University Hospital of North Norway

BACKGROUND: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). METHODS: We estimated the incidence of infections with 16 antibiotic resistance-bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011-12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. FINDINGS: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148-763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480-38 430) attributable deaths and 874 541 (768 837-989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. INTERPRETATION: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases. FUNDING: European Centre for Disease Prevention and Control.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Abstract Background This review aims to present a consensus for optimal perioperative care in rectal/pelvic surgery, and to provide graded recommendations for items for an evidenced‐based enhanced recovery protocol. Methods Studies were selected with particular attention paid to meta‐analyses, randomized controlled trials and large prospective cohorts. For each item of the perioperative treatment pathway, available English‐language literature was examined, reviewed and graded. A consensus recommendation was reached after critical appraisal of the literature by the group. Results For most of the protocol items, recommendations are based on good‐quality trials or meta‐analyses of good‐quality trials (evidence grade: high or moderate). Conclusions Based on the evidence available for each item of the multimodal perioperative care pathway, the Enhanced Recovery After Surgery (ERAS) Society, European Society for Clinical Nutrition and Metabolism (ESPEN) and International Association for Surgical Metabolism and Nutrition (IASMEN) present a comprehensive evidence‐based consensus review of perioperative care for rectal surgery.

We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4-polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.

BACKGROUND: Homocysteine is a risk factor for cardiovascular disease. We evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infarction. METHODS: The trial included 3749 men and women who had had an acute myocardial infarction within seven days before randomization. Patients were randomly assigned, in a two-by-two factorial design, to receive one of the following four daily treatments: 0.8 mg of folic acid, 0.4 mg of vitamin B12, and 40 mg of vitamin B6; 0.8 mg of folic acid and 0.4 mg of vitamin B12; 40 mg of vitamin B6; or placebo. The primary end point during a median follow-up of 40 months was a composite of recurrent myocardial infarction, stroke, and sudden death attributed to coronary artery disease. RESULTS: The mean total homocysteine level was lowered by 27 percent among patients given folic acid plus vitamin B12, but such treatment had no significant effect on the primary end point (risk ratio, 1.08; 95 percent confidence interval, 0.93 to 1.25; P=0.31). Also, treatment with vitamin B6 was not associated with any significant benefit with regard to the primary end point (relative risk of the primary end point, 1.14; 95 percent confidence interval, 0.98 to 1.32; P=0.09). In the group given folic acid, vitamin B12, and vitamin B6, there was a trend toward an increased risk (relative risk, 1.22; 95 percent confidence interval, 1.00 to 1.50; P=0.05). CONCLUSIONS: Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction. A harmful effect from combined B vitamin treatment was suggested. Such treatment should therefore not be recommended. (ClinicalTrials.gov number, NCT00266487.).

Acute aortic dissection (AAD) is a life-threatening condition associated with high morbidity and mortality rates, and it remains a challenge to diagnose and treat. The International Registry of Acute Aortic Dissection was established in 1996 with the mission to raise awareness of this condition and provide insights to guide diagnosis and treatment. Since then, >7300 cases have been included from >51 sites in 12 countries. Although presenting symptoms and physical findings have not changed significantly over this period, the use of computed tomography in the diagnosis has increased, and more patients are managed with interventional procedures: surgery in type A AAD and endovascular therapy in type B AAD; with these changes in care, there has been a significant decrease in overall in-hospital mortality in type A AAD but not in type B AAD. Herein, we summarized the key lessons learned from this international registry of patients with AAD over the past 20 years.

