University Hospital of Ioannina

BACKGROUND: Many causes of vision impairment can be prevented or treated. With an ageing global population, the demands for eye health services are increasing. We estimated the prevalence and relative contribution of avoidable causes of blindness and vision impairment globally from 1990 to 2020. We aimed to compare the results with the World Health Assembly Global Action Plan (WHA GAP) target of a 25% global reduction from 2010 to 2019 in avoidable vision impairment, defined as cataract and undercorrected refractive error. METHODS: We did a systematic review and meta-analysis of population-based surveys of eye disease from January, 1980, to October, 2018. We fitted hierarchical models to estimate prevalence (with 95% uncertainty intervals [UIs]) of moderate and severe vision impairment (MSVI; presenting visual acuity from <6/18 to 3/60) and blindness (<3/60 or less than 10° visual field around central fixation) by cause, age, region, and year. Because of data sparsity at younger ages, our analysis focused on adults aged 50 years and older. FINDINGS: Global crude prevalence of avoidable vision impairment and blindness in adults aged 50 years and older did not change between 2010 and 2019 (percentage change -0·2% [95% UI -1·5 to 1·0]; 2019 prevalence 9·58 cases per 1000 people [95% IU 8·51 to 10·8], 2010 prevalence 96·0 cases per 1000 people [86·0 to 107·0]). Age-standardised prevalence of avoidable blindness decreased by -15·4% [-16·8 to -14·3], while avoidable MSVI showed no change (0·5% [-0·8 to 1·6]). However, the number of cases increased for both avoidable blindness (10·8% [8·9 to 12·4]) and MSVI (31·5% [30·0 to 33·1]). The leading global causes of blindness in those aged 50 years and older in 2020 were cataract (15·2 million cases [9% IU 12·7-18·0]), followed by glaucoma (3·6 million cases [2·8-4·4]), undercorrected refractive error (2·3 million cases [1·8-2·8]), age-related macular degeneration (1·8 million cases [1·3-2·4]), and diabetic retinopathy (0·86 million cases [0·59-1·23]). Leading causes of MSVI were undercorrected refractive error (86·1 million cases [74·2-101·0]) and cataract (78·8 million cases [67·2-91·4]). INTERPRETATION: Results suggest eye care services contributed to the observed reduction of age-standardised rates of avoidable blindness but not of MSVI, and that the target in an ageing global population was not reached. FUNDING: Brien Holden Vision Institute, Fondation Théa, The Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation, Sightsavers International, and University of Heidelberg.

<h3>Importance</h3> Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. <h3>Objective</h3> To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. <h3>Evidence Review</h3> We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. <h3>Findings</h3> In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs). <h3>Conclusions and Relevance</h3> The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.

BACKGROUND: To contribute to the WHO initiative, VISION 2020: The Right to Sight, an assessment of global vision impairment in 2020 and temporal change is needed. We aimed to extensively update estimates of global vision loss burden, presenting estimates for 2020, temporal change over three decades between 1990-2020, and forecasts for 2050. METHODS: We did a systematic review and meta-analysis of population-based surveys of eye disease from January, 1980, to October, 2018. Only studies with samples representative of the population and with clearly defined visual acuity testing protocols were included. We fitted hierarchical models to estimate 2020 prevalence (with 95% uncertainty intervals [UIs]) of mild vision impairment (presenting visual acuity ≥6/18 and <6/12), moderate and severe vision impairment (<6/18 to 3/60), and blindness (<3/60 or less than 10° visual field around central fixation); and vision impairment from uncorrected presbyopia (presenting near vision <N6 or <N8 at 40 cm where best-corrected distance visual acuity is ≥6/12). We forecast estimates of vision loss up to 2050. FINDINGS: In 2020, an estimated 43·3 million (95% UI 37·6-48·4) people were blind, of whom 23·9 million (55%; 20·8-26·8) were estimated to be female. We estimated 295 million (267-325) people to have moderate and severe vision impairment, of whom 163 million (55%; 147-179) were female; 258 million (233-285) to have mild vision impairment, of whom 142 million (55%; 128-157) were female; and 510 million (371-667) to have visual impairment from uncorrected presbyopia, of whom 280 million (55%; 205-365) were female. Globally, between 1990 and 2020, among adults aged 50 years or older, age-standardised prevalence of blindness decreased by 28·5% (-29·4 to -27·7) and prevalence of mild vision impairment decreased slightly (-0·3%, -0·8 to -0·2), whereas prevalence of moderate and severe vision impairment increased slightly (2·5%, 1·9 to 3·2; insufficient data were available to calculate this statistic for vision impairment from uncorrected presbyopia). In this period, the number of people who were blind increased by 50·6% (47·8 to 53·4) and the number with moderate and severe vision impairment increased by 91·7% (87·6 to 95·8). By 2050, we predict 61·0 million (52·9 to 69·3) people will be blind, 474 million (428 to 518) will have moderate and severe vision impairment, 360 million (322 to 400) will have mild vision impairment, and 866 million (629 to 1150) will have uncorrected presbyopia. INTERPRETATION: Age-adjusted prevalence of blindness has reduced over the past three decades, yet due to population growth, progress is not keeping pace with needs. We face enormous challenges in avoiding vision impairment as the global population grows and ages. FUNDING: Brien Holden Vision Institute, Fondation Thea, Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation, Sightsavers International, and University of Heidelberg.

Brucellosis has been present for millennia and has managed to elude eradication, even in most developed countries. Brucellosis causes much clinical morbidity as well as an important loss of agricultural productivity in the developing world. In this era of international tourism, brucellosis has become a common imported disease in the developed world. This review article discusses the pathogenesis and treatment of the disease.

CONTEXT: Considerable controversy exists regarding the association of omega-3 polyunsaturated fatty acids (PUFAs) and major cardiovascular end points. OBJECTIVE: To assess the role of omega-3 supplementation on major cardiovascular outcomes. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through August 2012. STUDY SELECTION: Randomized clinical trials evaluating the effect of omega-3 on all-cause mortality, cardiac death, sudden death, myocardial infarction, and stroke. DATA EXTRACTION: Descriptive and quantitative information was extracted; absolute and relative risk (RR) estimates were synthesized under a random-effects model. Heterogeneity was assessed using the Q statistic and I2. Subgroup analyses were performed for the presence of blinding, the prevention settings, and patients with implantable cardioverter-defibrillators, and meta-regression analyses were performed for the omega-3 dose. A statistical significance threshold of .0063 was assumed after adjustment for multiple comparisons. DATA SYNTHESIS: Of the 3635 citations retrieved, 20 studies of 68,680 patients were included, reporting 7044 deaths, 3993 cardiac deaths, 1150 sudden deaths, 1837 myocardial infarctions, and 1490 strokes. No statistically significant association was observed with all-cause mortality (RR, 0.96; 95% CI, 0.91 to 1.02; risk reduction [RD] -0.004, 95% CI, -0.01 to 0.02), cardiac death (RR, 0.91; 95% CI, 0.85 to 0.98; RD, -0.01; 95% CI, -0.02 to 0.00), sudden death (RR, 0.87; 95% CI, 0.75 to 1.01; RD, -0.003; 95% CI, -0.012 to 0.006), myocardial infarction (RR, 0.89; 95% CI, 0.76 to 1.04; RD, -0.002; 95% CI, -0.007 to 0.002), and stroke (RR, 1.05; 95% CI, 0.93 to 1.18; RD, 0.001; 95% CI, -0.002 to 0.004) when all supplement studies were considered. CONCLUSION: Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.

