscles); (3) the intensity and character of acute postoperative pain and its management; and (4) follow-up at intervals to 1 yr or more. In addition, there would be information about postoperative interventions that may influence pain, such as radiation therapy or chemotherapy. At long-term follow-up visits, patient function, physical signs, and symptoms would be evaluated using a standardized algorithm, including quantitative and descriptive pain assessments. We found no studies that contain all of these data.For this review, we specifically sought population data that reflect the incidence of chronic postoperative pain or predictors (medical, physiologic, and psychologic) of chronic pain. We selected five groups of surgeries (limb amputations, breast surgery, gallbladder surgery, lung surgery, and inguinal hernia surgery). These surgeries were selected because the incidence of pain is known to be high, thus improving the probability of detecting predictive factors. They also represent a range of major surgical procedures.We performed a computerized search of the medical literature using the OVID search engine (OVID Technologies, Wolters Kluwer, Amsterdam, The Netherlands). The search was performed on the entire database in January 1999 and covered 1966 through most of 1998. Additional articles published during the review process have also been included. Terms were used in their “exploded” format. The term “pain” was combined with the other appropriate term (e.g., “cholecystectomy”); also the text words associated with the pain syndromes were searched, resulting in more than 1,700 citations. Letters to the editor were not reviewed. Additionally, articles known to the authors but not found in the search were used. If the article contained data about persistent pain (12 weeks or more after surgery), it was considered for inclusion in this review. To calculate the incidence of pain, we used the number of individuals responding at the time the chronic pain data was gathered, and only used data from articles in which the methods section indicated that there was systematic collection of long-term pain information from patients. Studies of fewer than 50 patients were excluded in the incidence data analysis for breast surgery, gallbladder surgery, and lung surgery. Studies of fewer than 100 patients were excluded from the data analysis for inguinal hernia surgery. Amputation studies of 25 subjects or more were included because of the higher incidence of chronic pain.The reported incidence of phantom limb pain varies from 30 to 81% (table 1). Finch et al . 1reported pain in 30% of 57 long-term survivors of amputation for vascular insufficiency. Fisher and Hanspal 2described 93 consecutive amputees referred to a prosthetic rehabilitation clinic; therefore, selection bias may be a factor. The remainder of the studies (table 1) report an incidence of phantom limb pain of more than 50%. Sherman et al. 3noted at least a 78% incidence of phantom limb pain, and perhaps as high as 85%; however, their questionnaire response rate was not high (55%). Stump pain was noted in 66% of patients with phantom pain and in half of those without phantom pain; therefore, the overall stump pain incidence exceeds 60%. Wartan et al . 4reported a 62% incidence of phantom limb pain and 63% for stump pain. Similar to Sherman et al., 66% of patients with phantom limb pain also have stump pain. Smith and Thompson 5reported that pain was more common after amputation for cancer than for trauma, but this study was a chart review (phantom pain noted in medical record), and there were only eight amputations for trauma. No large studies systematically evaluate the incidence of phantom limb pain after trauma, vascular disease, and cancer-related surgeries. The presence of intense preoperative pain in the extremity increases the probability of phantom limb pain (from 33 to 72% at 3 months). 6,7Some early reports 8,9indicated that the incidence of phantom limb pain decreased with prolonged (72 h) preoperative epidural pain control, followed by postoperative epidural pain control. Both studies were small (23 and 24 patients, respectively at 6 months follow-up), and neither was properly randomized. In a subsequent randomized controlled study, 10this observation was not confirmed, but preoperative pain control was limited to 18 h, and the extent and intensity of perioperative blockade was not sufficient to control pain without supplemental systemic opioids.The effect of anesthesia (epidural, spinal, or general) alone has not been studied. Surgical handling of the major nerves is rarely mentioned, so we cannot assess the effect of nerve ligation or clipping versus section alone.Administration of chemotherapy increases the incidence of phantom limb pain. 5Stump pain at 1 week is significantly associated with phantom pain at 1 week, 6and long-term stump pain predicts long-term phantom limb pain. 3There is also a correlation between nonpainful phantom sensations and phantom pain. 4Control of acute postoperative pain with nerve sheath infusion of local anesthetic decreased the incidence of phantom limb pain in one series of 11 patients, 11but a subsequent randomized controlled trial (n = 14 at long term follow-up) 12failed to confirm this finding. Both of these studies are small, and the negative study 12does not have the statistical power to conclude that there is no significant effect. There has also been a negative retrospective report of this technique (n = 21). 