BACKGROUND: New methods have been used, with promising results, to treat full-thickness cartilage defects. The objective of the present study was to compare autologous chondrocyte implantation with microfracture in a randomized trial. We are not aware of any previous randomized studies comparing these methods. METHODS: Eighty patients without general osteoarthritis who had a single symptomatic cartilage defect on the femoral condyle in a stable knee were treated with autologous chondrocyte implantation or microfracture (forty in each group). We used the International Cartilage Repair Society, Lysholm, Short Form-36 (SF-36), and Tegner forms to collect data. An independent observer performed a follow-up examination at twelve and twenty-four months. Two years postoperatively, arthroscopy with biopsy for histological evaluation was carried out. The histological evaluation was done by a pathologist and a clinical scientist, both of whom were blinded to each patient's treatment. RESULTS: In general, there were small differences between the two treatment groups. At two years, both groups had significant clinical improvement. According to the SF-36 physical component score at two years postoperatively, the improvement in the microfracture group was significantly better than that in the autologous chondrocyte implantation group (p = 0.004). Younger and more active patients did better in both groups. There were two failures in the autologous chondrocyte implantation group and one in the microfracture group. No serious complications were reported. Biopsy specimens were obtained from 84% of the patients, and histological evaluation of repair tissues showed no significant differences between the two groups. We did not find any association between the histological quality of the tissue and the clinical outcome according to the scores on the Lysholm or SF-36 form or the visual analog scale. CONCLUSIONS: Both methods had acceptable short-term clinical results. There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point. LEVEL OF EVIDENCE: Therapeutic study, Level I-1a (randomized controlled trial [significant difference]). See Instructions to Authors for a complete description of levels of evidence.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

OBJECTIVES: To describe a consensus review of optimal perioperative care in colorectal surgery and to provide consensus recommendations for each item of an evidence-based protocol for optimal perioperative care. DATA SOURCES: For every item of the perioperative treatment pathway, available English-language literature has been examined. STUDY SELECTION: Particular attention was paid to meta-analyses, randomized controlled trials, and systematic reviews. DATA EXTRACTION: A consensus recommendation for each protocol item was reached after critical appraisal of the literature by the group. DATA SYNTHESIS: For most protocol items, recommendations are based on good-quality trials or meta-analyses of such trials. CONCLUSIONS: The Enhanced Recovery After Surgery (ERAS) Group presents a comprehensive evidence-based consensus review of perioperative care for colorectal surgery. It is based on the evidence available for each element of the multimodal perioperative care pathway.

PURPOSE: Quality of life (QOL) is an important concept in the field of health and medicine. QOL is a complex concept that is interpreted and defined differently within and between disciplines, including the fields of health and medicine. The aims of this study were to systematically review the literature on QOL in medicine and health research and to describe the country of origin, target groups, instruments, design, and conceptual issues. METHODS: A systematic review was conducted to identify research studies on QOL and health-related quality of life (HRQOL). The databases Scopus, which includes Embase and MEDLINE, CINAHL, and PsycINFO were searched for articles published during one random week in November 2016. The ten predefined criteria of Gill and Feinstein were used to evaluate the conceptual and methodological rigor. RESULTS: QOL research is international and involves a variety of target groups, research designs, and QOL measures. According to the criteria of Gill and Feinstein, the results show that only 13% provided a definition of QOL, 6% distinguished QOL from HRQOL. The most frequently fulfilled criteria were: (i) stating the domains of QOL to be measured; (ii) giving a reason for choosing the instruments used; and (iii) aggregating the results from multiple items. CONCLUSION: QOL is an important endpoint in medical and health research, and QOL research involves a variety of patient groups and different research designs. Based on the current evaluation of the methodological and conceptual clarity of QOL research, we conclude that the majority QOL studies in health and medicine have conceptual and methodological challenges.

BACKGROUND: Radical prostatectomy is widely used in the treatment of early prostate cancer. The possible survival benefit of this treatment, however, is unclear. We conducted a randomized trial to address this question. METHODS: From October 1989 through February 1999, 695 men with newly diagnosed prostate cancer in International Union against Cancer clinical stage T1b, T1c, or T2 were randomly assigned to watchful waiting or radical prostatectomy. We achieved complete follow-up through the year 2000 with blinded evaluation of causes of death. The primary end point was death due to prostate cancer, and the secondary end points were overall mortality, metastasis-free survival, and local progression. RESULTS: During a median of 6.2 years of follow-up, 62 men in the watchful-waiting group and 53 in the radical-prostatectomy group died (P=0.31). Death due to prostate cancer occurred in 31 of 348 of those assigned to watchful waiting (8.9 percent) and in 16 of 347 of those assigned to radical prostatectomy (4.6 percent) (relative hazard, 0.50; 95 percent confidence interval, 0.27 to 0.91; P=0.02). Death due to other causes occurred in 31 of 348 men in the watchful-waiting group (8.9 percent) and in 37 of 347 men in the radical-prostatectomy group (10.6 percent). The men assigned to surgery had a lower relative risk of distant metastases than the men assigned to watchful waiting (relative hazard, 0.63; 95 percent confidence interval, 0.41 to 0.96). CONCLUSIONS: In this randomized trial, radical prostatectomy significantly reduced disease-specific mortality, but there was no significant difference between surgery and watchful waiting in terms of overall survival.

BACKGROUND: The optimal treatment for cartilage lesions has not yet been established. The objective of this randomized trial was to compare autologous chondrocyte implantation with microfracture. This paper represents an update, with presentation of the clinical results at five years. METHODS: Eighty patients who had a single chronic symptomatic cartilage defect on the femoral condyle in a stable knee without general osteoarthritis were included in the study. Forty patients were treated with autologous chondrocyte implantation, and forty were treated with microfracture. We used the International Cartilage Repair Society, Lysholm, Short Form-36, and Tegner forms to collect clinical data, and radiographs were evaluated with use of the Kellgren and Lawrence grading system. RESULTS: At two and five years, both groups had significant clinical improvement compared with the preoperative status. At the five-year follow-up interval, there were nine failures (23%) in both groups compared with two failures of the autologous chondrocyte implantation and one failure of the microfracture treatment at two years. Younger patients did better in both groups. We did not find a correlation between histological quality and clinical outcome. However, none of the patients with the best-quality cartilage (predominantly hyaline) at the two-year mark had a later failure. One-third of the patients in both groups had radiographic evidence of early osteoarthritis at five years. CONCLUSIONS: Both methods provided satisfactory results in 77% of the patients at five years. There was no significant difference in the clinical and radiographic results between the two treatment groups and no correlation between the histological findings and the clinical outcome. One-third of the patients had early radiographic signs of osteoarthritis five years after the surgery. Further long-term follow-up is needed to determine if one method is better than the other and to study the progression of osteoarthritis.

BACKGROUND: Application of evidence-based perioperative care protocols reduces complication rates, accelerates recovery and shortens hospital stay. Presently, there are no comprehensive guidelines for perioperative care for gastrectomy. METHODS: An international working group within the Enhanced Recovery After Surgery (ERAS®) Society assembled an evidence-based comprehensive framework for optimal perioperative care for patients undergoing gastrectomy. Data were retrieved from standard databases and personal archives. Evidence and recommendations were classified according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system and were discussed until consensus was reached within the group. The quality of evidence was rated 'high', 'moderate', 'low' or 'very low'. Recommendations were graded as 'strong' or 'weak'. RESULTS: The available evidence has been summarized and recommendations are given for 25 items, eight of which contain procedure-specific evidence. The quality of evidence varies substantially and further research is needed for many issues to improve the strength of evidence and grade of recommendations. CONCLUSION: The present evidence-based framework provides comprehensive advice on optimal perioperative care for the patient undergoing gastrectomy and facilitates multi-institutional prospective cohort registries and adequately powered randomized trials for further research.

BACKGROUND: Patency or thrombosis of the false lumen in type B acute aortic dissection has been found to predict outcomes. The prognostic implications of partial thrombosis of the false lumen have not yet been elucidated. METHODS: We examined 201 patients with type B acute aortic dissection who were enrolled in the International Registry of Acute Aortic Dissection between 1996 and 2003 and who survived to hospital discharge. Kaplan-Meier mortality curves were stratified according to the status of the false lumen (patent, partial thrombosis, or complete thrombosis) as determined during the index hospitalization. Cox proportional-hazards analysis was performed to identify independent predictors of death. RESULTS: During the index hospitalization, 114 patients (56.7%) had a patent false lumen, 68 patients (33.8%) had partial thrombosis of the false lumen, and 19 (9.5%) had complete thrombosis of the false lumen. The mean (+/-SD) 3-year mortality rate for patients with a patent false lumen was 13.7+/-7.1%, for those with partial thrombosis was 31.6+/-12.4%, and for those with complete thrombosis was 22.6+/-22.6% (median follow-up, 2.8 years; P=0.003 by the log-rank test). Independent predictors of postdischarge mortality were partial thrombosis of the false lumen (relative risk, 2.69; 95% confidence interval [CI], 1.45 to 4.98; P=0.002), a history of aortic aneurysm (relative risk, 2.05; 95% CI, 1.07 to 3.93; P=0.03), and a history of atherosclerosis (relative risk, 1.87; 95% CI, 1.01 to 3.47; P=0.05). CONCLUSIONS: Mortality is high after discharge from the hospital among patients with type B acute aortic dissection. Partial thrombosis of the false lumen, as compared with complete patency, is a significant independent predictor of postdischarge mortality in these patients.