The treatment of inflammatory bowel disease (IBD) has been revolutionised over the past decade by the increasing use of immunomodulators. With such immunomodulation, the potential for opportunistic infection is a key safety concern for patients with IBD. Opportunistic infections pose particular problems for the clinician: they are often difficult to recognise and are associated with appreciable morbidity or mortality, because they are potentially serious and hard to treat effectively. This led the European Crohn's and Colitis Organisation (ECCO) to update the previous Consensus meeting on opportunistic infections in IBD. To organise the work, infections were classified into six major topics. Guideline statements of 2009 were analysed systematically by the chairs and the working parties. In parallel, the working parties performed a systematic literature search of their topic with the appropriate key words using Medline/Pubmed and the Cochrane database, as well as their own files. The evidence level (EL) was graded according to the 2011 Oxford Centre for Evidence-Based Medicine (http://www.cebm.net/index.aspx?o=5653). Provisional update guideline statements were then posted on a weblog. Discussions and exchange of the literature evidence among the working party members was then performed on the weblog. The working parties then met in Lille on the 15th–16th of November 2012 to agree on the statements. Consensus was defined as agreement by > 80% of participants, termed a Consensus Statement and numbered for convenience in the document. This paper is the product of work by gastroenterologists, infectious disease experts and pediatricians. It provides guidance on the prevention, detection and management of opportunistic infections in patients of all age categories with IBD. After a section on definitions and risk factors for developing opportunistic infection, there are five sections on different infectious agents, followed by a section on information and guidance for patients with IBD travelling frequently or to less economically developed countries. In the final section, a systematic work up and vaccination programme is proposed for consideration in patients exposed to immunomodulator therapies. The final document on each topic was written by the workgroup leader and their working party. Statements are intended to be read in context with qualifying comments and not read in isolation. The final text was edited for consistency of style by JF Rahier, F Magro, R Eliakim and JF Colombel before being circulated and approved by the participants. In some areas the level of evidence is generally low, which reflects the paucity of randomised controlled trials. Consequently expert opinion is included where appropriate. An immunocompromised host has an alteration in phagocytic, cellular, or humoral immunity that increases the risk of an infectious complication or an opportunistic process. Patients may also be immunocompromised if they have a breach of their skin or mucosal defense barriers that permits microorganisms to cause either local or systemic infection.1 There is no clearcut definition of an immunocompromised state. Three categories are recognised by the Centers for Disease Control,2 depending on the severity of immunosuppression: Persons who are severely immunocompromised not as a result of HIV infection: Severe immunosuppression can be the result of congenital immunodeficiency, leukemia, lymphoma, generalised malignancy or therapy with alkylating agents, antimetabolites, radiation, or high doses of corticosteroids (2 mg/kg body weight, or > 20 mg/day of prednisolone, Section 2.4.1) Persons with HIV infection Persons with conditions that cause limited immune deficits (e.g. hyposplenism and renal failure) An opportunistic infection may be defined as a usually progressive infection by a microorganism that has limited (or no) pathogenic capacity under ordinary circumstances, but which is able to cause serious disease as a result of the predisposing effect of another disease or of its treatment.3 Patients with IBD should not be routinely considered to have altered immunocompetence [EL5] per se, despite evidence of impaired innate mucosal immunity. Different immunomodulators may alter immune responsiveness by different mechanisms and to varying degrees, but there is currently no single method of evaluating the effects of immunosuppression on the immune system [EL5] From genome wide association studies there is increasing evidence of an aberrant immune response in IBD.4 Susceptibility loci involve both the innate and adaptive immune response towards a diminished diversity of commensal microbiota.5 Description of the numerous mechanisms contributing to this dysimmunity is beyond the scope of this article. Despite evidence of defective mucosal immunity, there is no proof of a systemic immune defect in patients with IBD in the absence of concomitant immunomodulator therapy. Patients with IBD are therefore rendered immunocompromised through their treatment. Immunomodulators commonly used in inflammatory bowel disease are corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, anti-tumor necrosis factor agents, or other biologics. Their modes of action differ, but they all compromise to some extent the immune To there is no to immunosuppression in patients with IBD. 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morbidity and and has potential for in immunocompromised may be the of This but complication of is in immunocompromised There is no for Patients should be if they have a of or infection, to and should be for patients with to should be considered for patients with who are therapy. or are as of and infection with but is not and are for Patients with or should be for section for of in skin or the or in doses for often a not of immunomodulators or systemic immunomodulators should not be infection, may be or for is in a with or may cause or therapy for IBD. therapy with or and of are and other or of or treatment can be and the for consideration on a is in patients with but cause or an The risk of is of patients should be by for to a of or of doses of should be for patients should the of to of immunomodulator therapy can be a of all therapy patients should therapy should not be infection with or In the of infection immunomodulator treatment should be and immunomodulator therapy in if therapy can be all have over and has [EL5] is often or in immunocompromised or or In a of in five of 20 of IBD on an risk of for and in a is also with an risk of IBD patients with were thiopurines, as patients evidence of five with In with a of the is with a doses of of and should be by of (or for to the is or or the up in a or they should be for It is to a which may for by patients with IBD should doses of a or the before immunomodulators are should be of all high of (or for a or are to be on high as are prednisolone, or for or for immune should be an with IBD has to or on exposed After patients should be for and in the of the provides both and It is in and a single is routinely for of over of IBD patients immunomodulators before and as for to therapy with of or are not considered to safety and are not as for of that may be in patients with the and safety of this vaccination is not in IBD patients with immunomodulators should and are is not for of or can be in or a skin The of on the are and and can in no and are on the and of the and the of the or not and for have but work is to the and to for are not to to the or action in and therapy should be treatment doses and the or with are to therapy is Immunomodulators should not be or Patients should be and with It may be to immunomodulator therapy for infection before of immunomodulator therapy should be considered In infection immunomodulator therapy may be considered and immunomodulator therapy In the of disease immunomodulator the should be in with appropriate Immunomodulators should be In the in the with of by is the of and the risk of infection in the is associated with a risk of patients and with of infection and of In has an risk of among IBD on In the of therapy a of for of The risk to result in for of but to be with a for In patients on thiopurines, of the were usually of in patients not on therapy. infection may pose a particular among patients under in the infectious associated of infectious have been in patients on is with or renal has been to the risk of in renal but the risk of in IBD is to this should be considered before of immunomodulator then be used in to in patients the The and are for infection is by the detection and the with usually or has a high for or in high risk and but The limited IBD or increases in of associated and by a is to infectious and in to the of for is not an as are often not therapy not the of infectious in therapy may be for have no in the treatment of the limited infection with and and therapy should be or if In infection, therapy with or may be despite the of are for infection, but are should be for and management of of therapy may result in of In the absence of or of is the of therapy for may also be for is for with if with immunomodulators In patients with of immunomodulator therapy should be considered vaccination is for and according to or past infection with is not a for immunomodulator therapy It is immunomodulators can the of the but there are of in immunocompromised studies in an risk of infection and studies in by IBD also that were the risk of infection and a using of and is in In a of and was approved in are and high infection in on local vaccination is for before of In the of or local vaccination to in some depending on of The is in for with vaccination for a can be to immunocompromised IBD to to immunocompromised through age and who not or all doses they were with being with and in this doses of the were and of and to or is a of or and reflects infection the are for of infection, because not all patients and can a or to of is for of a infection, but infection is and usually is limited to the detection of in immunocompromised is as for the is to patients on immunomodulators they have a is not for in the because there is currently no evidence that or treatment the risk of to in this for or of infections are for and studies a of associated with and in with IBD to the The risk of an associated with and has also been to in patients on immunomodulator the a in not in of IBD and In all factors and are if with IBD and on immunomodulators are to have as high risk patients according to local or The that who are immunocompromised should be the of and may be considered for of their infection with is no to and in particular are considered of IBD in with Crohn's and may be associated with infection with of There are of an of in immunocompromised of immunomodulators may be in patients with with on immunomodulators not a there are of in patients who have been on for is with a but the risk of the IBD by has to be considered and with the in patients therapy have been in Patients on immunomodulator therapy are considered to an risk for the of infection vaccination with is an to The is not not to have an on the of inflammatory bowel disease vaccination of patients on immunomodulators is in with is in patients immunomodulator in on therapy patients with a of should treatment in the of or not an has been treatment should be on an in with on the of infection in patients with IBD. the of not in IBD patients immunosuppression is generally considered to the risk of vaccination is the method for infection and is therefore for patients on immunomodulators in the for Disease of are should be used for age and is not for patients on immunomodulators. In the may be used for on IBD patients on immunomodulators are considered to be risk and vaccination has been with and proof of is There is to that vaccination may be less in patients with IBD The use of may also response to the immune response to vaccination in patients with IBD and is not associated with a

