High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

Exploring the immunological relevance of pre-transplant donor-specific antibody in intestinal transplantation, with special consideration to the liver.

Despite recent advances that have improved outcomes following intestinal transplantation (ITx), achieving long-term patient survival and rejection-free survival is still challenging. Understanding the relevance of pre-transplant human leukocyte antigen (HLA) donor-specific antibody (DSA) in ITx and the immunomodulatory potential of the liver within the allograft is crucial to providing an accurate assessment of pre-transplant immunological risk, which could influence and improve post-transplant outcomes further. This was the primary objective of this retrospective study of 95 adult ITx transplants which took place at Cambridge University Hospitals (United Kingdom) between 2007 and 2019. Two novel programs were developed and validated to identify DSA (tested by Luminex single antigen beads) in this dataset. Data analysis utilised Kaplan-Meier survival methods, and statistical analysis was performed using log-rank tests and adjusted Cox models. Fifty-four (57%) ITx cases contained a liver, and 36 (38%) were sensitised to HLA. Pre-transplant DSA > 500 mean fluorescent intensity appeared to negatively affect post-ITx patient survival and rejection outcomes. Additionally, liver-inclusive allografts seemed to show particular resistance to HLA class I DSA. Our data hints towards consistency with other ITx studies where deleterious effects of DSA have been demonstrated, and where liver inclusion is protective from HLA class I DSA. This is in line with current national guidelines for immunological risk. Our publicly available research programs could support future large or multicentre studies where statistically relevant data might be gained.

Diffuse Cerebral Edema With Uncal Herniation Leading to Brain Death in Patient With Fulminant Susac syndrome: Rare Complication of Rare Disease.

Susac Syndrome was first described as an inflammatory microangiopathy of the brain and retina. Since then, multiple articles have been published in attempts to improve the understanding of this rare disease. Clinically Susac Syndrome is known to present with triad of encephalopathy, sensorineural hearing loss and branch of retinal artery occlusion (BRAO), along with characteristic "snowball" or "spoke" appearing white matter lesions of the corpus callosum. It has been characterized by vast heterogeneity in terms of its presenting symptoms, severity, and clinical course. Although subset of patients present with severe forms of Susac Syndrome and can develop prominent residual neurologic deficits, it has been reported to be mostly non-life-threatening and only few fatal cases have been described in the literature. Based on the available case reports with fatal outcome, mortality has been related to the systemic complications either during acute disease flare or during chronic-progressive phase. We describe a case of fulminant Susac Syndrome complicated by the sudden and rapid progression of diffuse cerebral edema leading to brain herniation and ultimate brain death, in order to increase awareness of this rare and catastrophic complication.

BSHI and BTS UK guideline on the detection of alloantibodies in solid organ (and islet) transplantation.

Solid organ transplantation represents the best (and in many cases only) treatment option for patients with end-stage organ failure. The effectiveness and functioning life of these transplants has improved each decade due to surgical and clinical advances, and accurate histocompatibility assessment. Patient exposure to alloantigen from another individual is a common occurrence and takes place through pregnancies, blood transfusions or previous transplantation. Such exposure to alloantigen's can lead to the formation of circulating alloreactive antibodies which can be deleterious to solid organ transplant outcome. The purpose of these guidelines is to update to the previous BSHI/BTS guidelines 2016 on the relevance, assessment, and management of alloantibodies within solid organ transplantation.

A pilot evaluation of the role of a children's wellbeing practitioner (CWP) in a child and adolescent mental health service (CAMHS).

