The London College

The COVID-19 pandemic has resulted in over 4.3 million confirmed cases and over 290,000 deaths globally. It has also sparked fears of an impending economic crisis and recession. Social distancing, self-isolation and travel restrictions have lead to a reduced workforce across all economic sectors and caused many jobs to be lost. Schools have closed down, and the need for commodities and manufactured products has decreased. In contrast, the need for medical supplies has significantly increased. The food sector is also facing increased demand due to panic-buying and stockpiling of food products. In response to this global outbreak, we summarise the socio-economic effects of COVID-19 on individual aspects of the world economy.

Photoacoustic (PA) imaging, also called optoacoustic imaging, is a new biomedical imaging modality based on the use of laser-generated ultrasound that has emerged over the last decade. It is a hybrid modality, combining the high-contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound imaging. In essence, a PA image can be regarded as an ultrasound image in which the contrast depends not on the mechanical and elastic properties of the tissue, but its optical properties, specifically optical absorption. As a consequence, it offers greater specificity than conventional ultrasound imaging with the ability to detect haemoglobin, lipids, water and other light-absorbing chomophores, but with greater penetration depth than purely optical imaging modalities that rely on ballistic photons. As well as visualizing anatomical structures such as the microvasculature, it can also provide functional information in the form of blood oxygenation, blood flow and temperature. All of this can be achieved over a wide range of length scales from micrometres to centimetres with scalable spatial resolution. These attributes lend PA imaging to a wide variety of applications in clinical medicine, preclinical research and basic biology for studying cancer, cardiovascular disease, abnormalities of the microcirculation and other conditions. With the emergence of a variety of truly compelling in vivo images obtained by a number of groups around the world in the last 2-3 years, the technique has come of age and the promise of PA imaging is now beginning to be realized. Recent highlights include the demonstration of whole-body small-animal imaging, the first demonstrations of molecular imaging, the introduction of new microscopy modes and the first steps towards clinical breast imaging being taken as well as a myriad of in vivo preclinical imaging studies. In this article, the underlying physical principles of the technique, its practical implementation, and a range of clinical and preclinical applications are reviewed.

A load theory of attention in which distractor rejection depends on the level and type of load involved in current processing was tested. A series of experiments demonstrates that whereas high perceptual load reduces distractor interference, working memory load or dual-task coordination load increases distractor interference. These findings suggest 2 selective attention mechanisms: a perceptual selection mechanism serving to reduce distractor perception in situations of high perceptual load that exhaust perceptual capacity in processing relevant stimuli and a cognitive control mechanism that reduces interference from perceived distractors as long as cognitive control functions are available to maintain current priorities (low cognitive load). This theory resolves the long-standing early versus late selection debate and clarifies the role of cognitive control in selective attention.

Approximate methods for estimating the numbers of synonymous and nonsynonymous substitutions between two DNA sequences involve three steps: counting of synonymous and nonsynonymous sites in the two sequences, counting of synonymous and nonsynonymous differences between the two sequences, and correcting for multiple substitutions at the same site. We examine complexities involved in those steps and propose a new approximate method that takes into account two major features of DNA sequence evolution: transition/transversion rate bias and base/codon frequency bias. We compare the new method with maximum likelihood, as well as several other approximate methods, by examining infinitely long sequences, performing computer simulations, and analyzing a real data set. The results suggest that when there are transition/transversion rate biases and base/codon frequency biases, previously described approximate methods for estimating the nonsynonymous/synonymous rate ratio may involve serious biases, and the bias can be both positive and negative. The new method is, in general, superior to earlier approximate methods and may be useful for analyzing large data sets, although maximum likelihood appears to always be the method of choice.

Many system security departments treat users as a security risk to be controlled. The general consensus is that most users are careless and unmotivated when it comes to system security. In a recent study, we found that users may indeed compromise computer security mechanisms, such as password authentication, both knowing and unknowingly. A closer analysis, however, revealed that such behavior is often caused by the way in which security mechanisms are implemented, and users ’ lack of knowledge. We argue that to change this state of affairs, security departments need to communicate more with users, and adopt a user-centered design approach.