13As mentioned previously, data regarding epidural analgesia 8–10as a method to decrease the incidence of phantom limb pain conflict.Most authorities believe that phantom limb sensation and phantom limb pain are central phenomena and explain them using the neuromatrix theory expounded by Melzack. 14,15That is, there is a matrix in the central nervous system for the perception of a body part, and this matrix exists even when the body part does not. Sherman et al . 3emphasized that multiple etiologies may lead to phantom limb pain, based on the inconsistency of therapeutic responses.The incidence of phantom limb pain decreases during the first year after amputation, as does the frequency of painful episodes 7,16; however, about half the individuals with long-term phantom pain report no decrease in the intensity of this pain. 3Phantom limb pain is common after extremity amputation, and documented predictors of this pain include preamputation pain and persistent stump pain (acute and chronic). No conclusive studies have evaluated the effect of acute or subacute stump pain control on long-term stump pain or on long-term phantom limb pain. Also no psychologic studies have evaluated patients before amputation for predictors of chronic pain.Long-term pain after thoracotomy, the postthoracotomy pain syndrome (PTPS), may have an incidence of more than 50%. 17,18Six studies met our inclusion–exclusion criteria (table 2), assessing 878 patients, of whom 417 (47%) had PTPS. Katz et al . 2could not predict PTPS from preoperative psychologic testing (state or trait anxiety, depression inventory) or preoperative pain sensitivity as determined by pressure algometry. This study (n = 23) was the extension of a previous acute pain study; it therefore lacks statistical power and may be subject to selection bias. Perttunen et al . 19noted the presence of preoperative pain in 17% of their patients but did not analyze it as an independent risk factor.Several recent case series report that video-assisted thoracoscopic lung surgery (VATS) is associated with a low incidence of PTPS. Walker et al . 20reported only 1 case of 83 (1.2%), and Mouroux et al . 21noted a 3% incidence of PTPS, but neither group reports systematically looking for PTPS. In a large retrospective survey, Landreneau et al . 22(table 2) noted a lower incidence of pain in patients who had VATS compared with those who underwent lateral thoracotomy (30 vs. 44%); however, pain medication requirements did not differ. The difference in pain incidence was statistically significant only during the first year after surgery. In a small (n = 30), nonrandomized prospective study, Furrer et al. 23found a 36% incidence of PTPS in patients undergoing VATS wedge resection, and a 33% incidence of PTPS in a matched group of patients undergoing lobectomy by a classic posterolateral thoracotomy. However, the results are confounded because the thoracotomy group received thoracic epidural analgesia with local anesthetic and opioid, whereas the thoracoscopic group received intravenous patient-controlled opioids. Nomori et al. 24retrospectively and Benedetti et al. 25prospectively (case series) reported a decreased severity of chronic pain after anterolateral thoracotomy when compared with classic posterolateral thoracotomy (mean visual analog scale [VAS] score, 6 of 100 vs. 21 of 100). Both studies were small (24 and 42 patients), and chronic postoperative pain was not a primary outcome parameter. In descriptions of the surgical technique for posterolateral thoracotomy, details about whether a rib was resected or about how the intercostal nerves were handled were missing from most reports.A recent report by Obata et al . 26(table 2) found a significant effect of intraoperative plus postoperative epidural analgesia when compared with just postoperative epidural analgesia (decreasing the incidence of pain at 6 months from 67% to 33%). This is a prospective, randomized, single-blind study.The intensity of acute postoperative pain is a statistically significant predictor 18,27of PTPS (36 vs. 56% PTPS for minor vs. moderate to severe acute pain). As mentioned previously herein, the combination of intraoperative plus postoperative epidural analgesia with local anesthetic was associated with a decreased incidence of pain at 6 months. An attempt at preemptive analgesia 28had not improved analgesia on long-term follow-up. 18Another small study found that the type of postoperative analgesia affected the incidence of pain at 12 weeks (less pain with epidural analgesia or intercostal nerve cryoablation), but data of only 33 subjects divided among four treatment regimens were reported. 