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Introduction: Red blood cell transfusions (RBCT) represent a potentially modifiable risk factor for HLA sensitisation and adverse outcomes post transplantation. Evidence of the clinical impact of post-transplant RBCT has been infrequently reported. Herein, we performed a systematic review of available literature to assess the prevalence of RBCT post kidney transplant, and the effect of transfusion on transplant outcomes. Methods: We included studies from 2000 to July 2022, published on Medline, Embase and the Transplant Library. Results: Ten studies were analysed which included a total of 32,817 kidney transplant recipients, with a median transfusion prevalence of 40% (range 18-64%). There was significant heterogeneity between studies in terms of patient and allograft characteristics, immunological risk, and immunosuppression protocols. Analysis of unadjusted outcomes showed that post-transplant RBCTs are associated with inferior patient survival, allograft loss, rejection and donor specific antibodies. Adjusted outcomes were described where available, and supported the adverse associations seen in the unadjusted models in many studies. Discussion: This review demonstrates that RBCT post-transplant are common and maybe associated with inferior outcomes, highlighting the urgent need for high quality prospective evidence of the effect of RBCTs on transplant outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier, CRD42022348763767.

We compared neutralising antibody titres of convalescent samples collected before and after the emergence of novel strains of SARS-CoV-2, against the wild-type virus (WT), Alpha (B.1.1.7) and Beta (B.1.351) variants. Plasma collected in 2020 before emergence of variants showed reduced titres against the Alpha variants, and both sets of samples demonstrated significantly reduced titres against Beta. Comparison of microneutralisation titres to those obtained with pseudotype and HAT assays showed a good correlation of titres and effects of strain variation, supporting the use of these simpler assays for assessment of convalescent plasma potency against currently circulating and emerging strains of SARS-CoV-2.

Background Convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation for COVID-19 treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial that potentially influence treatment outcomes. Methods SARS-CoV-2 RNA in nasopharyngeal swabs collected pre-treatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. Results Of 1274 subjects, 90% were PCR-positive with viral loads 118-1.7x10 11 IU/ml. Median viral loads were 40-fold higher in those seronegative for IgG antibodies (n=354; 28%) compared to seropositives (n=939; 72%). Frequencies of B.1.1.7 increased from

The rodent Pig-a assay is a flow cytometric, phenotype-based method used to measure in vivo somatic cell mutation. An Organization for Economic Co-operation and Development (OECD) test guideline is currently being developed to support routine use of the assay for regulatory purposes (OECD project number 4.93). This article provides advice on best practices for designing and conducting rodent Pig-a studies in support of evaluating test substance safety, with a focus on the rat model. Various aspects of assay conduct, including laboratory proficiency, minimum number of animals per dose group, preferred treatment and blood sampling schedule, and statistical analysis are described.

Diffusion tensor magnetic resonance imaging (DTI) can be used to reconstruct the brachial plexus in 3D via tracts connecting contiguous diffusion tensors with similar primary eigenvector orientations. When creating DTI tractograms, the turning angle of connecting lines (step angle) must be prescribed by the user; however, the literature is lacking detailed geometry of brachial plexus to inform such decisions. Therefore, the spinal cord and brachial plexus of 10 embalmed adult cadavers were exposed bilaterally by posterior dissection. Photographs were taken under standardised conditions and spatially calibrated in MATLAB. The roots of the brachial plexus were traced from the dorsal root entry zone for 5 cm laterally using a 2.5-mm2 Cartesian grid overlay. The trace was composed of points connected by lines, and the turning angle between line segments (the step angle) was resolved. Our data show that the geometry of the roots increased in tortuosity from C5 to T1, with no significant differences between sides. The 1st thoracic root had the most tortuous course, turning through a maximum angle of 56° per 2.5 mm (99% CI 44° to 70°). Significantly higher step angles and greater variability were observed in the medial 2 cm of the roots of the brachial plexus, where the dorsal and ventral rootlets coalesce to form the spinal root. Throughout the brachial plexus, the majority of step angles (>50%) were smaller than 20° and