BACKGROUND: In 2017, the Children and Young People's Improving Access to Psychological Therapies (CYP-IAPT) project was extended to deliver low-intensity Cognitive Behavioural Therapy (CBT), delivered by Children's Wellbeing Practitioners (CWPs), but to date evaluation is sparse. AIMS: To evaluate low-intensity interventions delivered by trainee CWPs for the treatment of anxiety and depression in a child and adolescent mental health service (CAMHS). METHOD: The evaluation adopted a quantitative, within-subjects, cross-sectional design. The outcome measures of 98 service users aged 8-17 years were included in the evaluation. Service users were children and young people accessing CAMHS in the North East of England. Outcome measures included the Revised Children's Anxiety and Depression Scale (RCADS-47) and Goal Based Outcomes (GBOs). Descriptive data relating to the types of interventions used and outcomes following CWP involvement were also explored. RESULTS: Analysis of pre and post intervention data highlighted significant reduction in symptomatology across all RCADS subscales and composite total scales, and significant goal progress as measures by GBO's. Effect sizes ranged from moderate to large (d = 0.75 - 0.90) across all subscales of the RCADS. Large effect sizes were found for depression, total anxiety and total RCADS scores (d = 0.86, d = 1.12, d = 1.14), and GBOs (d = -1.33). CONCLUSIONS: Findings support the potential value of low intensity CBT interventions delivered by CWPs in reducing anxiety and depression in this population. Recommendations for the development of the CWP role and CWP services are discussed.

Safety and Tolerability of Concentrated Intraventricular Nicardipine for Poor-Grade Aneurysmal Subarachnoid Hemorrhage-Related Vasospasm.

Objective: To report the preliminary safety, tolerability, and cerebral spinal fluid (CSF) sampling utility of serial injections of concentrated intraventricular nicardipine (IVN) in the treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods: We report the clinical, radiographic, and laboratory safety and tolerability data of a retrospective case series from a single academic medical center. All patients with aSAH developed vasospasm despite enteral nimodipine and received serial injections of concentrated IVN (2.5 mg/mL). CSF injection safety, tolerability, and utility are defined and reported. Results: A total of 59 doses of concentrated IVN were administered to three patients with poor-grade SAH. In Case 1, a 33-year-old man with modified Fisher scale (mFS) grade 4 and Hunt-Hess scale (HH) score 4 received 26 doses; in Case 2, a 36-year-old woman with mFS grade 4 and HH score 5 received 13 doses; and in Case 3, a 70-year-old woman with mFS grade 3 and HH score 4 received 20 doses. No major safety or tolerability events occurred. Two patients were discharged to a rehabilitation facility, and one died after discharge from the hospital. Conclusions: A concentrated 4 mg IVN dose (2.5 mg/mL) in a 1.6 mL injection appears relatively safe and tolerable and potentially offers a second-line strategy for treating refractory vasospasm in poor-grade SAH without compromising intracranial pressure or cerebral perfusion pressure.

Zero-Calibrating External Ventricular Drains: Exploring Practice.

ABSTRACT: BACKGROUND: Guidelines call for the removal of the nonvented cap (NVC) on the flushless transducer applied to the external ventricular drain (EVD) to zero the device to atmospheric pressure. Some hospitals have abandoned this practice to prevent opening the system to air. No data exist to determine the safest, most effective method of EVD zero-calibration. METHODS: A multidisciplinary team was assembled to use reflective practice to evaluate current zero-calibration of EVD practice. RESULTS: Clinical Nursing Focus showed recommendations largely out of date without detailed rationale or a high level of evidence. Manufacturer recommendations were fragmented and did not address rationale for technique. Bedside trial showed equivalence when comparing intracranial pressure (ICP) tidal, ICP after EVD zero with NVC removal, and ICP after EVD zero without NVC removal. CONCLUSION: Institutional guidelines were changed to reflect zero-calibration of EVD without NVC removal in systems that are amendable to this procedure. Further study is needed to determine best practice.

REadmission PREvention in SepSis: Development and Validation of a Prediction Model.

