Warwick Hospital

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

Unmanned aerial vehicles (UAVs) have attracted great interest in rapid deployment for both civil and military applications. UAV communication has its own distinctive channel characteristics compared to the widely used cellular or satellite systems. Accurate channel characterization is crucial for the performance optimization and design of efficient UAV communication. However, several challenges exist in UAV channel modeling. For example, the propagation characteristics of UAV channels are under explored for spatial and temporal variations in non–stationary channels. Additionally, airframe shadowing has not yet been investigated for small size rotary UAVs. This paper provides an extensive survey of the measurement methods proposed for UAV channel modeling that use low altitude platforms and discusses various channel characterization efforts. We also review from a contemporary perspective of UAV channel modeling approaches, and outline future research challenges in this domain.

Informed by a series of systematic reviews, scoping reviews and evidence updates from the International Liaison Committee on Resuscitation, the 2021 European Resuscitation Council Guidelines present the most up to date evidence-based guidelines for the practice of resuscitation across Europe. The guidelines cover the epidemiology of cardiac arrest; the role that systems play in saving lives, adult basic life support, adult advanced life support, resuscitation in special circumstances, post resuscitation care, first aid, neonatal life support, paediatric life support, ethics and education.

Aerial dispersal using silk ('ballooning') has evolved in spiders (Araneae), spider mites (Acari) and in the larvae of moths (Lepidoptera). Since the 17th century, over 500 observations of ballooning behaviours have been published, yet there is an absence of any evolutionary synthesis of these data. In this paper the literature is reviewed, extensively documenting the known world fauna that balloon and the principal behaviours involved. This knowledge is then incorporated into the current evolutionary phylogenies to examine how ballooning might have arisen. Whilst it is possible that ballooning co-evolved with silk and emerged as early as the Devonian (410-355 mya), it is arguably more likely that ballooning evolved in parallel with deciduous trees, herbaceous annuals and grasses in the Cretaceous (135-65 mya). During this period, temporal (e.g. bud burst, chlorophyll thresholds) and spatial (e.g. herbivory, trampling) heterogeneities in habitat structuring predominated and intensified into the Cenozoic (65 mya to the present). It is hypothesized that from the ancestral launch mechanism known as 'suspended ballooning', widely used by individuals in plant canopies, 'tip-toe' and 'rearing' take-off behaviours were strongly selected for as habitats changed. It is contended that ballooning behaviour in all three orders can be described as a mixed Evolutionary Stable Strategy. This comprises individual bet-hedging due to habitat unpredictability, giving an underlying randomness to individual ballooning, with adjustments to the individual ballooning probability being conferred by more predictable habitat changes or colonization strategies. Finally, current methods used to study ballooning, including modelling and genetic research, are illustrated and an indication of future prospects given.

The phyllosphere represents the habitat provided by the aboveground parts of plants, and on a global scale supports a large and complex microbial community. Microbial interactions in the phyllosphere can affect the fitness of plants in natural communities, the productivity of agricultural crops, and the safety of horticultural produce for human consumption. The structure of phyllosphere communities reflects immigration, survival and growth of microbial colonists, which is influenced by numerous environmental factors in addition to leaf physico-chemical properties. The recent use of culture-independent techniques has demonstrated considerable previously unrecognized diversity in phyllosphere bacterial communities. Furthermore, there is significant recent evidence that plant genotype can play a major role in determining the structure of phyllosphere microbial communities. The main aims of this review are: (i) to discuss the diversity of phyllosphere microbial populations; (ii) to consider the processes by which microbes colonize the phyllosphere; (iii) to address the leaf characteristics and environmental factors that determine the survival and growth of colonists; (iv) to discuss microbial adaptations that allow establishment in the phyllosphere habitat and (v) to evaluate evidence for plant genotypic control of phyllosphere communities. Finally, we suggest approaches and priority areas for future research on phyllosphere microbiology.

Plants are constantly exposed to attack by an array of diverse pathogens but lack a somatically adaptive immune system. In spite of this, natural plant populations do not often suffer destructive disease epidemics. Elucidating how allelic diversity within plant genes that function to detect pathogens (resistance genes) counteracts changing structures of pathogen genes required for host invasion (pathogenicity effectors) is critical to our understanding of the dynamics of natural plant populations. The RPP13 resistance gene is the most polymorphic gene analyzed to date in the model plant Arabidopsis thaliana. Here we report the cloning of the avirulence gene, ATR13, that triggers RPP13-mediated resistance, and we show that it too exhibits extreme levels of amino acid polymorphism. Evidence of diversifying selection visible in both components suggests that the host and pathogen may be locked in a coevolutionary conflict at these loci, where attempts to evade host resistance by the pathogen are matched by the development of new detection capabilities by the host.

Thrombotic thrombocytopenic purpura (TTP) was first described by Moschowitz (1924). The classic pentad of diagnostic features has been recognized for many years. However, several other syndromes are also characterized by similar features. These include haemolytic uraemic syndrome (HUS), eclampsia and the HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). The concept has arisen that they might represent an overlapping spectrum of disease, although with varying pathophysiological features (see Table I). The recent characterization of a novel von Willebrand factor (VWF)-cleaving metalloprotease activity (Furlan et al, 1996; Tsai, 1996) and its deficiency or inhibition in some forms of microangiopathic haemolysis (Furlan et al, 1997, 1998; Tsai & Lian, 1998) has led to speculation that a pathogenic mechanism for individual patients can be defined more readily and appropriate treatment introduced more rapidly. However, there is still considerable confusion, a lack of properly conducted randomized clinical trials and poor co-ordination of clinical data. This is, in part, because these patients present to a range of specialists including haematologists, obstetricians, nephrologists and infectious disease physicians. These guidelines attempt to define the various clinical subtypes, specify the recognized diagnostic features and look critically at management options. It is acknowledged that there is a lack of evidence from well-conducted studies on which to support some of the recommendations made. Thrombotic thrombocytopenic purpura (TTP) is rare. The reported incidence is 3·7 per million (Torok et al, 1995). However, its prompt recognition and treatment is vital, as delays in initiating treatment have been shown to adversely affect outcome (Pereira et al, 1995). TTP is a clinical diagnosis. It is characterized by the classic pentad of thrombocytopenia, microangiopathic haemolytic anaemia, fluctuating neurological signs, renal impairment and fever, often with insidious onset. Neurological impairment has multiple manifestations including headache, bizarre behaviour, transient sensorimotor deficits (TIAs), seizure and coma. Presence of coma at presentation is a poor prognostic indicator (Pereira et al, 1995; Sarode et al, 1997). Additional complications may be seen: gastrointestinal ischaemia (manifest as abdominal pain) and serous retinal detachment are recognized associations. However, up to 35% of TTP patients do not have neurological symptoms or signs at presentation (Rock et al, 1991). As the triad of acute renal insufficiency, MAHA and thrombocytopenia defines HUS, diagnostic uncertainty may arise. Moreover, fever and renal impairment are present in only a minority of patients (Rock et al, 1991, 1998). In practice, therefore, a diagnosis of TTP may be made in the presence of a microangiopathic haemolytic anaemia and thrombocytopenia in the absence of any other identifiable cause. A number of different clinical variants of TTP have been documented. Clinical subtype may influence management and those recognized are listed in Table II. The predominant histological abnormality found in TTP is the formation of platelet microvascular thrombi. The renal and cerebral circulations are primarily affected, thus accounting for the clinical features of the disease. Excessive platelet aggregation occurs when platelet-rich plasma (PRP) from patients with congenital TTP is exposed to shear stress (Moake et al, 1994). This is mediated by ultra-large VWF multimers (ULVWF) (Moake et al, 1994; Karpman et al, 1997). ULVWF are not a normal constituent of circulating plasma. Instead, VWF circulates as smaller multimeric forms resulting from proteolytic degradation of ULVWF. VWF fragments with mobility corresponding to 189, 176 and 140 kDa are consistently detected in normal plasma in addition to the predominant 225 kDa subunit (Zimmerman et al, 1986; Tsai et al, 1991). These originate as a consequence of cleavage of a single peptide bond between residues Tyr-842 and Met-843 of the mature subunit (Dent et al, 1991). Identical fragments may be generated in vivo by a novel metalloproteinase activity (Furlan et al, 1996; Tsai, 1996). The protease has recently been characterized as a new member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin type-I motif) family, ADAMTS13 (Fujikawa et al, 2001; Gerritsen et al, 2001; Levy et al, 2001). Deficiency of this VWF-cleaving protease (VWF-CP) activity has been associated with acquired and congenital TTP. While all cases of idiopathic TTP have, to date, been associated with severe protease deficiency, secondary TTP may occur in the context of normal protease activity (Veyradier et al, 2001). In a series of 111 patients with thrombotic microangiopathies of whom 66 manifested with TTP (25 idiopathic and 41 secondary) and 45 with HUS, protease deficiency had a sensitivity of 89% and specificity of 91% for TTP. Initial reports suggested that idiopathic TTP is secondary to an inhibitory auto-antibody of IgG subtype (Furlan et al, 1998; Tsai & Lian, 1998), but in the above series, a protease inhibitor was identified in only 14 patients (56%). While congenital TTP appears secondary to a constitutional deficiency (Furlan et al, 1997, 1998), presentation may be delayed until adulthood (Lämmle et al, 2001). Cirrhosis (Mannucci et al, 2001), uraemia (Mannucci et al, 2001), acute inflammation (Mannucci et al, 2001), disseminated intravascular coagulation (DIC) (Loof et al, 2001) and malignancy (Oleksowicz et al, 1999) have now also been associated with reduced VWF-CP activity. Thus, although sensitive, reduced VWF-CP activity is not specific for TTP. Moreover, this model fails to explain the anatomical distribution of thrombi. The endothelium is a heterogeneous organ and is subject to regulation by multiple factors, including cytokines (Drake et al, 1993), microenvironment (Aird et al, 1997) and shear stress (White & Fujiwara, 1986). Alterations in any one of these parameters could influence either VWF-CP activity per se or the susceptibility of VWF to proteolysis. TTP is often characterized by severe thrombocytopenia, which may be useful in its differentiation from HUS. However, in one series, although the mean platelet count was lower in TTP than HUS (18 × 109/l vs 36 × 109/l), there was a wide range and considerable overlap (Vesely et al, 2000). Severe thrombocytopenia at diagnosis (platelet count < 20 × 109/l) has been suggested to be a poor prognostic indicator, conferring increased mortality (Rock et al, 1998), although this is not a uniform observation (Sarode et al, 1997). Thrombocytopenia is typically accompanied by overt microangiopathic haemolysis. Thus, examination of the blood film usually shows striking red cell fragmentation and polychromasia. However, schistocytes may be absent from the peripheral blood film in the first 24–48 h following clinical presentation. Routine coagulation profiles are usually normal (Monteagudo et al, 1991; Sagripanti et al, 1996; Rock et al, 1998), although slight increases in D-dimer, fibrin degradation products and thrombin–anti-thrombin complex (TAT) may be seen (Monteagudo et al, 1991; Sagripanti et al, 1996; Wada et al, 1998). Secondary DIC may, however, arise from prolonged tissue ischaemia and is an ominous prognostic indicator. Evidence of endothelial perturbation is demonstrated by increased plasma levels of plasminogen activator inhibitor (PAI-1) (Anthony et al, 1998) and thrombomodulin. The latter has also been identified as a poor prognostic factor (Wada et al, 1998). Plasma VWF levels are often elevated acutely (Rock et al, 1998). Abnormalities of VWF multimers are also common and were identified in 86% of patients either at the onset of or during an acute episode of TTP (Moake & McPherson, 1989). These ranged from the presence of ULVWF multimers in 31% to a relative decrease in the largest plasma VWF forms in 36%. Acute changes in VWF multimeric distribution do not appear to correlate with clinical outcome. However, the finding of ULVWF multimers during periods of remission has been associated with intermittent TTP (Moake & McPherson, 1989). Renal function is normal in the majority of patients: only 18% patients presenting to the Canadian Apheresis Group had evidence of renal impairment (Shumak et al, 1995). Liver function tests often show not only hyperbilirubinaemia but also a raised transaminase level. This is thought to represent hepatic ischaemia. Evans' syndrome may be excluded by a negative direct anti-globulin test. Recommended diagnostic laboratory investigations to be performed at presentation are given in Table III. In those TTP patients in whom significant renal impairment is a feature, it may be impossible to confidently exclude HUS. Where there is doubt, a presumptive diagnosis of TTP should be made and plasmapheresis initiated. Occasionally renal biopsy performed after recovery of the platelet count may allow accurate retrospective diagnosis. In TTP, arteriolar and capillary thrombosis is prominent. Thrombi are largely composed of platelets and stain strongly for VWF. Only weak staining for fibrin and fibrinogen is seen in contrast to those thrombi formed in DIC (Asada et al, 1985). Aneurysmal dilatation of arterioles may lead to the formation of glomeruloid structures with relative sparing of the glomeruli (Katoh & Shigematsu, 1999). These features should be contrasted with those seen in HUS when the primary histological changes are glomerular and arteriolar fibrin thrombi and subendothelial widening of the glomerular capillary wall on electron microscopy (Remuzzi & Ruggenenti, 1995). If a diagnosis of TTP is made, consideration must be given to the presence of precipitants. These are drugs, autoimmune disease, malignancy and infection, particularly Escherichia coli 0157:H7 and human immunodeficiency virus (HIV). Although E. coli 0157:H7 is more closely linked with HUS, there have been cases with typical TTP features (Morrison et al, 1986; Kovacs et al, 1990). Of note VWF-CP deficiency was detected in one of 29 children with epidemic HUS, 25 of whom were positive for verotoxin (Hunt et al, 2001). In some series, up to 14% of TTP episodes have been associated with HIV infection (Ucar et al, 1994), although mortality data from the United States for 1988–1991 gives a figure of only 4·4% (Torok et al, 1995). Risk appears greatest at CD4 counts of less than 250 × 109/l (de Man et al, 1997). Serological testing for HIV should, therefore, be performed at diagnosis in all patients. As treatment (see below) results in multiple donor exposure, hepatitis B and C serology is also recommended in all patients at presentation. Recommendation. While there is no available diagnostic test for TTP, TTP may be diagnosed and treatment initiated if a patient presents with a microangiopathic haemolytic anaemia and thrombocytopenia in the absence of any other identifiable clinical cause. Routine investigations at presentation should include the following: full blood count, film, clotting screen, lactate dehydrogenase (LDH), direct anti-globulin test, urea and electrolytes, liver function tests, and urine dipstick for protein. An underlying precipitant should be considered. It is recommended that HIV and hepatitis serology tests are performed at diagnosis (Grade C, level IV). The mainstay of treatment of acute TTP is daily plasma exchange. Prior to its institution, mortality rates were in excess of 90% and have now fallen to 10–30%. Plasma exchange is superior to plasma infusion. A prospective randomized study performed by the Canadian Apheresis Group assigned a total of 102 patients to receive either plasma exchange or infusion with fresh-frozen plasma (FFP) on 7 of the first 9 d after entry to the trial. Plasma exchange resulted in significantly superior response rates at both the end of the first treatment cycle and at 6 months (response rates 47% and 78%vs 25% and 49% respectively). Mortality was also reduced at 22%vs 37% (Rock et al, 1991). Plasma exchange should be instituted within 24 h of presentation as delay in treatment initiation may increase treatment failure (Pereira et al, 1995). Moreover, it would seem appropriate to commence plasma exchange as soon as practicable if renal impairment, cardiac failure or coma is present. Reduced level of consciousness has been identified as a poor prognostic factor with an overall survival of 54% (Sarode et al, 1997). The duration of plasma exchange therapy required to achieve remission is highly variable. The average number of procedures required for remission in the above study was 15·8 (range 3–36). As the premature omission of a single plasma exchange may be associated with exacerbation, patients should be treated in centres able to provide a daily plasmapheresis service. Although undoubtedly efficacious, the optimal plasma exchange regimen has not been determined. In the Canadian apheresis trial, 1·5 × plasma volume exchange was performed on the first 3 d followed by 1·0 plasma volume exchange thereafter. Whether this intensity is superior to single plasma volume replacement from presentation is unclear. Currently, many centres initiate single-volume plasma exchange at presentation, reserving more intensive exchange for resistant cases. Similarly, the optimal duration of plasma exchange is unknown. It is empirically recommended that daily exchanges should continue for a minimum of 2 d after complete remission is obtained, defined as normal neurological status, platelet count and LDH with a rising haemoglobin. This is in agreement with the American Association of Blood Banks (AABB), which recommends daily plasma exchange until the platelet count is above 150 × 109/l for 2 to 3 d (AABB Extracorporeal Therapy Committee, 1992). Although it is accepted practice to taper the frequency of exchange procedures rather than stopping abruptly in an effort to minimize the risk of early relapse; this is not based on randomized clinical trials. The optimal replacement fluid administered also remains contentious. Possibly of note, cryosupernatant lacks the largest VWF multimers that are present in FFP and cryoprecipitate. Cryosupernatant is at least as efficacious as FFP. When used in previously untreated patients, the response rate was 75% after seven exchanges. Survival was 95% at 1 month, which compared favourably with historical control subjects treated with FFP (Rock et al, 1996). In contrast, a prospective randomized trial performed by the North American TTP Group failed to identify a significant difference in outcome between plasmapheresis with FFP or cryosupernatant from diagnosis. It should be noted, however, that only 27 patients were included in this trial (Zeigler et al, 2001). Larger trials are required to address this issue and a randomized controlled trial comparing plasma exchange with FFP versus cryosupernatant is currently being performed in Canada. Side-effects secondary to plasmapheresis are common. In one study, 9·7% of procedures were complicated by adverse reactions with anaphylactoid reactions occurring in 0·25% (Mokrzycki & Kaplan, 1994). Solvent/detergent-treated (S/D) plasma not only reduces viral risk but may be beneficial in reducing allergic reactions. This is because the process of plasma pooling results in extreme dilution of those antibodies responsible for immune-mediated reactions. S/D plasma has a similar favourable multimer profile to cryosupernatant and has been used as replacement fluid from presentation (Evans et al, 1999). However, numbers treated are small and there is no published comparative data with FFP or cryosupernatant. Further clinical experience is required to ascertain the role of S/D plasma in the primary treatment of TTP. Although plasma exchange remains the treatment of choice, plasma infusion (30 ml/kg/d) may still be indicated if there is to be an unavoidable delay in plasma exchange. It must be undertaken with care, however, as cardiac function may be compromised and cardiac failure can be precipitated. Recommendation. Single-volume daily plasma exchange should be commenced at presentation (Grade A, level Ib) and ideally within 24 h of presentation (Grade C, level IV). Plasma exchange using cryosupernatant may be more efficacious than that using FFP (Grade B, level III). Daily plasma exchange should continue for a minimum of 2 d after complete remission is obtained (Grade C, level IV). Corticosteroids. Steroids have been widely used in the treatment of TTP although there is scanty evidence documenting their efficacy. However, patients with TTP lacking central nervous system abnormalities other than headache have been shown to respond to steroid treatment alone, although of 54 such patients 44% required plasma exchange because of deterioration or failure to improve (Bell et al, 1991). Steroids have also been combined with plasma exchange in initial treatment of TTP. The addition of intravenous methylprednisolone 2 mg/kg/d to daily plasma exchange resulted in a complete remission rate of 76% (Perotti et al, 1996). As yet, no trial has addressed whether such a combination approach is superior to plasma exchange alone. Not surprisingly, there is no consensus regarding dose or mode of administration. Despite the lack of evidence, the addition of steroids to plasma exchange as standard therapy is attractive. Recent findings suggest that a functional deficiency of a novel VWF-CP activity secondary to a circulating inhibitory antibody of IgG subtype is of prime importance in the pathogenesis of TTP (Furlan et al, 1998; Tsai & Lian, 1998). It would, therefore, appear reasonable to institute steroids in all patients. Recommendation. All patients should receive adjuvant corticosteroid therapy (Grade B, level III). To achieve potent immunosuppression while minimizing long-term steroid side-effects, pulse methylprednisolone 1 g i.v. for 3 d is recommended (Grade C, level IV). Anti-platelet agents. The use of anti-platelet agents in TTP remains controversial. Ticlopidine and its analogue clopidogrel inhibit ADP–platelet interactions and interfere with shear-induced aggregation and might, therefore, be to be of use in TTP. to the risk of from to when used as therapy for months after remission of TTP was et al, 1997). However, at in this trial was et al, 1998) and clopidogrel et al, have been associated with TTP. The incidence of TTP is 1 per patients treated while that following clopidogrel is per million As the latter is similar to the reported incidence of idiopathic TTP an remains controversial. in both antibody to VWF-CP have been identified et al, Tsai et al, 2000). In with plasmapheresis is treatment with reported survival rates of and is superior to plasma infusion et al, 2000). these and clopidogrel should be in patients with a of TTP. and have both been used in the initial treatment of TTP. A response rate at 6 months was when and were administered in with plasma exchange (Rock et al, 1991). In a prospective randomized trial to address the of the addition of and to standard treatment exchange and a similar overall response was obtained in both however, a to reduced mortality at d in those treated with anti-platelet agents. excess was seen in the treatment et al, in contrast to the findings of a small retrospective study in which complications in of 14 patients anti-platelet et al, It should be noted, however, that were administered in these patients Although not of there is a for therapy when the platelet count × 109/l as a in platelet count during recovery has been associated with Recommendation. should be commenced on platelet recovery (platelet count × 109/l) (Grade C, level IV). cell is an of However, there is no single to the for red cell Identical survival rates resulted when a was given based on a of 7 rather than in critically patients et al, 1999). As TTP may be complicated by haemolysis and cardiac secondary to microvascular a patient should be to clinical after consideration of the and of All patients should receive are there is as they have been associated with disease et al, et al, centres the use of in an attempt to minimize secondary However, neurological features are absent in 35% of patients and only occur in a minority of the patients (Rock et al, 1991). Secondary rather than primary of with would, therefore, seem Although fever is one of the features of TTP, an underlying infection should be if infection may response to plasma exchange or early B should be given to all patients and can be administered using a platelet of × Recommendation. cell should be administered to clinical (Grade B, level III). is required in all patients. are in TTP there is B is recommended in all patients (Grade C, level IV). Despite the in there remains a with a or response to plasma exchange disease may be defined as thrombocytopenia (platelet count < 150 × 109/l) or LDH after a total of seven daily plasma exchange of this of patients is and a wide range of has been randomized clinical trials have not been performed because of the and of this of plasma exchange. are reports documenting to plasma exchange in cases of TTP following the of either cryosupernatant et al, or S/D plasma et al, 1996) for FFP. S/D plasma lacks the largest plasma VWF multimers and this may be of therefore, there is a response to plasma exchange after 7 d or clinical deterioration daily plasma an replacement fluid should be While fresh-frozen plasma has been used in the management of TTP et al, clinical experience is at present S/D VWF multimeric is not Whether cryosupernatant has a role in the management of TTP clinical of plasma exchange has also been used in cases of TTP with the of either h or plasma volume exchanges. this approach is Recommendation. In the presence of disease an plasma lacking VWF multimeric cryosupernatant or S/D plasma should be used for plasma exchange (Grade C, level IV). of plasma exchange procedures should also be in cases (Grade C, level IV). Although is often used in the treatment of TTP, published its only reports or small retrospective these suggest that the of in TTP may be associated with platelet recovery et al, et al, et al, 1994). A role for the early of 3 d of has also been following a small retrospective study et al, 1998). However, such practice would a risk of of clinical this finding can be by controlled should be for cases. A number of have been with no for any single A of 1 3 to d for a total of is as it may while efficacy. dose have, however, been used The mechanism of of remains unclear. Recommendation. 1 3 to d for a total of is recommended in TTP (Grade C, level IV). has also been for the treatment of TTP, particularly those in patients experience intermittent et al, & et al, 1998). daily and therapy have been used although reported numbers are is to be a potent and this is thought to its efficacy. Although is associated with an increased risk of there are reports of its to the treatment of et al, 1998), severe intermittent et al, 1998) and TTP et al, 1997). This is with the autoimmune model of TTP and While be excluded in these patients, clinical and response 7 to 14 d after initiating may, therefore, to be a useful in these patients. However, remains The optimal duration of treatment is with after of therapy et al, 1998; et al, 1998). The optimal range is also levels of have been The of this must also be considered. Recommendation. immunosuppression using either or is indicated in severe or TTP (Grade C, level IV). The of VWF-CP is now to the clinical that TTP currently a heterogeneous of It has been recognized that plasma exchange is in the treatment of TTP, that an process might be This is by the recent finding that VWF-CP activity was normal in seven and only reduced in one of patients with TTP et al, 1999). treatment for this of patients is, however, of TTP has been reported following initiation of et al, although therapy is a recognized risk with total for TTP. In the latter should be Whether might be useful in such patients is unclear. this has been in the treatment of TTP in which plasma exchange is often found to be In one small retrospective series, it was found to be of in seven of patients had been to plasma exchange et al, 1997). Recommendation. and TTP are often to plasma exchange. may be (Grade C, level IV). Although remission is now in patients, remains from the Canadian Apheresis Group that a up to of TTP patients has up to after the (Shumak et al, 1995). All patients should be of the of and to early if symptoms of it is impossible to identify those patients at greatest although the presence of ULVWF during periods of remission is associated with intermittent disease (Moake & McPherson, 1989). is no consensus whether there is any that might this has been as a of reducing the small retrospective study including patients results with rates from to per when the was performed during remission et al, 1996). However, acute of TTP have

Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. Enzymes metabolising dicarbonyls, glyoxalase 1 and aldoketo reductases, provide an efficient and stress-response enzyme defence against dicarbonyl stress. Dicarbonyl stress is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites, and by exposure to exogenous dicarbonyls. It contributes to ageing, disease and activity of cytototoxic chemotherapeutic agents.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

BACKGROUND: Phosphorus (P) is an essential macronutrient for plants. Plants take up P as phosphate (Pi) from the soil solution. Since little Pi is available in most soils, P fertilizers are applied to crops. However, the use of P fertilizers is unsustainable and may cause pollution. Consequently, there is a need to develop more P-use-efficient (PUE) crops and precise methods to monitor crop P-status. SCOPE: Manipulating the expression of genes to improve the PUE of crops could reduce their P fertilizer requirement. This has stimulated research towards the identification of genes and signalling cascades involved in plant responses to P deficiency. Genes that respond to P deficiency can be grouped into 'early' genes that respond rapidly and often non-specifically to P deficiency, or 'late' genes that impact on the morphology, physiology or metabolism of plants upon prolonged P deficiency. SUMMARY: The use of micro-array technology has allowed researchers to catalogue the genetic responses of plants to P deficiency. Genes whose expression is altered by P deficiency include various transcription factors, which are thought to coordinate plant responses to P deficiency, and other genes involved in P acquisition and tissue P economy. Several common cis-regulatory elements have been identified in the promoters of these genes, suggesting that their expression might be coordinated. It is suggested that knowledge of the genes whose expression changes in response to P deficiency might allow the development of crops with improved PUE, and could be used in diagnostic techniques to monitor P deficiency in crops either directly using 'smart' indicator plants or indirectly through transcript profiling. The development of crops with improved PUE and the adoption of diagnostic technology could reduce production costs, minimize the use of a non-renewable resource, reduce pollution and enhance biodiversity.

The pathogenesis of fatal cerebral malaria (CM) is not well understood, in part because data from patients in whom a clinical diagnosis was established prior to death are rare. In a murine CM model, platelets accumulate in brain microvasculature, and antiplatelet therapy can improve outcome. We determined whether platelets are also found in cerebral vessels in human CM, and we performed immunohistopathology for platelet-specific glycoprotein, GPIIb-IIIa, on tissue from multiple brain sites in Malawian children whose fatal illness was severe malarial anemia, CM, or nonmalarial encephalopathy. Platelets were observed in 3 locations within microvessels: between malaria pigment and leukocytes, associated with malaria pigment, or alone. The mean surface area of platelet staining and the proportion of vessels showing platelet accumulation were significantly higher in patients with CM than in those without it. Platelet accumulation occurs in the microvasculature of patients with CM and may play a role in the pathogenesis of the disease.

Temperature compensation contributes to the accuracy of biological timing by preventing circadian rhythms from running more quickly at high than at low temperatures. We previously identified quantitative trait loci (QTL) with temperature-specific effects on the circadian rhythm of leaf movement, including a QTL linked to the transcription factor FLOWERING LOCUS C (FLC). We have now analyzed FLC alleles in near-isogenic lines and induced mutants to eliminate other candidate genes. We showed that FLC lengthened the circadian period specifically at 27 degrees C, contributing to temperature compensation of the circadian clock. Known upstream regulators of FLC expression in flowering time pathways similarly controlled its circadian effect. We sought to identify downstream targets of FLC regulation in the molecular mechanism of the circadian clock using genome-wide analysis to identify FLC-responsive genes and 3503 transcripts controlled by the circadian clock. A Bayesian clustering method based on Fourier coefficients allowed us to discriminate putative regulatory genes. Among rhythmic FLC-responsive genes, transcripts of the transcription factor LUX ARRHYTHMO (LUX) correlated in peak abundance with the circadian period in flc mutants. Mathematical modeling indicated that the modest change in peak LUX RNA abundance was sufficient to cause the period change due to FLC, providing a molecular target for the crosstalk between flowering time pathways and circadian regulation.

Chronic diarrhoea is a common problem, hence clear guidance on investigations is required. This is an updated guideline from 2003 for the investigations of chronic diarrhoea commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). This document has undergone significant revision in content through input by 13 members of the Guideline Development Group (GDG) representing various institutions. The GRADE system was used to appraise the quality of evidence and grading of recommendations.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Retroperitoneal masses not arising from major solid organs are uncommon. Although there is no simple method of classifying retroperitoneal masses, a reasonable approach is to consider the masses as predominantly solid or cystic and to subdivide these into neoplastic and nonneoplastic masses. Because the treatment options vary, it is useful to be able to differentiate these masses by using imaging criteria. Although the differential diagnosis of retroperitoneal masses can be narrowed down to a certain extent on the basis of imaging characteristics, patterns of involvement, and demographics, there is still a considerable overlap of imaging findings for these masses, and histologic examination is often required for definitive diagnosis. Computed tomography (CT) and magnetic resonance (MR) imaging play an important role in characterization and in the assessment of the extent of the disease and involvement of adjacent and distant structures. Familiarity with the CT and MR imaging features of various retroperitoneal masses will facilitate accurate diagnosis and staging for aggressive lesions.

Caesium (Cs+) is a potentially toxic mineral element that is released into the environment and taken up by plants. Although Cs+ is chemically similar to potassium (K+), and much is known about K+ transport mechanisms, it is not clear through which K+ transport mechanisms Cs+ is taken up by plant roots. In this study, the role of AtHAK5 in high affinity K+ and Cs+ uptake was characterized. It is demonstrated that AtHAK5 is localized to the plasma membrane under conditions of K+ deprivation, when it is expressed. Growth analysis showed that AtHAK5 plays a role during severe K+ deprivation. Under K+-deficient conditions in the presence of Cs+, Arabidopsis seedlings lacking AtHAK5 had increased inhibition of root growth and lower Cs+ accumulation, and significantly higher leaf chlorophyll concentrations than wild type. These data indicate that, in addition to transporting K+ in planta, AtHAK5 also transports Cs+. Further experiments showed that AtHAK5 mediated Cs+ uptake into yeast cells and that, although the K+ deficiency-induced expression of AtHAK5 was inhibited by low concentrations of NH4+ in planta, Cs+ uptake by yeast was stimulated by low concentrations of NH4+. Interestingly, the growth of the Arabidopsis atakt1-1 mutant was more sensitive to Cs+ than the wild type. This may be explained, in part, by increased expression of AtHAK5 in the atakt1-1 mutant. It is concluded that AtHAK5 is a root plasma membrane uptake mechanism for K+ and Cs+ under conditions of low K+ availability.

BACKGROUND: The incidence of blossom-end rot (BER) is generally associated with a calcium (Ca) deficiency in the distal portion of tomato fruits. The visible symptom is a necrotic lesion, which is presumed to be a consequence of cell death and the subsequent leakage of solutes into the extracellular space. Environmental factors that affect either fruit cell expansion or Ca delivery to the distal portion of the fruit influence the occurrence of BER. However, since no absolute, critical fruit Ca concentration for the occurrence of BER has been identified, it is now important to define the role of Ca in fruit cell physiology and to seek the cause of BER at the cellular level. HYPOTHESIS: Here, it is suggested that BER is initiated by a cellular dysfunction in the distal portion of a young fruit during rapid cell expansion. It is proposed that insufficient Ca(2+) is available for critical apoplastic and cytoplasmic functions when the cellular Ca demand imposed by vacuolation exceeds the Ca delivery to an expanding cell. A local Ca deficiency, therefore, may result in aberrant intracellular Ca(2+) signals, a weakening of cell walls and a loss of cellular integrity. Ultimately it may lead to cell death and the visible symptoms of BER. Several experimental strategies are suggested to confirm the occurrence of aberrant Ca(2+) concentrations in cells contributing to BER. PERSPECTIVE: Many genetic and genomic resources are becoming available for tomato. Ultimately, these will allow genes affecting the occurrence of BER to be identified. Such knowledge will inform breeding strategies to eliminate BER. In the meanwhile, increasing the apoplastic Ca concentration in susceptible fruit tissue should provide a simple and reliable, practical solution for the prevention of BER in tomatoes. It is suggested that current horticultural practices, such as the manipulation of the mineral composition of the feed or the growth environment, are not completely effective in reducing BER because they affect apoplastic Ca concentration in fruit tissue indirectly. Therefore, spraying Ca directly onto young fruits is recommended for the prevention of BER.

Phyllodes tumours are rare fibroepithelial lesions that account for less than 1% of all breast neoplasms. With the non-operative management of fibroadenomas widely adopted, the importance of phyllodes tumours today lies in the need to differentiate them from other benign breast lesions. All breast lumps should be triple assessed and the diagnosis of a phyllodes tumour considered in women, particularly over the age of 35 years, who present with a rapidly growing "benign" breast lump. Treatment can be by either wide excision or mastectomy provided histologically clear specimen margins are ensured. Nodal metastases are rare and routine axillary dissection is not recommended. Few reliable clinical and histological prognostic factors have been identified. Local recurrence occurs in approximately 15% of patients and is more common after incomplete excision. It can usually be controlled by further surgery. Repeated local recurrence has been reported without the development of distant metastases or reduced survival. Approximately 20% of patients with malignant phyllodes tumours develop distant metastases. Long term survival with distant metastases is rare. The role of chemotherapy, radiotherapy, and hormonal manipulation in both the adjuvant and palliative settings remain to be defined.

Adipose tissue is an active endocrine organ, and our knowledge of this secretory tissue, in recent years, has led us to completely rethink how our body functions and becomes dysregulated with weight gain. Human adipose tissue appears to act as a multifunctional secretory organ with the capacity to control energy homoeostasis through peripheral and central regulation of energy homoeostasis. It also plays an important role in innate immunity. However, the capability to more than double its original mass to cope with positive energy balance in obesity leads to many pathogenic changes. These changes arise within the adipose tissue as well as inducing secondary detrimental effects on other organs like muscle and liver, including chronic low-grade inflammation mediated by adipocytokines (adipokine inflammation). This inflammation is modulated by dietary factors and nutrients including glucose and lipids, as well as gut bacteria in the form of endotoxin or LPS. The aim of this current review is to consider the impact of nutrients such as glucose and lipids on inflammatory pathways, specifically within adipose tissue. Furthermore, how nutrients such as these can influence adipokine inflammation and consequently insulin resistance directly through their effects on secretion of adipocytokines (TNFα, IL6 and resistin) as well as indirectly through increases in endotoxin is discussed.

In dicots, pectins are the major structural determinant of the cell wall at the pollen tube tip. Recently, immunological studies revealed that esterified pectins are prevalent at the apex of growing pollen tubes, where the cell wall needs to be expandable. In contrast, lateral regions of the cell wall contain mostly de-esterified pectins, which can be cross-linked to rigid gels by Ca(2+) ions. In pollen tubes, several pectin methylesterases (PMEs), enzymes that de-esterify pectins, are co-expressed with different PME inhibitors (PMEIs). This raises the possibility that interactions between PMEs and PMEIs play a key role in the regulation of cell-wall stability at the pollen tube tip. Our data establish that the PME isoform AtPPME1 (At1g69940) and the PMEI isoform AtPMEI2 (At3g17220), which are both specifically expressed in Arabidopsis pollen, physically interact, and that AtPMEI2 inactivates AtPPME1 in vitro. Furthermore, transient expression in tobacco pollen tubes revealed a growth-promoting activity of AtPMEI2, and a growth-inhibiting effect of AtPPME1. Interestingly, AtPPME1:YFP accumulated to similar levels throughout the cell wall of tobacco pollen tubes, including the tip region, whereas AtPMEI2:YFP was exclusively detected at the apex. In contrast to AtPPME1, AtPMEI2 localized to Brefeldin A-induced compartments, and was found in FYVE-induced endosomal aggregates. Our data strongly suggest that the polarized accumulation of PMEI isoforms at the pollen tube apex, which depends at least in part on local PMEI endocytosis at the flanks of the tip, regulates cell-wall stability by locally inhibiting PME activity.