BACKGROUND: European citizens are increasingly being offered Internet health services. This study investigated patterns of health-related Internet use, its consequences, and citizens' expectations about their doctors' provision of e-health services. METHODS: Representative samples were obtained from the general populations in Norway, Denmark, Germany, Greece, Poland, Portugal and Latvia. The total sample consisted of 7934 respondents. Interviews were conducted by telephone. RESULTS: 44 % of the total sample, 71 % of the Internet users, had used the Internet for health purposes. Factors that positively affected the use of Internet for health purposes were youth, higher education, white-collar or no paid job, visits to the GP during the past year, long-term illness or disabilities, and a subjective assessment of one's own health as good. Women were the most active health users among those who were online. One in four of the respondents used the Internet to prepare for or follow up doctors' appointments. Feeling reassured after using the Internet for health purposes was twice as common as experiencing anxieties. When choosing a new doctor, more than a third of the sample rated the provision of e-health services as important. CONCLUSION: The users of Internet health services differ from the general population when it comes to health and demographic variables. The most common way to use the Internet in health matters is to read information, second comes using the net to decide whether to see a doctor and to prepare for and follow up on doctors' appointments. Hence, health-related use of the Internet does affect patients' use of other health services, but it would appear to supplement rather than to replace other health services.

BACKGROUND: The present interdisciplinary consensus review proposes clinical considerations and recommendations for anaesthetic practice in patients undergoing gastrointestinal surgery with an Enhanced Recovery after Surgery (ERAS) programme. METHODS: Studies were selected with particular attention being paid to meta-analyses, randomized controlled trials and large prospective cohort studies. For each item of the perioperative treatment pathway, available English-language literature was examined and reviewed. The group reached a consensus recommendation after critical appraisal of the literature. RESULTS: This consensus statement demonstrates that anaesthesiologists control several preoperative, intraoperative and postoperative ERAS elements. Further research is needed to verify the strength of these recommendations. CONCLUSIONS: Based on the evidence available for each element of perioperative care pathways, the Enhanced Recovery After Surgery (ERAS®) Society presents a comprehensive consensus review, clinical considerations and recommendations for anaesthesia care in patients undergoing gastrointestinal surgery within an ERAS programme. This unified protocol facilitates involvement of anaesthesiologists in the implementation of the ERAS programmes and allows for comparison between centres and it eventually might facilitate the design of multi-institutional prospective and adequately powered randomized trials.

OBJECTIVE: To assess prevalence, incidence, prognosis and progression of degenerative valvular aortic stenosis (AS). SETTING: The Tromsø Study and the University Hospital of North Norway. DESIGN: Population based prospective study. POPULATION: Over a 14 year span we performed three repeated echocardiographic examinations (1994, 2001 and 2008) of a random sample of initially 3273 participants. Data from the only hospital serving this population were included. RESULTS: There were 164 subjects with AS. Prevalence consistently increased with age, average values being 0.2% in the 50-59 year cohort, 1.3% in the 60-69 year cohort, 3.9% in the 70-79 year cohort and 9.8% in the 80-89 year cohort. The incidence rate in the study was 4.9‰/year. The mean annual increase in mean transvalvular pressure gradient was 3.2 mm Hg. The increase was lower in mild AS than in more severe disease, disclosing a non-linear development of the gradient, but with large individual variations. Mortality was not significantly increased in the asymptomatic AS-group (HR = 1.28), nor in those who received aortic valve replacement (n = 34, HR = 0.93), compared with the general population. CONCLUSION: This is the first study to document the incidence and prognosis of AS in a general population with surgery as a treatment option. It reveals an accelerated progression of the aortic mean gradient as the disease advances. The prognosis of AS seems to be comparable with the normal population in the asymptomatic stage and after successful surgery, indicating that the follow-up and timing of surgery has been adequate for this patient group.