AIMS: This report from the European Society of Cardiology (ESC) Atlas Project updates and expands upon the widely cited 2019 report in presenting cardiovascular disease (CVD) statistics for the 57 ESC member countries. METHODS AND RESULTS: Statistics pertaining to 2019, or the latest available year, are presented. Data sources include the World Health Organization, the Institute for Health Metrics and Evaluation, the World Bank, and novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery. New material in this report includes sociodemographic and environmental determinants of CVD, rheumatic heart disease, out-of-hospital cardiac arrest, left-sided valvular heart disease, the advocacy potential of these CVD statistics, and progress towards World Health Organization (WHO) 2025 targets for non-communicable diseases. Salient observations in this report: (i) Females born in ESC member countries in 2018 are expected to live 80.8 years and males 74.8 years. Life expectancy is longer in high income (81.6 years) compared with middle-income (74.2 years) countries. (ii) In 2018, high-income countries spent, on average, four times more on healthcare than middle-income countries. (iii) The median PM2.5 concentrations in 2019 were over twice as high in middle-income ESC member countries compared with high-income countries and exceeded the EU air quality standard in 14 countries, all middle-income. (iv) In 2016, more than one in five adults across the ESC member countries were obese with similar prevalence in high and low-income countries. The prevalence of obesity has more than doubled over the past 35 years. (v) The burden of CVD falls hardest on middle-income ESC member countries where estimated incidence rates are ∼30% higher compared with high-income countries. This is reflected in disability-adjusted life years due to CVD which are nearly four times as high in middle-income compared with high-income countries. (vi) The incidence of calcific aortic valve disease has increased seven-fold during the last 30 years, with age-standardized rates four times as high in high-income compared with middle-income countries. (vii) Although the total number of CVD deaths across all countries far exceeds the number of cancer deaths for both sexes, there are 15 ESC member countries in which cancer accounts for more deaths than CVD in males and five-member countries in which cancer accounts for more deaths than CVD in females. (viii) The under-resourced status of middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, ablation procedures, device implantation, and cardiac surgical procedures. CONCLUSION: Risk factors and unhealthy behaviours are potentially reversible, and this provides a huge opportunity to address the health inequalities across ESC member countries that are highlighted in this report. It seems clear, however, that efforts to seize this opportunity are falling short and present evidence suggests that most of the WHO NCD targets for 2025 are unlikely to be met across ESC member countries.

Euclid is a European Space Agency medium-class mission selected for launch in 2020 within the cosmic vision 2015-2025 program. The main goal of Euclid is to understand the origin of the accelerated expansion of the universe. Euclid will explore the expansion history of the universe and the evolution of cosmic structures by measuring shapes and red-shifts of galaxies as well as the distribution of clusters of galaxies over a large fraction of the sky. Although the main driver for Euclid is the nature of dark energy, Euclid science covers a vast range of topics, from cosmology to galaxy evolution to planetary research. In this review we focus on cosmology and fundamental physics, with a strong emphasis on science beyond the current standard models. We discuss five broad topics: dark energy and modified gravity, dark matter, initial conditions, basic assumptions and questions of methodology in the data analysis. This review has been planned and carried out within Euclid's Theory Working Group and is meant to provide a guide to the scientific themes that will underlie the activity of the group during the preparation of the Euclid mission.

This book focuses on the crucial importance of developmental work to psychotherapy and psychopathology. It offers an account of psychotherapy to integrate scientific knowledge of psychological development and represents psychological states in the minds of infants, children, adolescents, and adults.

Abstract The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT 1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use ( n = 1869). Two meta-analyses of overlapping studies examining the 5-HT 1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers ( n = 566), but weak evidence of an effect in those with a family history of depression ( n = 75). Another systematic review ( n = 342) and a sample of ten subsequent studies ( n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study ( n = 115,257) and one collaborative meta-analysis ( n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