29Benedetti et al. 25,30showed that intercostal nerve dysfunction (loss of the superficial abdominal reflex) is associated with more acute, subacute, and chronic (3 months) pain. Of 23 patients with intact reflexes on postoperative day 1, none had pain at 2 to 3 months, whereas 50% of individuals with persistent loss of the reflex still had pain at this time.The etiology of PTPS may depend on nerve damage because it is more severe after chest wall resection, 31–33and the loss of superficial abdominal reflexes is associated with an increased probability of PTPS. 25,30Another contributing factor is recurrence of tumor. 31For thoracoscopic surgeries and posterolateral thoracotomy, Landreneau et al . 22noted a 30% decrease in the incidence in pain reported by patients more than 12 months after surgery compared with those 3–12 months after surgery. The prospective study by Perttunen et al . 19noted the incidence of pain at 3, 6, and 12 months to be decreasing (80, 75, and 61%, respectively). Of patients with long-term pain after thoracotomy, up to half describe their pain as moderate or severe, 18and 66% are prescribed analgesics for the pain. 27Postthoracotomy pain syndrome is common. The predictors of this syndrome (when tumor recurrence is excluded) include the extent of acute postoperative pain and intercostal nerve dysfunction (which may link more acute pain and persistent pain). One prospective, randomized controlled study 28found that the combination of intraoperative plus postoperative thoracic epidural analgesia decreases the incidence of PTPS at 6 months.Table 3summarizes various studies of pain after breast surgery. Women who undergo breast surgery experience chest wall, breast, or scar pain (range, 11–57%), phantom breast pain (13–24%), and arm and shoulder pain (12–51%). The incidence of pain in one or more of these sites is close to 50% 1 yr after breast surgery for cancer. The postmastectomy pain syndrome (PMPS) has recently been reviewed, 34with some disagreement about which pains to include in this syndrome. Husted et al . 35documented that, of 163 women who had undergone mastectomy with axillary node dissection, 45% reported cicatrix pain, 45% reported arm, neck, or shoulder pain, and only 21% were symptom free (symptoms included pain, paresthesia, lymphedema, and impaired shoulder function) 1–5 yr after surgery. Moderate to severe pain was reported by 16 patients (10%). Krøner et al . 36reported a significant relation between preoperative breast pain and postoperative phantom breast pain in a prospective study of 120 patients. In contrast, Tasmuth et al., 37,38in a prospective study of 93 patients, did not find the presence of preoperative pain to be a predictive but only patients had pain before surgery. depression and were more common in patients in whom chronic pain when compared with those in whom chronic pain did not statistical was not type of surgery may the incidence of pain. Tasmuth et al. that chronic pain was more common after breast surgery than after surgery in their large retrospective study, but did not confirm this in prospective et al., their questionnaire of women who had undergone breast surgery, found that mastectomy combined with of a breast a higher incidence of pain than did mastectomy alone et al . in the of the nerve at 3 months after axillary node in of women in whom the nerve was and in of women in whom it was et al . that axillary increased the of arm and of psychologic et al . found the extent of axillary with the incidence of arm pain and et al . a analysis of factors that the patient to chronic pain after breast cancer surgery. The extent of acute postoperative pain and the number of of postoperative analgesics were the predictors of persistent pain in the breast and the Additionally, postoperative radiation therapy was a risk factor for chronic pain in the breast and the et al . that axillary radiation therapy increased the incidence of arm pain and et al . Krøner et al . a relation between phantom breast sensations and radiation but their studies were and only sought a of of the pain after breast surgery has been to nerve whether from surgery or and that and sensation decreased nerve in the long-term in of women undergoing and of women undergoing but pain data were not reported. was in the of the nerve in of women undergoing axillary In in of women with these was associated with a higher incidence of arm pain and arm symptoms and were more common after breast surgery with axillary node The among pain, and preoperative psychologic have not been among women undergoing breast natural history of pain during the first year after surgery has