In a population-based study of 6,386 men and women aged 25--84 years in Tromsø, Norway, in 1994--1995, the authors assessed the age- and sex-specific distribution of the abdominal aortic diameter and the prevalence of and risk factors for abdominal aortic aneurysm. Renal and infrarenal aortic diameters were measured with ultrasound. The mean infrarenal aortic diameter increased with age. The increase was more pronounced in men than in women. The age-related increase in the median diameter was less than that in the mean diameter. An aneurysm was present in 263 (8.9%) men and 74 (2.2%) women (p < 0.001). The prevalence of abdominal aortic aneurysm increased with age. No person aged less than 48 years was found with an abdominal aortic aneurysm. Persons who had smoked for more than 40 years had an odds ratio of 8.0 for abdominal aortic aneurysm (95% confidence interval: 5.0, 12.6) compared with never smokers. Low serum high density lipoprotein cholesterol was associated with an increased risk for abdominal aortic aneurysm. Other factors associated with abdominal aortic aneurysm were a high level of plasma fibrinogen and a low blood platelet count. Antihypertensive medication (ever use) was significantly associated with abdominal aortic aneurysm, but high systolic blood pressure was a risk factor in women only. This study indicates that risk factors for atherosclerosis are also associated with increased risk for abdominal aortic aneurysm.

PURPOSE: The major value of prognostic markers in potentially curable non-small cell lung cancer (NSCLC) should be to guide therapy after surgical resection. In this regard, the patients' immune status at the time of resection may be important and also measurable. The immune system has paradoxical roles during cancer development. However, the prognostic significance of tumor-infiltrating lymphocytes is controversial. The aim of this study is to elucidate the prognostic significance of epithelial and stromal lymphocyte infiltration in NSCLC. EXPERIMENTAL DESIGN: Tissue microarrays from 335 resected NSCLC, stage I to IIIA were constructed from duplicate cores of viable and representative neoplastic epithelial and stromal areas. Immunohistochemistry was used to evaluate the epithelial and stromal CD4+, CD8+, and CD20+ lymphocytes. RESULTS: In univariate analyses, increasing numbers of epithelial CD8+ (P = 0.023), stromal CD8+ (P = 0.002), epithelial CD20+ (P = 0.023), stromal CD20+ (P < 0.001), and stromal CD4+ (P < 0.001) lymphocytes correlated significantly with an improved disease-specific survival. No such relation was noted for epithelial CD4+ cells. Furthermore, a low level of stromal CD8+ lymphocyte infiltration was associated with an increased incidence of angiolymphatic invasion (P = 0.032). In multivariate analyses, a high number of stromal CD8+ (P = 0.043) and CD4+ (P = 0.002) cells were independent positive prognostic factors for disease-specific survival. CONCLUSIONS: High densities of CD4+ and CD8+ lymphocytes in the stroma are independent positive prognostic indicators for resected NSCLC patients. This may suggest that these cells are mediating a strong antitumor immune response in NSCLC.

BACKGROUND: The clinical case report has a long-standing tradition in the medical literature. While its scientific significance has become smaller as more advanced research methods have gained ground, case reports are still presented in many medical journals. Some scholars point to its limited value for medical progress, while others assert that the genre is undervalued. We aimed to present the various points of view regarding the merits and limitations of the case report genre. We searched Google Scholar, PubMed and select textbooks on epidemiology and medical research for articles and book-chapters discussing the merits and limitations of clinical case reports and case series. RESULTS: The major merits of case reporting were these: Detecting novelties, generating hypotheses, pharmacovigilance, high applicability when other research designs are not possible to carry out, allowing emphasis on the narrative aspect (in-depth understanding), and educational value. The major limitations were: Lack of ability to generalize, no possibility to establish cause-effect relationship, danger of over-interpretation, publication bias, retrospective design, and distraction of reader when focusing on the unusual. CONCLUSIONS: Despite having lost its central role in medical literature in the 20th century, the genre still appears popular. It is a valuable part of the various research methods, especially since it complements other approaches. Furthermore, it also contributes in areas of medicine that are not specifically research-related, e.g. as an educational tool. Revision of the case report genre has been attempted in order to integrate the biomedical model with the narrative approach, but without significant success. The future prospects of the case report could possibly be in new applications of the genre, i.e. exclusive case report databases available online, and open access for clinicians and researchers.