The guideline group was selected to be representative of UK-based medical experts. MEDLINE and EMBASE were searched systematically for publications in English, using the keywords: thrombotic thrombocytopenia purpura (TTP), ADAMTS13, plasma exchange (PEX) and relevant key words related to the subsections of this guideline. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH. The guideline was then reviewed by a sounding board of British haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com. The objective of this guideline is to provide healthcare professionals with clear, up-to-date, and practical guidance on the management of TTP and related thrombotic microangiopathies, defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Thrombotic thrombocytopenic purpura (TTP) is rare, with a reported incidence of six cases per million per year in the UK (Scully et al, 2008). It is an important diagnosis to make because the untreated mortality is 90%, which can be reduced with the prompt delivery of plasma exchange (PEX). Early death still occurs: approximately half of the deaths in the regional UK registry occurred within 24 h of presentation, primarily in women (Scully et al, 2008). In the last 15 years there has been a marked increase in the understanding of the pathogenesis of TTP. It is now recognized that congenital and acute acquired TTP are due to a deficiency of von Willebrand factor (VWF) cleaving protein, also known as ADAMTS1, (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 – von Willebrand factor cleaving protein) (Fujikawa et al, 2001; Levy et al, 2001). In the absence of ADAMTS13, ultra large multimers of VWF (ULVWF) released from endothelium are not cleaved appropriately, and cause spontaneous platelet aggregates in conditions of high shear, such as in the microvasculature of the brain, heart and kidneys. Congenital TTP is due to an inherited deficiency of ADAMTS13, but acquired immune TTP is due to the reduction of ADAMTS13 by autoantibodies directed against ADAMTS13 (Furlan et al, 1998a; Tsai & Lian, 1998). Other clinical forms of thrombotic microangiopathy (TMA) occur in the absence of severe deficiency. Diagnosis can be difficult, as there is clinical overlap with haemolytic uraemic syndrome (HUS), autoimmune disease and a spectrum of pregnancy-related problems. Thrombotic thrombocytopenic purpura was originally characterized by a pentad of thrombocytopenia, MAHA, fluctuating neurological signs, renal impairment and fever, often with insidious onset. However, TTP can present without the full pentad; up to 35% of patients do not have neurological signs at presentation and renal abnormalities and fever are not prominent features. The revised diagnostic criteria state that TTP must be considered in the presence of thrombocytopenia and MAHA alone (Galbusera et al, 2006). This can result in an increased referral of other TMAs (Table 1). TTP remains a diagnosis based on clinical history, examination of the patient and the blood film. ADAMTS 13 assays help to confirm the diagnosis and monitor the course of the disease and possible need for additional treatments. Presenting symptoms and signs are summarized in Table 2 and reflect widespread multi organ thromboses. Neurological impairment has multiple presentations including headache, altered personality, reduced cognition, transient ischaemic attacks, fits and fluctuating levels of consciousness including coma; the latter is a poor prognostic sign. Acute renal failure requiring haemodialysis is rare in TTP and more indicative of HUS (Coppo et al, 2006; Scully et al, 2008). Additional ischaemic complications may be seen, such as abdominal pain due to intestinal ischaemia. Consumption of platelets in platelet-rich thrombi results in thrombocytopenia. The median platelet count is typically 10–30 × 109/l at presentation (Dervenoulas et al, 2000; Vesely et al, 2003; Coppo et al, 2006; Tuncer et al, 2007; Scully et al, 2008). Mechanical fragmentation of erythrocytes during flow through partially occluded, high shear small vessels causes a MAHA. Median haemoglobin levels on admission are typically 80–100 g/l, with schistocytes in the film, low haptoglobin levels and raised reticulocyte counts due to haemolysis. The direct Coombs test is negative. The combination of haemolysis and tissue ischaemia produces elevated lactate dehydrogenase (LDH) values. The clotting screen (prothrombin time, activated partial thromboplastin time and fibrinogen) is usually normal. A virology screen pre-treatment is necessary to exclude human immunodeficency virus (HIV) and other viral-associated TTP, and as a baseline prior to plasma exposure. Troponin T levels are raised in 50% of acute idiopathic TTP cases (Hughes et al, 2009), highlighting that cardiac involvement is common. Raised troponin levels are a sinister finding, for coronary artery occlusion is a common mode of early death. The incidence of symptomatic heart failure is increased in patients who have been given a recent platelet transfusion (Gami et al, 2005) (Table 3). Blood must be taken prior to treatment to assess baseline ADAMTS13 activity. Severely reduced ADAMTS13 activity (<5%) ± the presence of an inhibitor or IgG antibodies, confirms the diagnosis (Peyvandi et al, 2004; Coppo et al, 2006; Ferrari et al, 2007; Scully et al, 2007a). Decreased ADAMTS13 activity (<40% but >5%) has been reported in a wide variety of non-TTP conditions such as uraemia, inflammatory states, post-operatively and during pregnancy (Loof et al, 2001; Mannucci et al, 2001; Moore et al, 2001). The specificity of severe ADAMTS13 deficiency (<5%) in distinguishing acute TTP from HUS is 90% (Bianchi et al, 2002; Zheng et al, 2004) ADAMTS13 assays currently available include assays of activity, antigen and neutralizing or non-neutralizing anti-ADAMTS13 autoantibodies. Functional assays measuring ADAMTS13 activity are based on the failure of the patient plasma to degrade VWF multimers or synthetic VWF peptides. Inhibitory autoantibodies can be titrated in vitro using classical mixing studies and non-neutralizing antibodies can be detected by Western blotting or enzyme-linked immunosorbent assays (Peyvandi et al, 2010). 1 The diagnosis of TTP should be treated as a medical emergency (1A). 2 The initial diagnosis of TTP should be made on clinical history, examination and routine laboratory parameters of the patient, including blood film review (1A). 3 In view of the high risk of preventable, early deaths in TTP, treatment with PEX should be initiated as soon as possible, preferably within 4–8 h, regardless of the time of day at presentation, if a patient presents with a MAHA and thrombocytopenia in the absence of any other identifiable clinical cause (1B). 4 Serological tests for HIV, hepatitis B virus and hepatitis C virus, autoantibody screen and when appropriate, a pregnancy test, should be performed at presentation (1A). 5 Pre-treatment samples should be obtained to measure ADAMTS13 activity levels and to detect anti-ADAMTS13 antibodies. Measurement of ADAMTS 13 antigen levels is also useful in congenital TTP cases (1B). Congenital TTP is a rare disorder, with over 100 patients described worldwide, but this is likely to be an underestimate. It has a varied phenotype and can present at any age. As a general rule, those with more severe phenotypes present early: 1 Neonates typically have severe neonatal jaundice. Blood film examination may show schistocytes together with red cell anisocytosis. (Scully et al, 2006a). 