OBJECTIVE: To assess the relative risk of perinatal mortality, severe preterm delivery, and low birth weight associated with previous treatment for precursors of cervical cancer. DATA SOURCES: Medline and Embase citation tracking from January 1960 to December 2007. Selection criteria Eligible studies had data on severe pregnancy outcomes for women with and without previous treatment for cervical intraepithelial neoplasia. Considered outcomes were perinatal mortality, severe preterm delivery (<32/34 weeks), extreme preterm delivery (<28/30 weeks), and low birth weight (<2000 g, <1500 g, and <1000 g). Excisional and ablative treatment procedures were distinguished. RESULTS: One prospective cohort and 19 retrospective studies were retrieved. Cold knife conisation was associated with a significantly increased risk of perinatal mortality (relative risk 2.87, 95% confidence interval 1.42 to 5.81) and a significantly higher risk of severe preterm delivery (2.78, 1.72 to 4.51), extreme preterm delivery (5.33, 1.63 to 17.40), and low birth weight of <2000 g (2.86, 1.37 to 5.97). Laser conisation, described in only one study, was also followed by a significantly increased chance of low birth weight of <2000 g and <1500 g. Large loop excision of the transformation zone and ablative treatment with cryotherapy or laser were not associated with a significantly increased risk of serious adverse pregnancy outcomes. Ablation by radical diathermy was associated with a significantly higher frequency of perinatal mortality, severe and extreme preterm delivery, and low birth weight below 2000 g or 1500 g. CONCLUSIONS: In the treatment of cervical intraepithelial neoplasia, cold knife conisation and probably both laser conisation and radical diathermy are associated with an increased risk of subsequent perinatal mortality and other serious pregnancy outcomes, unlike laser ablation and cryotherapy. Large loop excision of the transformation zone cannot be considered as completely free of adverse outcomes.