© 2020 The Authors. Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10 -4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Background and Aims: Awake craniotomy often results in postoperative aphasia. Over the last several decades, neurosurgical technologies have evolved, increasing resection precision for the surgeon (e.g., intraoperative fMRI). However, one ongoing concern reported by surgical teams is delineating the extent of tissue that can be safely resected – remove too little and one may not get the desired result; remove too much and one risks impairing language function. Despite technological advances and considerable progress in the neuroanatomy of language, the Penfield three-task approach (counting, naming, reading; based on the Wernicke-Geschwind model) for intraoperative language mapping remains the standard. Although this can elicit speech-arrest and “aphasic” errors, the basic tasks are not aligned with current language models and fail to probe subtler language functions that are often impaired postoperatively (De Witte & Marien, 2013). For example, stimulation of anterior and posterior cortex could invoke reading problems due to different reasons (e.g., phonology, vision). Preserving language function is therefore reliant on probing a spectrum of multimodal functions during cortical mapping. This requires a test-battery driven by a multifaceted theoretical framework (MRI, experimental neuropsychology etc.). The first step towards developing such a tool is to establish which intraoperative tasks are effective in mapping language function and minimising aphasic symptoms. Methods: A systematic review was conducted. Databases were searched for articles using key terms (e.g., “brain tumour” AND “neurosurgery” AND “language” etc.). This returned 7294 articles screened for inclusion by title, abstract and full-text by independent reviewers based on the following criteria: 1) patients aged >18 years; 2) brain tumour excision under awake conditions or general anaesthesia; 3) validated language outcomes for pre-, intra- and post-operative assessment. Data were extracted from eligible papers including intervention (intraoperative tasks) and outcomes (language function pre-, intra- and post-operatively), and are currently being analysed. Results: It is expected that adopting a multimodal approach will provide better outcomes than the traditional Penfield approach. For example, employing tasks engaging different input modalities (e.g., phonology, vision) and measuring a range of processes (e.g., rhyme judgement, pattern recognition) will provide a better profile of language functioning for the surgeon. Not all modalities and processes will be affected by the tumour and resection location so task delivery should be optimised as a function of patient group (e.g., semantic tasks are more beneficial for anterior temporal resection). Conclusions: For the first time the results from this review will allow predictions to be made regarding the best combination of tasks for mapping and preserving language function in and out of theatre. It will consider important factors such as tumour location, from which more valid conclusions may be reached on how to tailor interventions. Data from cortical mapping may also provide insights into the neuroanatomy of language. The findings will provide a basis for the development of specific tasks that comprehensively and concisely assess the functions associated with a particular region pre-, intra-, and post- operatively. Such a tool is not only relevant for craniotomy but for diagnosis of different language impairments in non-tumour patients.

We will present a new web-based resource for the assessment of language disorders in English monolinguals and Welsh/English bilingual adults with neurological deficits. Although both languages are typically affected in bilinguals, few valid tools are available to accurately and comprehensively assess both languages, and none in Welsh-English speakers. This impedes both accurate diagnosis and therapeutic efforts. The goal of this work was to provide a secure user-friendly platform to allow clinicians to administer and score tests on-line or offline. The battery includes 16 different tests developed to measure the same abilities in Welsh and in English and to be of comparable difficulty in the two languages. These tests assess a range of language skills: spoken word production (picture naming, naming to definition, translation, repetition), reading (reading aloud, lexical decision, paragraph reading) and written production (spelling to dictation, delayed copy, written picture description). The tests manipulate and/or control for key psycholinguistic variables (e.g., word frequency, length, concreteness, Welsh-English similarity, grammatical class, lexicality). In the on-line version, all tests are programmed to allow automatic and standardized presentation of auditory or visual stimuli. The program also records oral or written responses and response times for each stimulus, and provide summary scores broken down by stimulus category. Each test package includes: a) an introductory section explaining the test aims and rationale, b) instructions on how to administer the test, c) scoring instructions and scoring sheets and d) performance indicators (e.g., Z-score) based on control data from 120 neurologically healthy participants (40 English monolinguals and 80 Welsh-English bilinguals, broken down by age, language and educational level. The presentation will include demos of the interface and of computerized test administration and scoring. Note that this new resource is suitable for the assessment of both English monolingual and Welsh-English bilingual adults. ESRC/MRC; Bangor ESRC Impact Acceleration Account

Prosthesis embodiment, the feeling of a prosthesis being part of the user, is reported by some prosthesis users. Myoelectric prostheses are electrically powered which produce a delay with fixed and variable components. The latter introduces uncertainty over hand behaviour, likely influencing embodiment. Embodiment may also be influenced by hand appearance. An Immersive Virtual Reality experimental study is currently in preparation. It involves anatomically-intact participants to systematically measure the impact of movement delays and appearance on embodiment of a virtual prosthesis. This includes a head-mounted display and motion tracking of a myoelectric prosthesis, with various virtual appearances and hand-movement delays.

The aim of the proposed study is to determine if a virtual human can\ud evoke a measurable inhibitory response to anti-social stimuli within the prefrontal\ud cortex. Justification, protocol and demonstrator are described here. The work\ud follows a previous study demonstrating that neural inhibitory responses can be\ud measured within an immersive virtual reality display. We have adopted the approach\ud of combining functional Near Infrared Spectroscopy (fNIRS) and virtual reality\ud head-mounted display. Haemodynamic changes will be measured in healthy\ud participants and subsequently, subjects with mental deficits, as both engage in\ud interactions that seek to evoke a response that would normally be inhibited.\ud Disinhibition is an aspect of social response exaggerated by several deficits of mind,\ud including dementia, autism and Tourette’s syndrome. This research could improve\ud tools for understanding, diagnosis and treatment of such condition.