2 More frequently, the diagnosis is made later in infancy or childhood (Schiff et al, 2004), typically with thrombocytopenia, MAHA, jaundice and elevated LDH, although some children may only have an isolated thrombocytopenia. Neurological symptoms, such as hemiparesis, hemiplegia or seizures, occur in 35% of cases (Loirat et al, 2006). 3 Patients may present in adulthood. In women, pregnancy is a common precipitant and is associated with a significant neonatal morbidity and mortality (Fujimura et al, 2009). Rarely ‘late-onset phenotype’ cases may not develop symptoms until their 50s and 60s with isolated cerebral events or renal disease ((Fujimura et al, 2011). Asymptomatic male cases have been reported, usually detected because they have affected siblings. Patients with congenital TTP have persistently low levels of ADAMTS13, but they can be asymptomatic until a further precipitating event results in a frank TTP episode. Events include febrile episodes, infections, vaccinations, excess alcohol intake and pregnancy (Furlan et al, 1997, 1998b; Schneppenheim et al, 2003). Congenital TTP has been missed in the past, because the diagnosis has not been considered, or diagnosed as idiopathic thrombocytopenic purpura or ‘atypical’ HUS (Veyradier et al, 2003), illustrating the importance of consideration of the diagnosis, review of the blood film and measurement of ADAMTS13 . The diagnosis of congenital TTP is dependent on detecting ADAMTS13 activity <5%, in the absence of antibodies to ADAMTS13. In the last few years molecular diagnosis has been used to confirm the diagnosis, and either a homozygous or compound heterozygote defect in ADAMTS13 is found. Testing of siblings and other first-degree relatives at risk should be considered. 1 Congenital TTP should be considered in neonates presenting with severe jaundice. Presentation may also occur in childhood or as an adult (1A). 2 The diagnosis of congenital TTP should be considered in children and adults with unexplained thrombocytopenia (1B). 3 The diagnosis of congenital TTP is confirmed by ADAMTS13 activity <5%, absence of antibody and confirmation of homozygous or compound heterozygous defects of the ADAMTS13 gene (1A). Acute idiopathic TTP is the most common form of TTP. It is an autoimmune disease characterized by antibodies, usually IgG, directed against ADAMTS13. The incidence is four to six cases per million of the population per year in the United States (Miller et al, 2004; Terrell et al, 2005) and six cases per million per year in the UK (Scully et al, 2008). Thrombotic thrombocytopenia purpura may be the initial presenting feature of HIV disease or in those with low CD4 counts following non- compliance with antiviral treatment (Ucar et al, 1994; Gervasoni et al, 2002). Remission is dependent upon improving the immune status of the patient, for stopping highly active anti retroviral therapy (HAART) can result in acute TTP relapse (Miller et al, 2005), but continued use of HAART usually prevents further relapses. TTP in HIV-positive individuals may be associated with the presence of severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies. Those with severe ADAMTS13 deficiency (<5%) have fewer acquired immunodeficiency syndrome-related complications and higher CD4+ T cell counts, compared to HIV-TTP with ADAMTS13 levels >5%, who have an increased mortality (Malak et al, 2008). Pregnancy can be the initiating event for approximately 5–25% of TTP cases (Ridolfi & Bell, 1981; Vesely et al, 2004; Scully et al, 2008), which are late onset adult congenital TTP or acute idiopathic TTP. Differentiating TTP from the more common pregnancy-related TMAs, such as pre-eclampsia, syndrome elevated low and HUS is difficult, if TTP presents (Table Thrombosis in the in untreated TTP and results in death and is a continued risk of relapse during with levels of ADAMTS13 have a risk of relapse et al, 2003; Scully et al, to be for of TTP cases et al, 2003; Scully et al, 2008). can cause an disorder, typically in TTP is recognized in with with an incidence of per patients but has been described with and there is there is a et al, 2009). et al, Vesely et al, 2003; et al, 2004; Scully et al, 2008), et al, and used to hepatitis C et al, 2007; et al, 2007; et al, have been associated with TTP. are of acquired TTP associated with such as the and therapy (Scully et al, 2008). such as and can cause HUS but not TTP. 1 associated with of TTP include and which should be to relapse in patients with a of TTP 2 with TTP should be microangiopathy is a MAHA and thrombocytopenia that It may reflect associated with infections, such as A and disease has important from TTP, absence of ADAMTS13 rare neurological a poor to PEX and of of et al, Thrombotic microangiopathy in with a variety of & 2001). Presentation may be either at an early of or associated with ADAMTS13 activity is not reduced in patients et al, 2001). haemolytic anaemia has been reported in with acute a of of ADAMTS13 activity was only reduced and not with the of TTP or patients were treated with PEX and et al, 2009). associated typically with is treated with which in some cases renal not typically associated with but may be associated with symptoms, to TTP, should be treated with PEX et al, 2011). The factor HUS and TTP is the presence of renal in the of defects in HUS is defined & and use of the in cases et al, et al, but may also have a in severe et al, 2011). A of the treatment is in preferably with is the of treatment and has reduced mortality from over 90% to It of and ADAMTS13. in of PEX to early mortality et al, PEX remains the treatment of large plasma are if there is to be a in PEX has been to be to plasma at the of the treatment and at and and et al, The of PEX and the of to is highly but is in TTP (Coppo et al, 2006). has not been In the plasma exchange was performed on the 3 by exchange et al, More such as may be in cases if there is such as neurological or cardiac The of an PEX has been to as other are often initiated or et al, 2008). should for a of 2 defined as platelet count of has not been to relapse & 1998). is at as as plasma et al, et al, The UK of the use of plasma in TTP patients to the risk of and immune (Scully et al, plasma reduced levels of but an increased thrombotic has not been reported in cases where with low molecular and low was used the platelet count was × 109/l (Scully et al, ADAMTS13 activity is present in in and et al, In the is the plasma for use in in those to the risk of et al, has been associated with increased of PEX and in TTP et al, 2001; et al, 2008). A using compared to and et al, 2006). such as and to be more prior to the use of plasma (Scully et al, 1 PEX should be with using plasma in and (1B). 2 The of exchange can be reduced to when the clinical and laboratory test results are 3 in and or of PEX should be considered in cases 4 PEX should for a of 2 platelet count has been × and then or of ADAMTS13 are not treatment of plasma or the use of a factor ADAMTS13, such as et al, which has a small and can be given in the or of has been used with reported although there is of ADAMTS13 in such to ADAMTS 13 have not been detected following the use of that ADAMTS13 has a of only (Furlan et al, et al, 2004), the clinical of of plasma or are such that are only to a platelet and haemoglobin the of treatment on the therapy to the platelet count and at of and other The who have a platelet count most of the time, only 1 plasma or should be used to congenital TTP 2 for congenital TTP should be to the phenotype (1A). Diagnosis of TTP is if In any with a and as to the diagnosis that and can present in the PEX should be considered. TTP in the PEX may of pregnancy with delivery of a et al, et al, et al, Scully et al, is the treatment of for although delivery not of TTP. Pre-treatment ADAMTS13 assays congenital and acquired TTP from other In and syndrome ADAMTS13 activity is reduced but antibodies to ADAMTS13 are not found. with an with in and is with artery should be used to assess if there is and to assess blood alone may be in with congenital TTP. However, at delivery PEX may be to levels of ADAMTS13. The of plasma during pregnancy is In acquired TTP, is to relapse in A reduction in ADAMTS13 activity at the of pregnancy may therapy to during has been used in pregnancy in autoimmune and et al, 2011). 