Anaemia is the most common systemic complication and extraintestinal manifestation of inflammatory bowel disease [IBD].1–3 In the majority of cases, IBD-associated anaemia is a unique example of the combination of chronic iron deficiency and anaemia of chronic disease [ACD].4,5 Other more rare causes of anaemia in IBD include vitamin B12 and folate deficiency, toxic effects of medications, and others. The impact of anaemia on the quality of life of IBD patients is substantial. It affects various aspects of quality of life such as physical, emotional, and cognitive functions, the ability to work, hospitalization, and healthcare costs.6 Anaemia in IBD is not just a laboratory marker; it is a complication of IBD that needs appropriate diagnostic and therapeutic approaches.3 Despite the broad use of anti-inflammatory therapy, anaemia may recur fast after successful therapy. As anaemia is a serious medical condition that may become life threatening [if blood transfusions are not available or compatible], preventive measures should be considered. Prevention of anaemia and maintenance of iron and vitamin stores are therefore warranted. The goal of this consensus initiated by the European Crohn’s and Colitis Organisation [ECCO] was to establish European consensus guidelines for the diagnosis, treatment and prevention of iron deficiency and iron deficiency anaemia [IDA], but also for non-iron deficiency anaemia and associated conditions. The consensus is based in parts on a previous evidence-based consensus publication on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases.7 The strategy to reach the consensus involved several steps and follows the standard operating procedures for consensus guidelines of ECCO. An open call for chairs and participants for this consensus was made [see acknowledgements and www.ecco-ibd]. Participants were selected by the Guidelines Committee of ECCO [GuiCom] on the basis of their publication record and a personal statement. Four working groups [WGs] were formed: WG 1 on Diagnosis of anaemia, WG 2 on Treatment of iron deficiency anaemia, WG 3 on Prevention of iron deficiency anaemia, and WG 4 on Management of non-iron deficiency anaemia. Participants were asked to answer relevant questions on current practise and areas of controversy related to the diagnosis and management of anaemia in IBD based on their experience as well as evidence from the literature [Delphi procedure].8 In parallel, the WG members performed a systematic literature search of their topic with the appropriate key words using Medline/PubMed/ISI/Scopus and the Cochrane database, as well as their own files. The evidence level [EL] was graded according to the Oxford Centre for Evidence-Based Medicine.9 Provisional guideline statements [with supporting text] were then written by the WG chairs, based upon answers to the questionnaire, and were circulated among the WG members, prompting discussions and exchange of literature evidence. The proposed statements and the supporting text were submitted to an online platform for online discussion and two online voting procedures, among all consensus participants for the first voting procedure and also for all national representatives of ECCO for the second voting procedure. The WGs finally met in Frankfurt on June 28, 2013 for a face-to-face discussion and to vote and consent on the statements. Technically this was done by projecting the statements and revising them on screen until a consensus was reached. Consensus was defined as agreement by more than 80% of participants, termed a Consensus Statement and numbered for convenience in the document. The final manuscript was written by the WG chairs in conjunction with the WG members and was revised for consistency by CG and AD. An update of this current consensus guideline is planned in about 4 years. The currently used WHO definition of anaemia [Table 1] applies also to patients with IBD. All patients with IBD should be assessed for the presence of anaemia. The major forms of anaemia in IBD are iron deficiency anaemia, anaemia of chronic disease and anaemia of mixed origin [EL 5] Minimum hemoglobin and hematocrit levels used to define anaemia in people living at sea level. 10 Minimum hemoglobin and hematocrit levels used to define anaemia in people living at sea level. 10 Normal hemoglobin varies with age and gender. Also other factors influence hemoglobin levels such as pregnancy, high altitudes, smoking, and ethnicity.11,12 The lower limits of normal hemoglobin concentration are even lower in African Americans [11.5g/dL for women, 12.9g/dL for men] and in the elderly. Interpretation of hemoglobin and hematocrit levels needs to consider such modulating factors. The definitions of anaemia in IBD is indifferent to other conditions and it is reasonable that WHO cut-offs apply.10 IBD patients should be regularly assessed for the presence of anaemia because of its high prevalence, its impact on quality of life, and comorbidity.13 About two-thirds of such patients have anaemia at diagnosis. During follow-up the prevalence and causes of anaemia may change.14 In children anaemia is even more common [about 70%] than in adults [about 30–40%].15 For laboratory screening, complete blood count, serum ferritin, and C-reactive protein [CRP] should be used. For patients in remission or mild disease, measurements should be performed every 6 to 12 months. In outpatients with active disease such measurements should be performed at least every 3 months [EL 5]. Patients at risk for vitamin B12 or folic acid deficiency [eg small bowel disease or resection] need proper surveillance. Serum levels of vitamin B12 and folic acid should be measured at least annually, or if macrocytosis is present in the absence of thiopurine use [EL 4] The risk of developing anaemia relates to disease activity, because both blood loss and ACD are triggered by intestinal inflammation. Complete [or full] blood count, CRP, and serum ferritin are minimum requirements to detect anaemia, an inflammatory flare, or iron deficiency at an early stage. Diagnostic measurement of complete blood counts and CRP has been part of previous recommendations in IBD.7,16 The recommended timelines are based on expert opinion and reflect common clinical practice, but do not apply to hospitalized patients. In patients with extensive small bowel resection, extensive ileal Crohn’s disease, ileal-anal pouch, evidence of vitamin B12 or folic acid deficiency should be assessed more frequently than once a year.17 Anaemia workup should be initiated if the hemoglobin is below normal. The minimum workup includes red blood cell indices such as red cell distribution width [RDW] and mean corpuscular volume [MCV], reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation [TfS], and CRP concentration. More extensive workup includes serum concentrations of vitamin B12, folic acid, haptoglobin, the percentage of hypochromic red cells, reticulocyte hemoglobin, lactate dehydrogenase, soluble transferrin receptor, creatinine, and urea [EL 4]. Advice from a hematologist is appropriate if the cause of anaemia remains unclear after more extensive workup [EL 5] The purpose of these recommendations is to set an appropriate threshold to trigger action, and to advise on necessary tests. The initial workup of anaemia should follow a simple algorithm widely used in hematology [Figure 1]. Starting from the evaluation of MCV, the most common causes of anaemia in IBD may be recognized: microcytosis indicates iron-restricted anaemia [true or functional iron deficiency], macrocytosis may indicate B12 or folate deficiency, and normocytosis anaemia of chronic disease [ACD]. Thus, the MCV and mean corpuscular hemoglobin [MCH] are useful variables and available within the complete blood count. In ACD, they may be normal or low.18 Macrocytosis is indicative of vitamin deficiency, but also arises from thiopurine treatment [azathioprine or 6-mercaptopurine], other medications, alcohol abuse, hypothyroidism, or reticulocytosis. Anaemia classification based on MCV and reticulocytes. Anaemia