We present a technology demonstrator of the potential utility of our telepresence approach to supporting tele-therapy, in which client and remote therapist are immersed together. The aim is to demonstrate an approach in which a wide range of non-verbal communication between client and therapist can be contextualised within a shared simulation, even when the therapist is in the clinic and the client at home. The ultimate goal of the approach is to help the therapist to encourage the client to face a simulated threat while keeping them grounded in the safety of the present. The approach is to allow them to use non-verbal communication grounded in both the experience of the exposure and the current surroundings. While this is not new to exposure therapy, the challenges are: 1) to do this not only when the threat is simulated; and 2) when the client and therapist are apart. The technology approach combines immersive collaborative visualisation with free viewpoint 3D video based telepresence. The potential impact is to reduce dropout rate of exposure therapy for resistant clients.

Summary Data on the magnitude and risk factors for hypertension in sickle cell anaemia (SCA) are limited. A retrospective analysis of individuals with SCA aged ≥15 years enrolled from 2004–2014 at Muhimbili National Hospital, Tanzania was conducted to determine the prevalence, incidence and risk factors for hypertension. A total of 1013 individuals with SCA were analysed, of whom 571(56%) were females. The median age [interquartile range] was 17 [15–22] years. Four hundred and forty-one (44%) of the patients had relative hypertension [systolic blood pressure (SBP) 120–139 mmHg or diastolic blood pressure (DBP) 70–89 mmHg], and 79 (8%) had hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg). The incidence of hypertension was 64/1000 person years of observation and the 5-year survival rate was 0·71 [95% confidence interval (CI): 0·67–0·75]. In multivariate analysis, age>18 years, Hazard ratio (HR) 1·50 (95% CI: 1·03–2·18); pulse pressure, HR 0·64 (95% CI: 0·42 to 0·98); pulse rate, 1·02 (95% CI: 1·01–1·03); body mass index (BMI), HR 1·08 (95% CI: 1·03–1·13); blood transfusion, HR 2·50 (95% CI: 1·01–6·21) and haemoglobin, HR 1·12 (95% CI: 1·05–1·33) were independently associated with hypertension. In conclusion, despite the younger age, hypertension in this population was higher than that reported in others studies. Age, BMI, pulse pressure and haemoglobin were independently associated with hypertension in SCA.

Fetomaternal alloimmune thrombocytopenia (FMAIT) is the most common cause of severe neonatal thrombocytopenia in otherwise well, term infants. First pregnancies are often severely affected. This descriptive, population-based national study was undertaken in order to inform the case for antenatal screening. Cases were identified using three sources and capture-recapture techniques used to generate a robust incidence estimate. One hundred and seventy three cases were identified between October 2006 and September 2008. An extra 20 cases were estimated from capture-recapture analysis, giving an estimated incidence of clinically detected FMAIT of 12·4 cases per 100 000 total births (95%confidence interval: 10·7, 14·3). Fifty-two cases (30%) were known at the start of pregnancy; 120 (70%) were unknown (n=115) or unrecognized (n=5). Unknown cases were more likely to experience a haemorrhagic complication (67% vs. 5%) (P

Objective: Alloimmunization is a recognized complication of red blood cell (RBC) transfusion and causes delayed hemolytic transfusion reactions and provides problems sourcing compatible blood for future transfusions. Theobjective of this study was to determine the frequency of RBC alloimmunization in SCD patients in Tanzania where pretransfusion screening for alloantibodies is not practiced.Methods: In a cross-sectional study, SCD patients at Muhimbili Hospital Sickle Cell Clinic, Dar es Salaam, Tanzania, were investigated. The demographic characteristics and transfusion history were recorded. Blood samples were drawn from consenting, previously transfused patients and RBC alloimmunization was demonstrated using immunohematologic techniques.Results: There were 365 patients (median age, 16 years; 55.3% female) and they had received a median of 2 transfusion episodes. Fifteen patients (4.1%) possessed RBC alloantibodies. A total of 61 alloantibodies was found; 16 (26.2%) and 11 (18.0%), were directed against Kell and Rh blood group antigens, respectively.Conclusion: The rate of RBC alloimmunization in Tanzanian SCD patients was 4.1%. The low transfusion load may explain this immunization frequency. Nevertheless, our study confirms the significance of RBC alloimmunization as a complication in Tanzanian SCD patients. Therefore, there is need to improve immunohematologic testing in Tanzania so that RBC alloimmunization and its consequences may be prevented.Key Words: Red blood cell alloimmunization, Tanzanian sickle cell disease patients