not been In one study, the incidence of pain in the breast decreased from to from 3 weeks to 1 yr after surgery, whereas the incidence of decreased from to study, the incidence of arm pain decreased from 3 to months after surgery to respectively). incidence of phantom breast pain is from 3 weeks to 6 pain is common after breast surgery, and the major predictive factors are the extent of acute postoperative pain, the presence of pain before surgery, the type of surgery, nerve radiation and preoperative or abdominal pain after is common (range, but than the preoperative incidence of pain The syndrome has a number of in to abdominal pain, and may not have a factors include postoperative pain; pain by postoperative of pain by a other than gallbladder pain by a and other preoperative factors that the patient to an is a predictor of long-term pain and symptoms after other risk factors include symptoms before surgery. history of classic gallbladder symptoms is associated with risk of chronic pain and surgical to no significant difference in overall et al., a randomized controlled trial (n = noted that patients randomized to had more to whereas patients randomized to had more of scar pain and did not report pain incidence There to be no difference in chronic abdominal pain when is compared with et al . a 30% incidence of abdominal pain more than 1 yr after but this incidence did not include 16 patients with pain. et al . significantly more pain after than after surgery and that there was more intercostal nerve damage from the et al., a prospective study of 100 patients who underwent noted that pain at 6 weeks was a predictor of persistent pain and other symptoms at 1 yr and We found no studies that evaluated acute postoperative pain as a predictor of chronic are multiple etiologies of the including of and scar pain. The of factor has not been the frequency of persistent symptoms after patient after the is high, with authors that may to patient most patients with abdominal pain and believe that without surgery and that their improve after symptoms are common after as is chronic abdominal pain. factors include psychologic preoperative symptoms and pain at 6 weeks after surgery. studies of the syndrome have not scar pain and pain from other of chronic pain and number of studies have evaluated chronic pain after surgery, with the reported incidence of chronic pain from to (table The overall incidence from these studies is of pain was a primary outcome in only four these studies report a In a prospective study of surgery for a hernia had a higher incidence of moderate to severe pain at 12 months than did surgery for a primary for have a higher pain incidence at 6 months than those who are for by of vs. 1 of have had pain for a of time before data are about whether the surgical the incidence of chronic pain. et al., a prospective randomized controlled study that evaluated recurrence found a lower incidence of chronic pain after a when compared with an The study found a significantly lower incidence of pain at 12 months after a compared with an et al. no difference in the incidence of chronic pain in their prospective randomized controlled study that compared an to a and no difference in the incidence of pain in their case with and a incidence of chronic pain. of the studies that including pain, were more common early in their experience with hernia a prospective study, et al. not find statistically significant in chronic pain after or in a prospective analysis of et al., no significant in chronic pain between and in primary hernia surgery. the experience of the or the of is a factor in chronic pain or recurrence has been incidence of chronic pain in case series data from hernia is reports with higher of chronic pain from are no prospective studies of this extent of pain at 1 and weeks after surgery is a predictive factor pain at 1 length of type of the incidence of chronic pain. relation between postoperative dysfunction and chronic pain the that nerve damage is a pathologic factor. authors the pain is of the of the et al . the incidence of moderate to severe pain decreased from at weeks to at 1 Moderate to severe pain at 1 and weeks was the predictor of pain at 1 pain after hernia surgery is not but it to be common than chronic pain after the surgeries previously hernia surgery is a large number of individuals are affected by chronic pain. dysfunction has been to be a as has the intensity of early postoperative pain. The of acute pain therapy on the incidence of chronic pain is patient with surgical results is reported to be high, studies reported that chronic pain is common after these and this has been in a recent review. pain is to in of and and the of chronic pain after surgery should be is also there is significant in the incidence of chronic pain among these surgical for inguinal hernia and thoracic surgery). We believe that our review has been but the of search our