can be effectively classified by using a combination of MCV and reticulocytes. Micro-, normo- and macrocytic anaemias cover all forms of anaemia, and the reticulocyte count tells whether the bone marrow can respond by increasing erythropoiesis, which gives early and important information on the direction of the investigation. All deficiency states are excluded by increased reticulocytes. Retic, reticulocyte count; N, normal; Tsat, transferrin saturation; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; DAT, direct antibody test; Hb, hemoglobin; IDA, iron deficiency anaemia; FID, functional iron deficiency; MDS, myelodysplastic syndrome; N, normal; S-ferritin, serum ferritin; Tsat, transferrin saturation; *anaemia secondary to malignancy, infection, kidney disease etc. In the next step, reticulocyte count is considered. Low or ‘normal’ reticulocytes indicate inability to respond properly to anaemia, either because of deficiencies that result in inappropriate erythropoiesis or primary bone marrow disease. Increased reticulocytes indicate increased red cell formation and therefore exclude deficiencies. Instead, hemolysis should be sought after by estimation of serum concentrations of haptoglobin, lactate dehydrogenase, and bilirubin. The minimum workup should include complete blood count with MCV, reticulocytes, serum ferritin, transferrin saturation, and CRP. In accordance with the algorithm in Figure 1, more extensive workup may include vitamin B12, folic acid, haptoglobin, a differential white blood cell count, and bone marrow smear.19 A comprehensive list of anaemias classified with MCV and reticulocytes is given in Table 2. In some situations microcytosis and macrocytosis co-exist, so that the two may other and result in a normal A of the red can in this as is an of iron of anaemia by MCV and reticulocytes from of anaemia by MCV and reticulocytes from and white blood cell counts are also available within the complete blood count and to anaemia from A soluble of the transferrin in the and its concentration is to the of transferrin It is in in situations the bone marrow needs more both in and in iron deficiency [true or An soluble transferrin is a of erythropoiesis, in the of iron deficiency in the presence of [with normal or even serum The percentage of hypochromic red cells, the hemoglobin concentration of reticulocytes, and the red blood cell are also useful for the diagnosis of iron-restricted blood cell is a which the volume of and the volume of reticulocytes. disease is not associated with an in in and may not be by clinical may be to disease in patients with a or CRP. Diagnostic for iron deficiency on the level of inflammation. In patients or evidence of active disease, serum ferritin is an appropriate [EL In the presence of a serum ferritin to may be with iron deficiency [EL 4] In the iron deficiency anaemia and ACD is both conditions In the management of IBD patients with anaemia, the of the appropriate treatment is based on this deficiency may be by blood loss from the of the with iron or iron the In the absence of or clinical evidence of iron deficiency is if the serum ferritin is In the presence of serum ferritin levels can be high iron In such cases, is an appropriate to after iron therapy, serum ferritin levels well with iron iron ferritin and levels deficiency anaemia may cause an of or The concentration of in the serum is an of the iron available for erythropoiesis ferritin, chronic has on a that the and ferritin are to iron deficiency anaemia and ACD with a high diagnostic The measurement of percentage of hypochromic red and reticulocyte hemoglobin two measurements useful in the diagnosis of functional iron deficiency, can be in In the presence of or clinical evidence of the diagnostic for ACD are a serum ferritin and the serum ferritin level is and a combination of iron deficiency and ACD is [EL The ACD includes all anaemia associated with and by chronic disease. the of on to anaemia as well as the direct of in the bone More has also that has a on iron In patients with active various the of in the which iron from the of transferrin saturation and iron to the a of functional iron deficiency for erythropoiesis and also and The in also iron from the The may to ACD with functional iron deficiency and are common for with and others. iron deficiency is defined as a with normal or iron a of iron from the a transferrin saturation in and iron in the bone which ACD with is if the serum ferritin is and the is below An in hypochromic red a of reticulocyte hemoglobin indicate FID, but as these measurements are not available in the diagnosis of is made from the combination of and normal or In the serum ferritin may be useful to exclude iron deficiency [if the is MCV may be or normal in is not MCV is but this may also be the with ACD gives reticulocyte not all IBD patients with anaemia of In an may be all the involved in anaemia, but is or not anaemia of chronic disease may with or The definitions are useful in this Anaemia of chronic disease anaemia chronic disease and by inflammatory ACD with functional iron ACD can be by and normal or [or increased levels of hypochromic red in ACD anaemia of chronic inflammatory disease of anaemia this definition is widely used for anaemia the is to a of iron in the bone either by iron deficiency or is recommended in all IBD patients iron deficiency anaemia is present [EL 1] of life with of anaemia, and this is of clinical The to iron in patients anaemia is more and on the and is evidence of in iron deficiency anaemia in other conditions such as chronic and such evidence is not available in the of The goal of iron is to hemoglobin levels and iron stores [EL 1] The lower the hemoglobin, the is the to of An in hemoglobin of at least within 4 of treatment is an of iron should be as first treatment in patients with active with previous to with hemoglobin below and in patients need [EL 1] The treatment of iron deficiency anaemia with iron has relevant in IBD patients. iron is more a and is than Thus, iron are in the of IBD-associated anaemia and were recommended also in previous iron is and well both in the of and maintenance of iron stores in patients with iron are currently available for treatment of by and can be and iron in IBD patients are available from iron and iron of to iron have been is to treatment For iron are to The can be within are also available for which is for use in chronic kidney disease and is currently in a of other conditions associated with iron deficiency, IBD and The currently available iron are not and has been direct Thus, a direct of the currently available with to and other not as and other in various are not A is for iron as they a risk for serious The risk of iron in patients are as in is a transferrin saturation and serum ferritin should be used as limits for iron is as are to and are associated with The estimation of iron need is based on hemoglobin and and this is more for the treatment of in IBD patients than based on the [EL the iron in in hemoglobin in the is to used in clinical practice, and iron The a and simple [Table with the in patients with The simple and as well as a with the iron In this clinical the simple has been used for of In clinical practice, it is also used for of other iron of this include patients with hemoglobin below need an the estimation of iron needs in iron deficiency anaemia is not A minimum of should be for estimation of iron for estimation of iron iron is in patients with IBD and may be used in patients with mild anaemia, disease is and have not been to iron anaemia has been defined by the WHO as hemoglobin in and in indicate that iron may be as as iron in a has a in ferritin and hemoglobin in of the effects from iron are of iron from the is and iron is to the intestinal has been in in of IBD indicate that iron may disease and intestinal In a in African iron and increased on iron were done with on as indicate with a even in IBD patients with a of to more than iron is recommended in patients with IBD [EL The of iron from is in can to iron stores are and iron is In and women, iron treatment is in in IBD is as are associated with more effects and lower Patients with IBD should be for iron deficiency every 3 months for at least a after and 6 and 12 months [EL 4] iron anaemia by within 10 patients with IBD should be for iron deficiency every 3 months using a combination of hemoglobin, ferritin, transferrin saturation, and CRP. anaemia may be indicative of intestinal disease even if is clinical remission and inflammatory are normal [EL 5] A intestinal disease and on and the of blood loss and of anaemia on the other important for prevention of anaemia is the treatment of the this is in clinical the to anaemia on the ability to bowel A of iron deficiency in patients should the of a on inflammatory The goal of preventive treatment is to hemoglobin and serum ferritin levels within the normal [EL deficiency can cause and quality of life even anaemia is not In it is common in clinical to iron deficiency as the of disease in IBD patients. The to iron in patients with but anaemia may on the clinical and the The for are based on the that iron is for all of the of iron deficiency may anaemia. and cognitive loss of or may be present anaemia and may upon iron Also and can be IBD-associated iron deficiency and anaemia recur frequently and even after treatment with of iron deficiency is lower in patients with ferritin levels [EL Anaemia to recur frequently and fast after iron The of relates to the of iron stores by serum serum ferritin levels of of iron deficiency within the than levels below this it was that iron at ferritin levels of to successful treatment of iron deficiency anaemia with with iron should be initiated as as serum ferritin below or hemoglobin below 12 or to As iron deficiency anaemia frequently and iron maintenance may anaemia The whether can anaemia in patients been for IBD-associated was a patients Serum ferritin was assessed every 2 months and patients of ferritin levels below of patients lower in with patients the of the to until the of the a from is and of IBD were in the and were and the was not to detect a treatment on quality of life, a in of was in of The that of anaemia in patients with IBD. In to the and the such a to anaemia management the healthcare are more than as high for with IBD patients The of non-iron deficiency anaemia by MCV and reticulocytes is recommended [EL 5] The WHO for the hemoglobin are widely and should be used also for factors pregnancy, high and age be considered. Anaemia in IBD may have causes iron The causes of in IBD are indifferent to other conditions and can be classified according to MCV and reticulocytes [Table The initial of anaemia should follow the algorithm in Figure The classification of anaemia is in Table 2. It is not that more than cause of anaemia in a may the initial diagnosis of The risk of developing anaemia relates to disease activity, because both blood loss and anaemia of chronic disease are triggered by intestinal inflammation. For differential diagnosis it should be that the causes of in IBD can be or [Table 4]. of non-iron deficiency anaemia in from of non-iron deficiency anaemia in from Anaemia of chronic disease is the most anaemia in hospitalized patients and in from that are associated with chronic of such as chronic inflammatory or ACD is by a normal or MCV and or normal reticulocyte clinical are also causes of related to IBD to to and to B12 or folic acid deficiencies. Treatment of may include of IBD folic treatment of other causes of such as or use of in cases, such as or kidney secondary or bone marrow Patients with anaemia of chronic disease with an to iron and IBD may be for treatment [EL 1] with a hemoglobin level not [EL 5] The presence of anaemia of chronic disease is a of active disease. of IBD treatment should In two the of on hemoglobin and in patients with or it was that treatment hemoglobin levels with even after for disease In IBD patients to has been to by increasing serum and has been the to anaemia in some IBD As anaemia of chronic disease from erythropoiesis secondary to increased levels of as may bone marrow It is that the of than its effects on the bone marrow the The to iron can be by reticulocyte counts after iron Patients with a diagnosis of anaemia of chronic disease, anaemia or to and may be for indicate that a majority of patients with IBD respond to treatment with an in hemoglobin and of quality of treatment is to hemoglobin of in or is in therefore the measures iron should functional iron deficiency and ferritin levels should be Low transferrin and levels are associated with to iron and may be used for of of B12 and folate should be to anaemia [EL 5] and folate may in after ileal and deficiency to and serum levels should be measured in patients with high In cases, measurement of or can be Increased indicates deficiency of either B12 or folate with a than serum B12 is for B12 deficiency and has a Serum levels of vitamin B12 and folic acid should be measured at least annually, or if macrocytosis is Patients at risk for vitamin B12 or folic acid deficiency [eg small bowel disease or resection] need surveillance. The recommended timelines are based on expert and reflect common clinical practice, but do not apply to patients with extensive small bowel resection, extensive ileal Crohn’s disease, or ileal-anal used may erythropoiesis, both such as the of folate and as in the of or from folate deficiency, or acid have been related to a of hemolysis or In the treatment of anaemia, red blood cell may be hemoglobin concentration is below or if or risk factors are present [EL 4]. transfusions should be by iron [EL 4] In the transfusions of red blood were common in the treatment of anaemia in IBD. requirements with the of iron and transfusions to such as anaemia with anaemia, of all other The trigger to is and The to blood transfusions is not based on the hemoglobin but and blood transfusions and whether they are to in patients or in remains transfusions are widely used as an for of or anaemia. transfusions do not the and have Other iron with or should be of and after transfusions as these are a which not normal Management of in IBD should exclude other such as and effects of Patients with of anaemia of chronic disease should be also for the of an may be by and may be based on clinical and laboratory tests. In intestinal or extraintestinal with anaemia may the of macrocytosis and may cause mild In of of chronic disease, treatment of IBD should be in combination with treatment In active inflammatory may iron erythropoiesis, and to the anaemia of chronic disease. this of anaemia, the most important is to complete disease is not associated with an in and may not be by clinical may be also to disease in patients with a cause anaemia. other causes of anaemia are the should be or of should be and are for inflammatory bowel disease but they are associated with a of The of from to and bone marrow is of the most serious In has been associated with anaemia, and red cell have an of in in bone marrow The thiopurine and the majority of with In a with Crohn’s disease patients developing or treatment of be by these most In measurement is not and is by and blood can be by the presence of rare In an increased may result from of or ECCO has a of of The of is based on a used by the Committee of The is not at the ECCO and the of but also is open to on the ECCO a comprehensive of of of The ECCO Consensus Guidelines are based on an Consensus treatment are a for the and should not be based on the of the ECCO Consensus The European Crohn’s and Colitis Organisation of its members consensus may not be for information in in the ECCO Consensus of working groups for the ECCO Anaemia Consensus chairs are Diagnosis of A Treatment of iron deficiency Prevention of iron deficiency Management of non-iron deficiency The national representatives and in the online voting are to from the ECCO for to and the are to all an in and to the ECCO Consensus procedures on are also to as in this guideline in to this guideline an and to the of this guideline in clinical

OBJECTIVE: Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences. METHOD: The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression. RESULTS: The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time. CONCLUSIONS: Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.

Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n = 52), high-grade (HSIL; n = 92), invasive cervical cancer (ICC; n = 5) and healthy controls (n = 20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal = 2/20,10%; LSIL = 11/52,21%; HSIL = 25/92,27%; ICC = 2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P < 0.01), Anaerococcus tetradius (P < 0.05) and Peptostreptococcus anaerobius (P < 0.05) and lower levels of Lactobacillus jensenii (P < 0.01) compared to LSIL. Our results suggest advancing CIN disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression.

BACKGROUND: Cervical cancer screening has traditionally been based on cervical cytology. Given the aetiological relationship between human papillomavirus (HPV) infection and cervical carcinogenesis, HPV testing has been proposed as an alternative screening test. OBJECTIVES: To determine the diagnostic accuracy of HPV testing for detecting histologically confirmed cervical intraepithelial neoplasias (CIN) of grade 2 or worse (CIN 2+), including adenocarcinoma in situ, in women participating in primary cervical cancer screening; and how it compares to the accuracy of cytological testing (liquid-based and conventional) at various thresholds. SEARCH METHODS: We performed a systematic literature search of articles in MEDLINE and Embase (1992 to November 2015) containing quantitative data and handsearched the reference lists of retrieved articles. SELECTION CRITERIA: We included comparative test accuracy studies if all women received both HPV testing and cervical cytology followed by verification of the disease status with the reference standard, if positive for at least one screening test. The studies had to include women participating in a cervical cancer screening programme who were not being followed up for previous cytological abnormalities. DATA COLLECTION AND ANALYSIS: We completed a 2 x 2 table with the number of true positives (TP), false positives (FP), true negatives (TN), and false negatives for each screening test (HPV test and cytology) used in each study. We calculated the absolute and relative sensitivities and the specificities of the tests for the detection of CIN 2+ and CIN 3+ at various thresholds and computed sensitivity (TP/(TP + TN) and specificity (TN/ (TN + FP) for each test separately. Relative sensitivity and specificity of one test compared to another test were defined as sensitivity of test-1 over sensitivity of test-2 and specificity of test-1 over specificity of test-2, respectively. To assess bias in the studies, we used the Quality Assessment of Diagnostic test Accuracy Studies (QUADAS) tool. We used a bivariate random-effects model for computing pooled accuracy estimates. This model takes into account the within- and between-study variability and the intrinsic correlation between sensitivity and specificity. MAIN RESULTS: We included a total of 40 studies in the review, with more than 140,000 women aged between 20 and 70 years old. Many studies were at low risk of bias. There were a sufficient number of included studies with adequate methodology to perform the following test comparisons: hybrid capture 2 (HC2) (1 pg/mL threshold) versus conventional cytology (CC) (atypical squamous cells of undetermined significance (ASCUS)+ and low-grade squamous intraepithelial lesions (LSIL)+ thresholds) or liquid-based cytology (LBC) (ASCUS+ and LSIL+ thresholds), other high-risk HPV tests versus conventional cytology (ASCUS+ and LSIL+ thresholds) or LBC (ASCUS+ and LSIL+ thresholds). For CIN 2+, pooled sensitivity estimates for HC2, CC and LBC (ASCUS+) were 89.9%, 62.5% and 72.9%, respectively, and pooled specificity estimates were 89.9%, 96.6%, and 90.3%, respectively. The results did not differ by age of women (less than or greater than 30 years old), or in studies with verification bias. Accuracy of HC2 was, however, greater in European countries compared to other countries. The results for the sensitivity of the tests were heterogeneous ranging from 52% to 94% for LBC, and 61% to 100% for HC2. Overall, the quality of the evidence for the sensitivity of the tests was moderate, and high for the specificity.The relative sensitivity of HC2 versus CC for CIN 2+ was 1.52 (95% CI: 1.24 to 1.86) and the relative specificity 0.94 (95% CI: 0.92 to 0.96), and versus LBC for CIN 2+ was 1.18 (95% CI: 1.10 to 1.26) and the relative specificity 0.96 (95% CI: 0.95 to 0.97). The relative sensitivity of HC2 versus CC for CIN 3+ was 1.46 (95% CI: 1.12 to 1.91) and the relative specificity 0.95 (95% CI: 0.93 to 0.97). The relative sensitivity of HC2 versus LBC for CIN 3+ was 1.17 (95% CI: 1.07 to 1.28) and the relative specificity 0.96 (95% CI: 0.95 to 0.97). AUTHORS' CONCLUSIONS: Whilst HPV tests are less likely to miss cases of CIN 2+ and CIN 3+, these tests do lead to more unnecessary referrals. However, a negative HPV test is more reassuring than a negative cytological test, as the cytological test has a greater chance of being falsely negative, which could lead to delays in receiving the appropriate treatment. Evidence from prospective longitudinal studies is needed to establish the relative clinical implications of these tests.

OBJECTIVE: To assess the effect of treatment for cervical intraepithelial neoplasia (CIN) on obstetric outcomes and to correlate this with cone depth and comparison group used. DESIGN: Systematic review and meta-analysis. DATA SOURCES: CENTRAL, Medline, Embase from 1948 to April 2016 were searched for studies assessing obstetric outcomes in women with or without previous local cervical treatment. DATA EXTRACTION AND SYNTHESIS: Independent reviewers extracted the data and performed quality assessment using the Newcastle-Ottawa criteria. Studies were classified according to method and obstetric endpoint. Pooled risk ratios were calculated with a random effect model and inverse variance. Heterogeneity between studies was assessed with I(2) statistics. MAIN OUTCOME MEASURES: Obstetric outcomes comprised preterm birth (including spontaneous and threatened), premature rupture of the membranes, chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage, and cervical stenosis. Neonatal outcomes comprised low birth weight, admission to neonatal intensive care, stillbirth, APGAR scores, and perinatal mortality. RESULTS: 71 studies were included (6 338 982 participants: 65 082 treated/6 292 563 untreated). Treatment significantly increased the risk of overall (<37 weeks; 10.7% v 5.4%; relative risk 1.78, 95% confidence interval 1.60 to 1.98), severe (<32-34 weeks; 3.5% v 1.4%; 2.40, 1.92 to 2.99), and extreme (<28-30 weeks; 1.0% v 0.3%; 2.54, 1.77 to 3.63) preterm birth. Techniques removing or ablating more tissue were associated with worse outcomes. Relative risks for delivery at <37 weeks were 2.70 (2.14 to 3.40) for cold knife conisation, 2.11 (1.26 to 3.54) for laser conisation, 2.02 (1.60 to 2.55) for excision not otherwise specified, 1.56 (1.36 to 1.79) for large loop excision of the transformation zone, and 1.46 (1.27 to 1.66) for ablation not otherwise specified. Compared with no treatment, the risk of preterm birth was higher in women who had undergone more than one treatment (13.2% v 4.1%; 3.78, 2.65 to 5.39) and with increasing cone depth (≤10-12 mm; 7.1% v 3.4%; 1.54, 1.09 to 2.18; ≥10-12 mm: 9.8% v 3.4%, 1.93, 1.62 to 2.31; ≥15-17 mm: 10.1% v 3.4%; 2.77, 1.95 to 3.93; ≥20 mm: 10.2% v 3.4%; 4.91, 2.06 to 11.68). The choice of comparison group affected the magnitude of effect. This was higher for external comparators, followed by internal comparators, and ultimately women with disease who did not undergo treatment. In women with untreated CIN and in pregnancies before treatment, the risk of preterm birth was higher than the risk in the general population (5.9% v 5.6%; 1.24, 1.14 to 1.35). Spontaneous preterm birth, premature rupture of the membranes, chorioamnionitis, low birth weight, admission to neonatal intensive care, and perinatal mortality were also significantly increased after treatment. : CONCLUSIONS: Women with CIN have a higher baseline risk for prematurity. Excisional and ablative treatment further increases that risk. The frequency and severity of adverse sequelae increases with increasing cone depth and is higher for excision than for ablation.

OBJECTIVES/HYPOTHESIS: Lemierre's syndrome is characterized by a history of recent oropharyngeal infection, clinical or radiological evidence of internal jugular vein thrombosis, and isolation of anaerobic pathogens, mainly Fusobacterium necrophorum. It was once called the forgotten disease because of its rarity, but it may not be that uncommon after all. This review aims to provide physicians with an update on the etiology, management, and prognosis of Lemierre's syndrome. METHODS: Systematic review using the terms: Lemierre's syndrome, postanginal septicemia, fusobacterium, internal jugular vein thrombosis. INCLUSION CRITERIA: English literature; reviews, case reports, and case series. EXCLUSION CRITERIA: variants or atypical Lemierre's syndrome cases, negative fusobacteria cultures, and papers without radiological evidence of thrombophlebitis. RESULTS: Eighty-four studies fulfilled our inclusion criteria. The male to female ratio was 1:1, 2, and the ages ranged from 2 months to 78 years (median, 22 years). Main sources of infection were tonsil, pharynx, and chest. Most common first clinical presentation was a sore throat, followed by a neck mass and neck pain. The most common offending micro-organism was F. necrophorum. Treatment modalities used were antimicrobial, anticoagulant, and surgical treatment. Morbidity was significant with prolonged hospitalization in the majority of patients. The overall mortality rate was 5%. CONCLUSIONS: Lemierre's syndrome may not be as rare as previously thought. This apparent increase in the incidence may be due to antibiotic resistance or changes in antibiotic prescription patterns. Successful management rests on the awareness of the condition, a high index of suspicion, and a multidisciplinary team approach.

OBJECTIVES: Three variants of the CARD15/NOD2 gene (SNP8, SNP12, and SNP13) have been associated with Crohn's disease (CD). We assessed the impact of NOD2 variants on the CD risk across diverse populations and examined possible associations with disease phenotype. METHODS: We performed a metaanalysis searching MEDLINE and EMBASE (last search 05/2004) and contacting field experts. RESULTS: Forty-two eligible studies contributed data on 206 comparisons. No variants were detected in Asians. In non-Jewish descent Caucasians carriage of SNP8, SNP12, or SNP13 had an odds ratio (OR) for CD of 2.20 (95% CI: 1.84-2.62), 2.99 (95% CI: 2.38-3.74), and 4.09 (95% CI: 3.23-5.18), respectively. For Jewish descent patients the corresponding ORs were 1.74, 1.93, and 2.45, respectively. The OR in carriers of at least two alleles was 17.1 (95% CI: 10.7-27.2). Large studies tended to yield more conservative estimates than smaller studies, so publication or other bias cannot be excluded. Among CD patients, carrying at least one high-risk variant increased slightly the risk for familial disease (OR = 1.49, (95% CI: 1.18-1.87)), modestly the risk of stenosing CD (OR = 1.94, (95% CI: 1.61-2.34)), and more prominently the risk of small bowel involvement (OR = 2.53, (95% CI: 2.01-3.16)). CONCLUSIONS: SNP8, SNP12, and SNP13 have differential effects on CD risk, with SNP13 having the strongest genetic effect. These NOD2 variants are also significant risk factors for CD phenotype, in particular ileal location.

OBJECTIVE: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East-West gradient in the incidence of IBD in Europe exists. DESIGN: A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. RESULTS: 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100,000 in 2010 for CD were 6.5 (range 0-10.7) in Western European centres and 3.1 (range 0.4-11.5) in Eastern European centres, for UC 10.8 (range 2.9-31.5) and 4.1 (range 2.4-10.3), respectively, and for IBDU 1.9 (range 0-39.4) and 0 (range 0-1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. CONCLUSIONS: An East-West gradient in IBD incidence exists in Europe. Among this inception cohort--including indolent and aggressive cases--international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤ 0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and/or tissue-specific miRNAs that are uncharacterized.

Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application. Optical coherence tomography (OCT) has been widely adopted in research on coronary atherosclerosis and adopted clinically to optimize percutaneous coronary intervention. In this Review, Jang and colleagues summarize this rapidly progressing field, with the aim of standardizing the use of OCT in coronary atherosclerosis.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) is the most common pre-malignant lesion. Atypical squamous changes occur in the transformation zone of the cervix with mild, moderate or severe changes described by their depth (CIN 1, 2 or 3). Cervical intraepithelial neoplasia is treated by local ablation or lower morbidity excision techniques. Choice of treatment depends on the grade and extent of the disease. OBJECTIVES: To assess the effectiveness and safety of alternative surgical treatments for CIN. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE and EMBASE (up to November 2012). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of alternative surgical treatments in women with cervical intraepithelial neoplasia. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risks of bias. Risk ratios that compared residual disease after the follow-up examination and adverse events in women who received one of either laser ablation, laser conisation, large loop excision of the transformation zone (LLETZ), knife conisation or cryotherapy were pooled in random-effects model meta-analyses. MAIN RESULTS: Twenty-nine trials were included. Seven surgical techniques were tested in various comparisons. No significant differences in treatment failures were demonstrated in terms of persistent disease after treatment. Large loop excision of the transformation zone appeared to provide the most reliable specimens for histology with the least morbidity. Morbidity was lower than with laser conisation, although the trials did not provide data for every outcome measure. There were not enough data to assess the effect on morbidity when compared with laser ablation. AUTHORS' CONCLUSIONS: The evidence suggests that there is no obvious superior surgical technique for treating cervical intraepithelial neoplasia in terms of treatment failures or operative morbidity.

Importance: Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile. Objective: To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19). Design, Setting, and Participants: In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece. Intervention: Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks. Main Outcomes and Measures: Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis. Results: A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003). Conclusions and Relevance: In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution. Trial Registration: ClinicalTrials.gov Identifier: NCT04326790.

<h3>Abstract</h3> <h3>Objective</h3> To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols. <h3>Design</h3> Systematic review and meta-analysis. <h3>Data sources</h3> Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016. <h3>Eligibility criteria</h3> Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months. <h3>Data synthesis</h3> Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I² statistics. <h3>Main outcome measures</h3> Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months). <h3>Results</h3> 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I²=77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I²=82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I²=90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I²=0%), 23% (two studies, 226/938 women, 20% to 26%; I²=97%), and 11% (three studies, 163/1033 women, 5% to 19%; I²=67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%. <h3>Conclusions</h3> Most CIN2 lesions, particularly in young women (&lt;30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring. <h3>Systematic review registration</h3> PROSPERO 2014: CRD42014014406.