Summary: Human induced pluripotent stem cells (hiPSCs), like embryonic stem cells, are under intense investigation for novel approaches to model disease and for regenerative therapies. Here, we describe the derivation and characterization of hiPSCs from a variety of sources and show that, irrespective of origin or method of reprogramming, hiPSCs can be differentiated on OP9 stroma towards a multi-lineage haemo-endothelial progenitor that can contribute to CD144+ endothelium, CD235a+ erythrocytes (myeloid lineage) and CD19+ B lymphocytes (lymphoid lineage). Within the erythroblast lineage, we were able to demonstrate by single cell analysis (flow cytometry), that hiPSC-derived erythroblasts express alpha globin as previously described, and that a sub-population of these erythroblasts also express haemoglobin F (HbF), indicative of fetal definitive erythropoiesis. More notably however, we were able to demonstrate that a small sub-fraction of HbF positive erythroblasts co-expressed HbA in a highly heterogeneous manner, but analogous to cord blood-derived erythroblasts when cultured using similar methods. Moreover, the HbA expressing erythroblast population could be greatly enhanced (44·0 ± 6·04%) when a defined serum-free approach was employed to isolate a CD31+ CD45+ erythro-myeloid progenitor. These findings demonstrate that hiPSCs may represent a useful alternative to standard sources of erythrocytes (RBCs) for future applications in transfusion medicine. © 2014 The Authors. British Journal of Haematology published by John Wiley and Sons Ltd.

INTRODUCTION: Initial abbreviated surgery with planned reoperation (damage control surgery) is frequently used for major trauma patients to rapidly control haemorrhage while limiting surgical stress. Although damage control surgery may decrease mortality risk among the severely injured, it may also be associated with several complications when inappropriately applied. We seek to scope the literature on trauma damage control surgery, identify its proposed indications, map and clarify their definitions, and examine the content and evidence on which they are based. We also seek to generate a comprehensive list of unique indications to inform an appropriateness rating process. METHODS AND ANALYSIS: We will search 11 electronic bibliographic databases, included article bibliographies and grey literature sources for citations involving civilian trauma patients that proposed one or more indications for damage control surgery or a damage control intervention. Indications will be classified into a predefined conceptual framework and categorised and described using qualitative content analysis. Constant comparative methodology will be used to create, modify and test codes describing principal findings or injuries (eg, bilobar liver injury) and associated decision variables (eg, coagulopathy) that comprise the reported indications. After a unique list of codes have been developed, we will use the organisational system recommended by the RAND/University of California, Los Angeles (RAND-UCLA) Appropriateness Rating Method to group principal findings or injuries into chapters (subdivided by associated decision variables) according to broader clinical findings encountered during surgical practice (eg, major liver injury). ETHICS AND DISSEMINATION: This study will constitute the first step in a multistep research programme aimed at developing appropriate, evidence-informed indications for damage control in civilian trauma patients. With use of an integrated knowledge translation intervention that includes collaboration with surgical practice leaders, this research may allow for development of indications that are more likely to be relevant to and used by surgeons. Ethics approval is not required for this study.

Pure alexia (PA) arises from damage to the left posterior fusiform gyrus (pFG) and the striking reading disorder that defines this condition has meant that such patients are often cited as evidence for the specialisation of this region to processing of written words. There is, however, an alternative view that suggests this region is devoted to processing of high acuity foveal input, which is particularly salient for complex visual stimuli like letter strings. Previous reports have highlighted disrupted processing of non-linguistic visual stimuli after damage to the left pFG, both for familiar and unfamiliar objects and also for novel faces. This study explored the nature of face processing deficits in patients with left pFG damage. Identification of famous faces was found to be compromised in both expressive and receptive tasks. Discrimination of novel faces was also impaired, particularly for those that varied in terms of second-order spacing information, and this deficit was most apparent for the patients with the more severe reading deficits. Interestingly, discrimination of faces that varied in terms of feature identity was considerably better in these patients and it was performance in this condition that was related to the size of the length effects shown in reading. This finding complements functional imaging studies showing left pFG activation for faces varying only in spacing and frontal activation for faces varying only on features. These results suggest that the sequential part-based processing strategy that promotes the length effect in the reading of these patients also allows them to discriminate between faces on the basis of feature identity, but processing of second-order configural information is most compromised due to their left pFG lesion. This study supports a view in which the left pFG is specialised for processing of high acuity foveal visual information that supports processing of both words and faces.

A series of N-substituted 2-aminopyrimidines were prepared and tested for pharmacological activity associated with stimulation of central and peripheral dopamine receptors using piribedil as the reference standard. Most of the new compounds showed some degree of dopaminergic activity although in many cases central activity was not accompanied by peripheral activity and vice versa. Clear relationships between structure and activity were not apparent and none of the new compounds possessed dopamine receptor blocking properties.