1 a be by a non-TTP pregnancy-related then the diagnosis of TTP must be considered and PEX should be 2 with congenital TTP should a and ADAMTS13 pregnancy and the (1A). 3 with an with a in is in with TTP (1A). 4 In with acquired TTP, ADAMTS13 activity should be pregnancy to help the need for therapy and (1B). 5 is for and women of should be of pregnancy and In those with severe ADAMTS13 there is in ADAMTS13 activity, as the CD4 count and HIV treatment with HAART and further therapy is for with or which do not cause a significant increase in complications et al, 2011). HAART should be given PEX to for time for 1 a patient with TTP is found to have HIV then should be and an HIV should be in management (1A). 2 TTP should be considered in an HIV-positive with a MAHA and thrombocytopenia (1A). 3 PEX in with HAART or should be as soon as the diagnosis of TTP is made (1B). 3 HAART should be given PEX therapy to time for (1A). 4 HAART should be continued to further relapse (1B). 5 In TTP, be considered is difficult, as stopping or to such as may has been with in a review was associated with an increased mortality et al, is of use of et al, et al, exchange has et al, The treatment of the is the of 1 PEX is not in the management of and (1A). 2 In associated further treatment for the should be considered (1A). are used in combination with PEX in the initial treatment of acute immune TTP. have to be associated with an patient and usually have et al, 2010). there is a combination of PEX and is to PEX 1 for – adult or high 1 should be considered (1B). studies have that is and in immune TTP, when patients to to PEX and and in acute idiopathic TTP et al, Scully et al, 2007a). has been used for 4 Patients in anti-ADAMTS13 IgG antibody levels and increased ADAMTS13 activity (Scully et al, 2007a). The risk of relapse to be reduced with use et al, 2007; Scully et al, 2011). PEX should be for at 4 h a & 2006; Scully et al, 2007a). more may during PEX et al, 2010). is of increased risk with in TTP A recent UK has in using as a therapy at presentation of TTP (Scully et al, 2011). 1 In acute idiopathic TTP with which are associated with a high should be considered on in with PEX and (1B). 2 Patients with or TTP should be (1B). A was used in patient with TTP et al, but further occurred of In a clinical of PEX with either or initial occurred in subsequently on and there was a relapse stopping of of the patients a relapse in the compared with of the patients a with an increase in ADAMTS13 activity and in antibodies to ADAMTS13 et al, In patients with renal is an but may and may be considered as therapy in patients with acute or acquired TTP the and of other used for and such as and use is associated with severe and has been in small of patients et al, et al, 2005), are not as of a clinical The mortality of in acute TTP was reported to be approximately In a of patients for acute and the was et al, et al, may be considered in the of TTP but has The TTP patients to PEX and with and without and et al, was in or and a of early death in the 15 in the group et al, 1 The clinical of in TTP is but they are (1B). 2 may be given during platelet count × cell transfusion and are during active haemolysis. It has been that transfusion in the is using a transfusion of this was not to those with cardiac disease et al, as cardiac is a feature of TTP, a higher haemoglobin may be in those with of cardiac involvement and acute haemolysis. to the risk of precipitating further thrombotic platelet are there is The risk of has been in acute TTP but is likely to be increased due to and acute routine should be given the platelet count has to × 109/l et al, 2003). B should be considered in TTP, a platelet of × 109/l has been but studies of are in the of continued PEX with 1 cell transfusion should be to clinical need if there is cardiac involvement (1A). 2 is during active haemolysis (1A). 3 are in TTP there is (1A). 4 with is platelet count has × (1B). is a of patients who present with TTP who subsequently show a or to PEX ± disease was defined as thrombocytopenia or a of PEX is not a of disease activity. have disease as of clinical symptoms or thrombocytopenia of PEX with the of or and the of further have some et al, et al, & & 2004; et al, 2008). is the of in disease (Scully et al, 2007a). of PEX and of can be considered in TTP (1B). is defined as an of acute TTP more and in of cases et al, & & The that over a of patients relapse et al, Patients with ADAMTS13 activity or an anti-ADAMTS13 antibody in a increase in relapse over 1 year (Peyvandi et al, 2008). In a further if ADAMTS13 was in relapse occurred in but if ADAMTS13 activity was only et al, The use of in an acute and the incidence of relapse (Scully et al, 2011). to patients should be the risk and the symptoms and signs of In patients who have TTP and where a reduction of ADAMTS 13 activity from levels to is therapy has been with of ADAMTS 13 activity (Scully et al, et al, 2009). Patients up with ADAMTS 13 1 PEX therapy are the of in disease (1B). 2 Patients should be symptoms, signs and risk of relapse with and (1A). 3 In patients with a reduction of ADAMTS 13 activity to <5%, therapy with can be considered (1B). uraemic syndrome is characterized by MAHA, thrombocytopenia and acute renal It associated with and cardiac and diagnostic overlap with TTP can It is important to HUS and TTP because the and management are (Table The is to et al, and et al, for further guidance in children and TTP and other TMAs The is to that haematologists, and are of the need to acute TTP as a medical emergency to early The of and in the should to in the the and in is to be and at the time of to the the British Society for Haematology the any for the of . 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Most adults with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR) will relapse. We examined the outcome of 609 adults with recurring ALL, all of whom were previously treated on the Medical Research Council (MRC) UKALL12/ECOG2993 study, where the overall survival (OS) of newly diagnosed patients is 38% (95% confidence interval [CI]=36%-41%) at 5 years. By contrast, OS at 5 years after relapse was 7% (95% CI=4%-9%). Factors predicting a good outcome after salvage therapy were young age (OS of 12% in patients younger than 20 years vs OS of 3% in patients older than 50 years; 2P<.001) and short duration of first remission (CR1) (OS of 11% in those with a CR1 of more than 2 years versus OS of 5% in those with a CR1 of less than 2 years; 2P<.001). Treatment received in CR1 did not influence outcome after relapse. In a very highly selected subgroup of patients who were able to receive HSCT after relapse, some were long-term survivors. We conclude from a large, unselected series with mature follow-up that most adults with recurring ALL, whatever their prior treatment, cannot be rescued using currently available therapies. Prevention of recurrence is the best strategy for long-term survival in this disease.

The minority stress model has been influential in guiding research on sexual and gender minority health and well-being in psychology and related social and health sciences. Minority stress has theoretical roots in psychology, sociology, public health, and social welfare. Meyer provided the first integrative articulation of minority stress in 2003 as an explanatory theory aimed at understanding the social, psychological, and structural factors accounting for mental health inequalities facing sexual minority populations. This article reviews developments in minority stress theory over the past two decades, focusing on critiques, applications, and reflections on its continued relevance in the context of rapidly changing social and policy contexts.

An international collaboration was set up to prospectively evaluate the role of allogeneic transplantation for adults with acute lymphoblastic leukemia (ALL) and compare autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53% versus 45% (P = .01), and the relapse rate was significantly lower (P < or = .001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46%) than those randomized to autologous transplantation (37%; P = .03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group. This study is registered at http://clinicaltrials.gov as NCT00002514.

Two hundred and thirty-five adolescents completed a questionnaire on the subject of eating attitudes, self-esteem, reasons for exercise, and their ideal versus current body size and shape. As predicted, boys were as likely to want to be heavier as lighter, whereas very few girls desired to be heavier. Only girls associated body dissatisfaction with the concept of self-esteem. Male self-esteem was not affected by body dissatisfaction. Specific reasons for exercise were found to correlate with low self-esteem and disordered eating, regardless of sex. The results are discussed in relation to burgeoning published research in this area.

BACKGROUND: Inherited bacteria have come to be recognised as important components of arthropod biology. In addition to mutualistic symbioses, a range of other inherited bacteria are known to act either as reproductive parasites or as secondary symbionts. Whilst the incidence of the alpha-proteobacterium Wolbachia is relatively well established, the current knowledge of other inherited bacteria is much weaker. Here, we tested 136 arthropod species for a range of inherited bacteria known to demonstrate reproductive parasitism, sampling each species more intensively than in past surveys. RESULTS: The inclusion of inherited bacteria other than Wolbachia increased the number of infections recorded in our sample from 33 to 57, and the proportion of species infected from 22.8% to 32.4%. Thus, whilst Wolbachia remained the dominant inherited bacterium, it alone was responsible for around half of all inherited infections of the bacteria sampled, with members of the Cardinium, Arsenophonus and Spiroplasma ixodetis clades each occurring in 4% to 7% of all species. The observation that infection was sometimes rare within host populations, and that there was variation in presence of symbionts between populations indicates that our survey will itself underscore incidence. CONCLUSION: This extensive survey demonstrates that at least a third of arthropod species are infected by a diverse assemblage of maternally inherited bacteria that are likely to strongly influence their hosts' biology, and indicates an urgent need to establish the nature of the interaction between non-Wolbachia bacteria and their hosts.

BACKGROUND: Increasing rates of mental health problems among adolescents are of concern. Teens who are most in need of mental health attention are reluctant to seek help. A better understanding of the help-seeking in this population is needed to overcome this gap. METHODS: Five databases were searched to identify the principal barriers, facilitators and interventions targeting help-seeking for common mental health problems in adolescents aged 10-19 years. The search was performed in June 2018 and updated in April 2019. Two independent screening processes were made using the eligibility criteria. Quality assessment of each study was performed, and findings summarised using a narrative synthesis. RESULTS: Ninety studies meet the inclusion criteria for this review for barrier and facilitators (n = 54) and interventions (n = 36). Stigma and negative beliefs towards mental health services and professionals were the most cited barriers. Facilitators included previous positive experience with health services and mental health literacy. Most interventions were based on psychoeducation, which focused on general mental health knowledge, suicide and self-harm, stigma and depression. Other types of interventions included the use of multimedia and online tools, peer training and outreach initiatives. Overall, the quality of studies was low to medium and there was no general agreement regarding help-seeking definition and measurements. CONCLUSION: Most of the interventions took place in an educational setting however, it is important to consider adolescents outside the educational system. Encouraging help-seeking should come with the increased availability of mental health support for all adolescents in need, but this is still a major challenge for Child and Adolescent Mental Health Services. There is also a need to develop shared definitions, theoretical frameworks and higher methodological standards in research regarding help-seeking behaviours in adolescents. This will allow more consistency and generalisability of findings, improving the development of help-seeking interventions and ensuring timely access to mental health treatments.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential conflict of interest is reported on the websites of the ESH and the ESC.

Many treatments have been identified that confer robust cardioprotection in experimental animal models of acute ischemia and reperfusion injury. However, translation of these cardioprotective therapies into the clinical setting of acute myocardial infarction (AMI) for patient benefit has been disappointing. One important reason might be that AMI is multifactorial, causing cardiomyocyte death via multiple mechanisms, as well as affecting other cell types, including platelets, fibroblasts, endothelial and smooth muscle cells, and immune cells. Many cardioprotective strategies act through common end-effectors and may be suboptimal in patients with comorbidities. In this regard, emerging data suggest that optimal cardioprotection may require the combination of additive or synergistic multitarget therapies. This review will present an overview of the state of cardioprotection today and provide a roadmap for how we might progress towards successful clinical use of cardioprotective therapies following AMI, focusing on the rational combination of judiciously selected, multitarget therapies. This paper emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

Abstract Background: Particulate air pollution’s physical health effects are well known, but associations between particulate matter (PM) exposure and mental illness have not yet been established. However, there is increasing interest in emerging evidence supporting a possible etiological link. Objectives: This systematic review aims to provide a comprehensive overview and synthesis of the epidemiological literature to date by investigating quantitative associations between PM and multiple adverse mental health outcomes (depression, anxiety, bipolar disorder, psychosis, or suicide). Methods: We undertook a systematic review and meta-analysis. We searched Medline, PsycINFO, and EMBASE from January 1974 to September 2017 for English-language human observational studies reporting quantitative associations between exposure to PM &amp;lt;1.0μm in aerodynamic diameter (ultrafine particles) and PM &amp;lt;2.5 and &amp;lt;10μm in aerodynamic diameter (PM2.5 and PM10, respectively) and the above psychiatric outcomes. We extracted data, appraised study quality using a published quality assessment tool, summarized methodological approaches, and conducted meta-analyses where appropriate. Results: Of 1,826 citations identified, 22 met our overall inclusion criteria, and we included 9 in our primary meta-analyses. In our meta-analysis of associations between long-term (&amp;gt;6 months) PM2.5 exposure and depression (n=5 studies), the pooled odds ratio was 1.102 per 10-μg/m3 PM2.5 increase (95% CI: 1.023, 1.189; I2=0.00%). Two of the included studies investigating associations between long-term PM2.5 exposure and anxiety also reported statistically significant positive associations, and we found a statistically significant association between short-term PM10 exposure and suicide in meta-analysis at a 0-2 d cumulative exposure lag. Discussion: Our findings support the hypothesis of an association between long-term PM2.5 exposure and depression, as well as supporting hypotheses of possible associations between long-term PM2.5 exposure and anxiety and between short-term PM10 exposure and suicide. The limited literature and methodological challenges in this field, including heterogeneous outcome definitions, exposure assessment, and residual confounding, suggest further high-quality studies are warranted to investigate potentially causal associations between air pollution and poor mental health. https://doi.org/10.1289/EHP4595

KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. M-channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation. Muscarinic closure results from activation of phospholipase C and consequent hydrolysis and depletion of membrane phosphatidylinositol-4,5-bisphosphate, which is required for channel opening. Some effects of M-channel closure, determined from transmitter action, selective blocking drugs (linopirdine and XE991) and KCNQ2 gene disruption or manipulation, are as follows: (i) in sympathetic neurons: facilitation of repetitive discharges and conversion from phasic to tonic firing; (ii) in sensory nociceptive systems: facilitation of A-delta peripheral sensory fibre responses to noxious heat; and (iii) in hippocampal pyramidal neurons: facilitation of repetitive discharges, enhanced after-depolarization and burst-firing, and induction of spontaneous firing through a reduction of action potential threshold at the axon initial segment. Several drugs including flupirtine and retigabine enhance neural Kv7/M-channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.