search did not all articles known to the authors that to the or incidence of chronic pain after the selected surgeries. for this include in not included in the at the time of (e.g., et al . and or “pain” not as a or used in the or (e.g., et al. As a we are not that we all articles that contain data to this a number of risk factors for prolonged pain after surgery and these factors (1) preoperative (2) intraoperative and (3) postoperative factors (table pain is a predictor of chronic pain for pain, breast pain, abdominal pain and symptoms after of these the of the preoperative pain that chronic pain to be pain of 1 or more in is a risk factor for persistent pain after has not been evaluated in the other surgeries has also been found to predict outcome after surgery. damage is an intraoperative factor that to chronic postoperative pain. undergoing thoracotomy are to have intercostal nerve dysfunction and to have PTPS. breast surgery, is associated with damage of that and to the nerve are associated with a lower incidence of pain. nerve damage does not pain because the incidence of decreased sensation was higher than the incidence of pain in the of the nerve after axillary node Benedetti et al. chronic pain in only 50% of individuals with intercostal nerve dysfunction after thoracotomy. nerve dysfunction to be associated with chronic pain. most predictive postoperative factor is the severity of acute postoperative pain after breast surgery, surgery, hernia radiation therapy increases the risk of chronic pain after breast surgery, chemotherapy increases the risk of phantom limb pain. acute pain chronic pain has been a that and factors and the severity of acute pain as factors in the of chronic pain. we believe that from nerve increases acute pain and early months) chronic pain. in the nervous system associated with acute pain, with the that pain should be considered a of the nervous not a symptom of some other If persistent pain after surgery results from may be be Obata et al . this in thoracotomy patients with intraoperative plus postoperative epidural but other studies of preemptive analgesia are from factors are also predictors of chronic pain. Of the surgical we reviewed, the only psychologic predictor has been The questionnaire for psychologic a that with depression are preoperative predictors of chronic pain after surgery. et al . when to predict chronic pain in acute pain patients. They that is not associated with an increased risk of of chronic low pain, but may reflect or in that are to chronic pain. The of et al. with the psychologic in chronic pain is common after amputation, inguinal hernia surgery, breast surgery, gallbladder surgery, and lung surgery, and this is also in recent review. of these data may be as chronic pain as one of acute postoperative pain is a predictor of chronic pain. studies should the factors of in the from acute to chronic pain. may in more and more rational early We that, in some patients, the type of nerve may explain the in acute pain and the chronic pain, but the extent of pain be by other psychologic and physiologic factors that pain

Crohn’s disease [CD] is a chronic inflammatory bowel disease [IBD] that can result in progressive bowel damage and disability1. CD can affect individuals of any age, from children to the elderly, 2, 3 and may cause significant morbidity and impact on quality of life. Up to one-third of patients present with complicated behaviour [strictures, fistula, or abscesses] at diagnosis4. Most patients over time will develop a complication, with roughly 50% of patients requiring surgery within 10 years of diagnosis5-7. As the precise aetiology of CD remains unknown, a curative therapy is not yet available8. Several agents are available for the medical treatment of CD. Medical agents include mesalazine [5-ASA], locally active steroids [such as budesonide], systemic steroids, thiopurines such as azathioprine [AZA] and mercaptopurine [MP], methotrexate [MTX], and biological therapies [such as anti-TNF, anti-integrins, and anti-IL12/23]. \nThe European Crohn’s and Colitis Organisation [ECCO] produces and regularly updates several guidelines aimed at providing evidence-based guidance on critical aspects of IBD care to all healthcare professionals who manage patients with IBD. To provide high-quality evidence-based recommendations on medical and surgical treatment in CD, ECCO decided to develop these guidelines by adopting the GRADE [Grading of Recommendations Assessment, Development, and Evaluation] approach9. GRADE is a systematic process for developing guidelines that addresses how to frame the healthcare questions, summarize the evidence, ..

OBJECTIVE: To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. DESIGN: We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. RESULTS: Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. CONCLUSIONS: We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples.