BSHI/BTS guidance on crossmatching before deceased donor kidney transplantation.

All UK H&I laboratories and transplant units operate under a single national kidney offering policy, but there have been variations in approach regarding when to undertake the pre-transplant crossmatch test. In order to minimize cold ischaemia times for deceased donor kidney transplantation we sought to find ways to be able to report a crossmatch result as early as possible in the donation process. A panel of experts in transplant surgery, nephrology, specialist nursing in organ donation and H&I (all relevant UK laboratories represented) assessed evidence and opinion concerning five factors that relate to the effectiveness of the crossmatch process, as follows: when the result should be ready for reporting; what level of donor HLA typing is needed; crossmatch sample type and availability; fairness and equity; risks and patient safety. Guidelines aimed at improving practice based on these issues are presented, and we expect that following these will allow H&I laboratories to contribute to reducing CIT in deceased donor kidney transplantation.

C-Reactive Protein and Covid-19 Severity: A Systematic Review.

BACKGROUND: COVID-19 clinical course has been quite unpredictable and efforts have been made to identify reliable markers that will help in early disease progression, prognosis and severity detection. Objective: This study thus aimed to provide evidence that will guide clinical management by reviewing studies that assessed CRP concentration and COVID-19 severity/outcome. METHODS: Three electronic databases, PubMed/Medline, Google Scholar, and JSTOR were searched to identify studies available online as at 1st September 2020 which assessed COVID-19 clinical outcome and CRP concentration. The search strategy involved words combination like "C-reactive protein" OR "inflammatory markers" OR "acute phase reactants" and "coronavirus 2019" OR ''COVID-19" OR "2019-nCoV" OR "SARS-CoV-2". RESULTS: Sixty-one articles were systematically reviewed out of 812 studies identified after duplicates were removed. The 61 studies comprised 13,891 COVID-19 patients made of 7,840 (56.4%) males and 6,051 (43.6%) females. All the papers revised were observational studies except one case-control and they cut across fifteen countries. The result of the review demonstrated that the severe cases had higher levels of C - reactive protein when compared to the mild cases in all the studies (100%). The increase in C-reactive protein was statistically significant in 78.7% of the cases. CONCLUSION: High levels of CRP are associated with COVID-19 severity. Highlights: Severe cases of COVID-19 is characterized with higher CRP levels. COVID-19 cases should be screened regularly for CRP to monitor severity.

Contexte: L'évolution clinique du COVID-19 a été assez imprévisible et des efforts ont été faits pour identifier des marqueurs fiables qui aideront à la progression précoce de la maladie, au pronostic et à la détection de la gravité. Objectif : Cette étude visait donc à fournir des preuves qui guideront la gestion clinique en passant en revue les études qui ont évalué la concentration de CRP et la gravité/l'issue du COVID-19. Méthodes: Trois bases de données électroniques, PubMed/Medline, Google Scholar et JSTOR, ont été consultées pour identifier les études disponibles en ligne au 1er septembre 2020 qui évaluaient le résultat clinique du COVID-19 et la concentration de CRP. La stratégie de recherche comportait des combinaisons de mots comme "protéine Créactive" OU "marqueurs inflammatoires" OU "réactifs de phase aiguë" et "coronavirus 2019" OU "COVID-19" OU "2019-nCoV" OU "SARS-CoV-2". Résultats: Soixante et un articles ont été systématiquement examinés sur les 812 études identifiées après suppression des doublons. Les 61 études comprenaient 13 891 patients atteints de COVID-19, dont 7 840 (56,4 %) hommes et 6 051 (43,6 %) femmes. Tous les articles examinés étaient des études d'observation, à l'exception d'un cas-témoin, et ils couvraient quinze pays. Le résultat de l'examen a démontré que les cas graves avaient des niveaux plus élevés de protéine C-réactive par rapport aux cas légers dans toutes les études (100%). L'augmentation de la protéine C-réactive était statistiquement significative dans 78,7% des cas. Conclusion: Des niveaux élevés de CRP sont associés à la sévérité du COVID-19. Mots clés: Protéine C-réactive, COVID-19, SRAS-COV-2 et Coronavirus. Points forts: Les cas graves de COVID-19 sont caractérisés par des niveaux de CRP plus élevés. · Les cas de COVID-19 doivent faire l'objet d'un dépistage régulier de la CRP afin de surveiller la gravité de la maladie.

The effect of source of supplemental dietary calcium and magnesium in the peripartum period, and level of dietary magnesium postpartum, on mineral status, performance, and energy metabolites in multiparous Holstein cows.

The objective of this study was to determine the effects of feeding different supplemental sources of Ca and Mg in the peripartum period, and different dietary levels of Mg postpartum, on plasma mineral status, performance, and aspects of energy metabolism in transition dairy cows. Multiparous Holstein cows (n = 41) were used in a completely randomized design with a 2 × 2 factorial arrangement of treatments starting at 28 d before expected parturition. Main effects were source assignments (CS = common sources of supplemental Ca and Mg, or MA = a blend of common and commercial mineral sources with supplemental minerals primarily from a commercial Ca-Mg dolomite source; MIN-AD, Papillon Agricultural Company Inc., Easton, MD) beginning at 21 d before due date; cows were further randomized within source treatments to 1 of 2 levels of Mg supplementation (LM = formulated postpartum diet Mg at 0.30% of dry matter (DM), or HM = formulated postpartum diet Mg at 0.45% of DM) beginning within 1 d after parturition. Final treatment groups included the following: common source, low Mg (CS-LM, n = 11); common source, high Mg (CS-HM, n = 11); MIN-AD, low Mg (MA-LM, n = 10); and MIN-AD, high Mg (MA-HM, n = 9). Treatment diets were fed and data collected through 42 d in milk. Postpartum plasma Mg concentrations tended to be higher for cows fed HM and cows fed CS, but no effects were observed on peripartum plasma Ca concentrations. Peripartum plasma P concentrations were higher for cows fed MA. Dry matter intake (DMI) in the prepartum period was higher for cows fed MA (CS = 15.9 vs. MA = 16.8 kg/d) and postpartum DMI was higher in some groups depending on week. Plasma nonesterified fatty acid concentrations were lower for cows fed MA during both the prepartum and postpartum periods. A source by level interaction was observed for postpartum plasma ß-hydroxybutyrate (BHB) concentrations such that cows fed CS-LM had numerically higher BHB and cows fed MA-LM had numerically lower BHB (geometric means; CS-LM = 7.9, CS-HM = 6.9, MA-LM = 6.3, and MA-HM = 7.3 mg/dL) than cows fed the other 2 treatments. Higher milk fat yield, milk fat content, and fat- and energy-corrected yield during wk 1 for cows fed MA resulted in source by week interactions for these outcomes. This study demonstrated that varying supplemental Ca and Mg sources and feeding rates had minimal effect on plasma Ca status despite differences in plasma Mg and P concentrations. Effects on DMI and plasma energy metabolites suggest an opportunity for strategic use of mineral sources in the transition period to promote metabolic health.

Transitional B lymphocytes are associated with protection from kidney allograft rejection: a prospective study.

Recent cross-sectional studies suggest an important role for transitional B lymphocytes (CD19 + CD24hiCD38hi) in promoting transplant tolerance, and protecting from late antibody-mediated rejection (ABMR). However, prospective studies are lacking. This study enrolled 73 de novo transplant recipients, and collected serial clinical, immunological and biochemical information over 48 ± 6 months. Cell phenotyping was conducted immediately prior to transplantation, and then on five occasions during the first year posttransplantation. When modeled as a time-dependent covariate, transitional B cell frequencies (but not total B cells or "regulatory" T cells) were associated with protection from acute rejection (any Banff grade; HR: 0.60; 95% CI: 0.37-0.95; p = 0.03). No association between transitional B cell proportions and either de novo donor-specific or nondonor-specific antibody (dnDSA; dnNDSA) formation was evident, although preserved transitional B cell proportions were associated with reduced rejection rates in those patients developing dnDSA. Three episodes of ABMR occurred, all in the context of nonadherence, and all associated with in vitro anti-HLA T cell responses in an ELISPOT assay (p = 0.008 versus antibody-positive patients not experiencing ABMR). This prospective study supports the potential relevance of transitional ("regulatory") B cells as a biomarker and therapeutic intervention in transplantation, and highlights relationships between humoral immunity, cellular immunity and nonadherence.

Meeting report: 3rd international transplant conference: how much risk can you take?

The 3rd International Transplant Conference took place on 31st October and 1st November 2014 at the University of Warwick, Coventry, UK. Key focal points of the meeting were the exploration of the molecular basis of antibody-antigen interactions and their relation to clinical practice and to share experiences and knowledge regarding strategies to transplant the 'high-risk' patient. In addition, lively debate sessions were hosted where controversial clinical and immunological themes were discussed by leading experts in the field.

Influence of preformed donor-specific antibodies and C4d on early liver allograft function.

INTRODUCTION. The impact of preformed donor-specific antibodies (DSA) is incompletely understood in liver transplantation. The incidence and impact of preformed DSA on early post liver transplant were assessed and these were correlated with compliment fragment C4d on allograft biopsy. METHODS. Pretransplant serum from 41 consecutive liver transplant recipients (brain dead donors; DBD = 27 and cardiac death donors; DCD = 14) were tested for class-specific anti-human leukocyte antigen (HLA) and compared against donor HLA types. Liver biopsies were taken during cold storage (t-1) and post-reperfusion (t0) stained with C4d and graded for preservation-reperfusion injury (PRI). RESULTS. Of the 41 recipients, 8 (20%) had anti-HLA class I/II antibodies pretransplant, 3 (7%) were confirmed preformed DSA; classes I and II (n=1) and class I only (n=2). No biopsies showed definite evidence of antibody-mediated rejection. Graft biopsies in overall showed only mild PRI with ischemic hepatocyte C4d pattern similar in both positive and negative DSA patients. One DSA-positive (33%) compared with four DSA-negative patients (10%) had significant early graft dysfunction; severe PRI causing graft loss from primary nonfunction was seen only in DSA-negative group. Allograft biopsy of preformed DSA-positive patient demonstrated only minimal PRI; however, no identifiable cause could be attributed to graft dysfunction other than preformed DSA. CONCLUSION. Preformed DSA are present in 5-10% liver transplant recipients. There is no association between anti-HLA DSA and PRI and C4d, but preformed DSA may cause early morbidity. Larger studies on the impact of DSA with optimization of C4d techniques are required.

Redox-mediated substrate recognition by Sdp1 defines a new group of tyrosine phosphatases.

Reactive oxygen species trigger cellular responses by activation of stress-responsive mitogen-activated protein kinase (MAPK) signalling pathways. Reversal of MAPK activation requires the transcriptional induction of specialized cysteine-based phosphatases that mediate MAPK dephosphorylation. Paradoxically, oxidative stresses generally inactivate cysteine-based phosphatases by thiol modification and thus could lead to sustained or uncontrolled MAPK activation. Here we describe how the stress-inducible MAPK phosphatase, Sdp1, presents an unusual solution to this apparent paradox by acquiring enhanced catalytic activity under oxidative conditions. Structural and biochemical evidence reveals that Sdp1 employs an intramolecular disulphide bridge and an invariant histidine side chain to selectively recognize a tyrosine-phosphorylated MAPK substrate. Optimal activity critically requires the disulphide bridge, and thus, to the best of our knowledge, Sdp1 is the first example of a cysteine-dependent phosphatase that couples oxidative stress with substrate recognition. We show that Sdp1, and its paralogue Msg5, have similar properties and belong to a new group of phosphatases unique to yeast and fungal taxa.

Developmental expression pattern screen for genes predicted in the C. elegans genome sequencing project.

Maximum use should be made of information generated in the genome sequencing projects. Toward this end, we have initiated a genome sequence-based, expression pattern screen of genes predicted from the Caenorhabditis elegans genome sequence data. We examined beta-galactosidase expression patterns in C. elegans lines transformed with lacZ reporter gene fusions constructed using predicted C. elegans gene promoter regions. Of the predicted genes in the cosmids analysed so far, 67% are amenable to the approach and 54% of examined genes yielded a developmental expression pattern. Expression pattern information is being made generally available using computer databases.

Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly.

Glial-cell line derived neurotrophic factor (GDNF) bound to its co-receptor GFRα1 stimulates the RET receptor tyrosine kinase, promoting neuronal survival and neuroprotection. The GDNF-GFRα1 complex also supports synaptic cell adhesion independently of RET. Here, we describe the structure of a decameric GDNF-GFRα1 assembly determined by crystallography and electron microscopy, revealing two GFRα1 pentamers bridged by five GDNF dimers. We reconsitituted the assembly between adhering liposomes and used cryo-electron tomography to visualize how the complex fulfils its membrane adhesion function. The GFRα1:GFRα1 pentameric interface was further validated both in vitro by native PAGE and in cellulo by cell-clustering and dendritic spine assays. Finally, we provide biochemical and cell-based evidence that RET and heparan sulfate cooperate to prevent assembly of the adhesion complex by competing for the adhesion interface. Our results provide a mechanistic framework to understand GDNF-driven cell adhesion, its relationship to trophic signalling, and the central role played by GFRα1.

A soft-bodied lophophorate from the Silurian of England.

Soft-bodied taxa comprise an important component of the extant lophophorate fauna, but convincing fossils of soft-bodied lophophorates are extremely rare. A small fossil lophophorate, attached to a brachiopod dorsal valve, is described from the Silurian (Wenlock Series) Herefordshire Lagerstätte of England. This unmineralized organism was bilaterally symmetrical and comprised a subconical body attached basally to the host and partially enclosed by a broad 'hood'; the body bore a small, coiled lophophore. Where the hood attached laterally, there is a series of transverse ridges and furrows. The affinities of this organism probably lie with Brachiopoda; the hood is interpreted as the homologue of a dorsal valve/mantle lobe, and the attachment as the homologue of the ventral valve and/or pedicle. The ridges are arranged in a manner that suggests constructional serial repetition, indicating that they are unlikely to represent mantle canals. Extant brachiopods are not serially structured, but morphological and molecular evidence suggests that their ancestors were. The new organism may belong to the brachiopod stem group, and might also represent a significant element of the Palaeozoic lophophorate fauna.

British Society for Histocompatibility & Immunogenetics and British Transplantation Society guidelines for the detection and characterisation of clinically relevant antibodies in allotransplantation.

Ongoing technological developments in antibody detection and characterisation allowing relative quantitation of HLA-specific antibody levels, combined with crossmatch results, now allow a graded assessment of patient potential donor immunological risk for allotransplantation, rather than a simple 'positive' or 'negative' categorization of crossmatch results. These developments have driven a thorough revision of the British Society for Histocompatibility & Immunogenetics and British Transplantation Society Guidelines for the Detection and Characterisation of Clinically Relevant Antibodies in Allotransplantation. These newly published revised Guidelines contain a number of recommendations as to best practice for antibody detection and crossmatching for the transplantation of a wide range of solid organs and tissues. These recommendations are briefly summarized in this article.

The Thai-Australian Health Alliance: developing health management capacity and sustainability for primary health care services.

CONTEXT: There have been recent calls for a renewed worldwide focus on primary health care. The Thai-Australian Health Alliance addresses this call by developing health care management capability in primary health care professionals in rural Thailand. OBJECTIVES: This paper describes the history and current activities of the Thai-Australian Health Alliance and its approaches to developing health care management capacity for primary care services through international collaborations in research, education and training over a sustained time period. METHODS: The Alliance's approach is described herein as a distributed network of practices with access to shared knowledge through collaboration. Its research and education approaches involve action research, multi-methods projects, and evaluative studies in the context of workshops and field studies. WHO principles underpin this approach, with countries sharing practical experiences and outcomes, encouraging leadership and management resource networks, creating clearing houses/knowledge centres, and harmonising and aligning partners with their country's health systems. FINDINGS: Various evaluations of the Alliance's activities have demonstrated that a capacity building approach that aligns researchers, educators and health practitioners in comparative and reflective activities can be effective in transferring knowledge and skills among a collaboration's partners. Project participants, including primary health care practitioners, health policy makers and academics embraced the need to acquire management skills to sustain primary care units. Participants believe that the approaches described herein were crucial to developing the management skills needed of health care professionals for rural and remote primary health care. The implementation of this initiative was challenged by pre-existing low opinions of the importance of the management role in health care, but with time the Alliance's activities highlighted for all the importance of health care management. Acceptance of its activities and goals are evidenced by the establishment of a Centre of Leadership Expertise in Health Management and the endorsement of the Phitsanulok Declaration by more than 470 primary health care practitioners, academics and policy makers. DISCUSSION AND CONCLUSION: Problems with the primary health care delivery system in rural Thailand continue, but the Alliance has successfully implemented a cross cultural strategic collaboration through a continuity of activities to augment practice management capacities in primary care practices.

[The fight against rabies in Africa: from recognition to action]. / Lutte contre la rage en Afrique: du constat à l'action.

As a follow-up to the first AfroREB (Africa Rabies Expert Bureau) meeting, held in Grand-Bassam (Côte-d'Ivoire) in March 2008, African rabies experts of the Afro-REB network met a second time to complete the evaluation of the rabies situation in Africa and define specific action plans. About forty French speaking rabies specialists from Northern, Western and Central Africa and Madagascar met in Dakar (Senegal), from March 16th to 19th, 2009. With the participation of delegates from Tunisia, who joined the AfroREB network this year, 15 French speaking African countries were represented. Experts from the Institut Pasteur in Paris, the Alliance for Rabies Control, and the Southern and Eastern African Rabies Group (SEARG, a network of rabies experts from 19 English speaking Southern and Eastern African countries) were in attendance, to participate in the discussion and share their experiences. AfroREB members documented 146 known human rabies cases in all represented countries combined for 2008, for a total population of 209.3 million, or an incidence of 0.07 cases per 100,000 people. Even admitting that the experts do not have access to all reported cases, this is far from the WHO estimation of 2 rabies deaths per 100,000 people in urban areas and 3.6 per 100,000 in rural Africa. It was unanimously agreed that the priority is to break the vicious cycle of indifference and lack of information which is the main barrier to human rabies prevention.

Three-dimensional visualization as a tool for interpreting locomotion strategies in ophiuroids from the Devonian Hunsrück Slate.

Living brittle stars (Echinodermata: Ophiuroidea) employ a very different locomotion strategy to that of any other metazoan: five or more arms coordinate powerful strides for rapid movement across the ocean floor. This mode of locomotion is reliant on the unique morphology and arrangement of multifaceted skeletal elements and associated muscles and other soft tissues. The skeleton of many Palaeozoic ophiuroids differs markedly from that in living forms, making it difficult to infer their mode of locomotion and, therefore, to resolve the evolutionary history of locomotion in the group. Here, we present three-dimensional digital renderings of specimens of six ophiuroid taxa from the Lower Devonian Hunsrück Slate: four displaying the arm structure typical of Palaeozoic taxa (Encrinaster roemeri, Euzonosoma tischbeinianum, Loriolaster mirabilis, Cheiropteraster giganteus) and two (Furcaster palaeozoicus, Ophiurina lymani) with morphologies more similar to those in living forms. The use of three-dimensional digital visualization allows the structure of the arms of specimens of these taxa to be visualized in situ in the round, to our knowledge for the first time. The lack of joint interfaces necessary for musculoskeletally-driven locomotion supports the interpretation that taxa with offset ambulacrals would not be able to conduct this form of locomotion, and probably used podial walking. This approach promises new insights into the phylogeny, functional morphology and ecological role of Palaeozoic brittle stars.

Association between modelled traffic-related air pollution and asthma score in the ECRHS.

The aim of our analysis was to study the association between air pollution and asthma among adults. For this goal, a previously developed "asthma score" was used. Persons aged 25-44 yrs were randomly selected (1991-1993) and followed up (2000-2002) within the European Community Respiratory Health Survey (ECRHS I and II, respectively). The asthma score was defined from 0 to 5, based on the positive answers to the following symptoms reported for the last 12 months: wheeze/breathlessness, chest tightness, dyspnoea at rest, dyspnoea after exercise and woken by dyspnoea. Participants' home addresses were linked to outdoor modelled NO2 estimates for 2001. Negative binomial regression was used to model the asthma score. The score from ECRHS II was positively associated with NO2 (ratio of the mean asthma score (RMS) 1.23, 95% CI 1.09-1.38, for an increase of 10 microg x m(-3)). After excluding participants with asthma and symptoms at baseline, the association remained (RMS 1.25, 95% CI 1.05-1.51), and was particularly high among those reporting a high score in ECRHS II. The latter probably reflects incident cases of asthma. Our results suggest that traffic-related pollution causes asthma symptoms and possibly asthma incidence in adults. The asthma score offers an alternative with which to investigate the course and aetiology of asthma in adults.

Ethnic variability in human leukocyte antigen-E haplotypes.

Human leukocyte antigen-E (HLA-E) is an important nonclassical major histocompatibility complex (MHC) class I (Ib) molecule that acts as the ligand for NKG2A/B/C receptors expressed on natural killer (NK) cells and T cells. Unlike the classical class I molecules, HLA-E is highly conserved in evolution and the biological significance of polymorphism is therefore unclear. Our aim was to investigate the polymorphism in HLA-E gene in three ethnic groups in the UK and to obtain population data relating to any variations observed at this locus. We developed a polymerase chain reaction-sequence-specific primer (PCR-SSP) method for identifying HLA-E single nucleotide polymorphisms (SNPs) in genomic DNA. This was used to investigate the genotype distribution and allele frequency of nine published SNPs in the coding region of HLA-E in 223 Euro-Caucasoid, 60 Afro-Caribbean and 52 Asian healthy individuals. Genotype frequencies were in Hardy-Weinberg equilibrium. No polymorphism was observed for seven previously reported SNPs and these should not be considered polymorphic. However, positions 1114 and 1446 were confirmed as polymorphic and different genotype frequencies were identified at nucleotide position 1114 between the three studied ethnic groups. We present these data together with the intragene haplotype frequencies in these populations. To our knowledge, this is the first description of population frequencies of nine different SNPs in HLA-E in three main large ethnic groups. The data generated from this study will be of importance in the context of describing the effect of HLA-E polymorphism in clinical settings such as transplantation and autoimmune diseases.

Vertebroplasty and kyphoplasty are associated with an increased risk of secondary vertebral compression fractures: a population-based cohort study.

UNLABELLED: To better understand the risk of secondary vertebral compression fracture (VCF) following a vertebroplasty or kyphoplasty, we compared patients treated with those procedures to patients with a previous VCF. The risk of subsequent fracture was significantly greater among treatment patients, especially within 90 days of the procedure. INTRODUCTION: Predominantly uncontrolled studies suggest a greater risk of subsequent vertebral compression fractures (VCFs) associated with vertebroplasty/kyphoplasty. To further understand this risk, we conducted a population-based retrospective cohort study using data from a large regional health insurer. METHODS: Administrative claims procedure codes were used to identify patients receiving either a vertebroplasty or kyphoplasty (treatment group) and a comparison group of patients with a primary diagnosis of VCF who did not receive treatment during the same time period. The main outcomes of interest, validated by two independent medical record reviewers, were any new VCFs within (1) 90 days, (2) 360 days, and (3) at adjacent vertebral levels. Multivariable logistic regression examined the association of vertebroplasty/kyphoplasty with new VCFs. RESULTS: Among 48 treatment (51% vertebroplasty, 49% kyphoplasty) and 164 comparison patients, treated patients had a significantly greater risk of secondary VCFs than comparison patients for fractures within 90 days of the procedure or comparison group time point [adjusted odds ratio (OR) = 6.8; 95% confidence interval (CI) 1.7-26.9] and within 360 days (adjusted OR = 2.9; 95% CI 1.1-7.9). CONCLUSIONS: Patients who had undergone vertebroplasty/kyphoplasty had a greater risk of new VCFs compared to patients with prior VCFs who did not undergo either procedure.

New burgess shale fossil sites reveal middle cambrian faunal complex.

Soft-bodied and lightly sclerotized Burgess shale fossils have been found at more than a dozen new localities in an area extending for 20 kilometers along the front of the Cathedral Escarpment in the Middle Cambrian Stephen Formation of the Canadian Rockies. Five different fossil assemblages from four stratigraphic levels have been recognized. These assemblages represent distinct penecontemporaneous marine communities that together make up a normal fore-reef faunal complex.