ABSTRACT: Hospital 30-day readmissions remain a major quality and cost indicator. Traditional readmission risk scores, such as LACE (length of stay, acuity of admission, Charlson comorbidity index, and emergency department visits), may be suboptimal in special patient populations, such as those with sepsis. As sepsis survivorship improves, there is a need to determine which variables might be associated with a decrease in 30-day readmission. We completed a retrospective analysis reviewing patients with sepsis who had unplanned 30-day readmissions. Multivariate regression analysis was performed for the REadmission PREvention in SepSis (REPRESS) model, which evaluated age, length of stay, Charlson disease count, Richmond Agitation-Sedation Scale score, discharge to a skilled nursing facility, and mobility for predictive significance in hospital readmission. Our REPRESS model performed better when compared with LACE for predicting readmission risk in a sepsis population.

Neuro R2 score: Predicting high-risk neurologic readmissions within 30 days.

OBJECTIVE: To evaluate clinical and demographic factors of patients with neurologic disorders to determine which patient characteristics are significant for predicting 30-day hospital readmissions to develop a readmission risk predictor specific to patients with neurologic disorders. METHODS: We performed a retrospective single-center chart review for all patients admitted to the Department of Neurology or neurologic intensive care unit from January 1, 2013, to December 31, 2017. Clinical and demographic factors were analyzed to determine the association with readmission. Multivariable logistic regression analysis was performed and validated to develop a simple tool (Neuro R2 score) for predicting patients with neurologic disorders at high risk for hospital readmission. RESULTS: After removal of planned readmissions and patients who died in the hospital, the records of 4,876 patients with 314 (6.4%) readmission events were analyzed. The strongest predictors for readmission were Charlson disease count (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.06-1.35, p = 0.005), urgent or emergent admission (OR 1.50, 95% CI 1.04-2.17, p = 0.031), discharge to rehabilitation (OR 1.66, 95% CI 1.16-2.35, p = 0.005), cancer (OR 1.70, 95% CI 1.15-2.50, p = 0.007), brain tumor (OR 1.82, 95% CI 1.08-3.09, p < 0.03), cerebrovascular disease (OR 2.18, 95% CI 1.53-3.11, p < 0.001), and discharge to skilled nursing facility (OR 2.43, 95% CI 1.65-3.57, p < 0.001). CONCLUSIONS: The Neuro R2 score was developed to predict readmission risk, specifically in patients with neurologic disorders. Future research could include further validation of this readmission risk tool and strategies to reduce readmission in patients with the highest risk.

Community-based prehabilitation before elective major surgery: the PREP-WELL quality improvement project.

Optimising health and well-being before elective major surgery via prehabilitation initiatives is important for good postoperative outcomes. In a busy tertiary centre in North East England, the lack of a formal prehabilitation service meant that opportunities were being missed to optimise patients for surgery. This quality improvement project aimed to implement and evaluate a community-based prehabilitation service for people awaiting elective major surgery: PREP-WELL. A multidisciplinary, cross-sector team introduced PREP-WELL in January 2018. PREP-WELL provided comprehensive assessment and management of perioperative risk factors in the weeks before surgery. During a 12-month pilot, patients were referred from five surgical specialties at James Cook University Hospital. Data were collected on participant characteristics, behavioural and health outcomes, intervention acceptability and costs, and process-related factors. By December 2018, 159 referrals had been received, with 75 patients (47%) agreeing to participate. Most participants opted for a supervised programme (72%) and were awaiting vascular (43%) or orthopaedic (35%) surgery. Median programme duration was 8 weeks. The service was delivered as intended with participants providing positive feedback. Health-related quality of life (HRQoL; EuroQol 5D (EQ-5D) utility) and functional capacity (6 min walk distance) increased on average from service entry to exit, with mean (95% CI) changes of 0.108 (-0.023 to 0.240) and 35 m (-5 to 76 m), respectively. Further increases in EQ5D utility were observed at 3 months post surgery. Substantially more participants were achieving recommended physical activity levels at exit and 3 months post surgery compared with at entry. The mean cost of the intervention was £405 per patient; £52 per week. The service was successfully implemented within existing preoperative pathways. Most participants were very satisfied and improved their risk profile preoperatively. Funding has been obtained to support service development and expansion for at least 2 more years. During this period, alternative pathways will be developed to facilitate wider access and greater uptake.

Distinct Polymorphisms in HLA Class I Molecules Govern Their Susceptibility to Peptide Editing by TAPBPR.

Understanding how peptide selection is controlled on different major histocompatibility complex class I (MHC I) molecules is pivotal for determining how variations in these proteins influence our predisposition to infectious diseases, cancer, and autoinflammatory conditions. Although the intracellular chaperone TAPBPR edits MHC I peptides, it is unclear which allotypes are subjected to TAPBPR-mediated peptide editing. Here, we examine the ability of 97 different human leukocyte antigen (HLA) class I allotypes to interact with TAPBPR. We reveal a striking preference of TAPBPR for HLA-A, particularly for supertypes A2 and A24, over HLA-B and -C molecules. We demonstrate that the increased propensity of these HLA-A molecules to undergo TAPBPR-mediated peptide editing is determined by molecular features of the HLA-A F pocket, specifically residues H114 and Y116. This work reveals that specific polymorphisms in MHC I strongly influence their susceptibility to chaperone-mediated peptide editing, which may play a significant role in disease predisposition.

Pharmacogenomics of Cytochrome P450 of Nimodipine Metabolism After Aneurysmal Subarachnoid Hemorrhage.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is a type of stroke that is life threatening with high rates of mortality, and many survivors are left with permanent neurologic deficits. Nimodipine is the treatment of choice for aSAH with the goal of reduction of delayed cerebral ischemia. It is the only evidence-based medication that has been shown to have improved outcomes for delayed cerebral ischemia; therefore, it is important for neuroscience nurses to be knowledgeable of the pharmacology and pharmacogenomics properties of this medication, including cytochrome P450 (CYP450) enzymes. METHODS AND RESULTS: This article reviews the CYP450 enzyme system including a review of the pharmacotherapy and pharmacogenomics of nimodipine for patients with aSAH illustrated with case study of a patient with abnormal drug metabolism. CONCLUSION: CYP450 enzymes can be inhibited or induced by multiple medications resulting in clinically significant differences in drug metabolism. Food and Drug Administration-approved medication nimodipine is the only medication shown to improve outcomes in patients with aSAH. Hence, it is important to have awareness of potential drug-to-drug interactions and pharmacogenomics of nimodipine when caring for critically ill patients with aSAH.

Associations between activity and participation in adults with multiple sclerosis: a cross sectional study.

OBJECTIVES: The aim of this study was to determine the association between walking ability in a clinical setting (activity capacity), walking ability in a person's daily environment (activity capability) and walking performance in daily life (activity performance), and the contribution of each activity construct to participation among people with multiple sclerosis (MS). DESIGN: Cross-sectional study. SETTING: Five MS therapy centres in England. PARTICIPANTS: Fifty-two adults (13 males) with MS who were independently ambulatory with or without a walking aid (mean (SD) age 55.4 (9.1) year). INTERVENTIONS: No intervention. MAIN OUTCOME MEASURES: Activity capacity, capability, and performance were assessed using the Six Minute Walk Test (6MWT), Twelve Item MS Walking Scale (MSWS-12), and steps/day measured using a pedometer worn for 6 days, respectively. Participation was assessed using the Impact on Participation and Autonomy questionnaire (IPA). RESULTS: Distance walked on the 6MWT was associated with MSWS-12 score (ß=-0.56, 95% CI -0.87 to -0.22) and steps/day (ß=129.49, 95% CI 48.48 to 207.57). MSWS-12 score was also associated with step count (ß=-87.35, 95% CI -172.29 to -15.71). 6MWT distance was associated with the autonomy indoors subscale of the IPA (ß=-0.02, 95% CI -0.04 to -0.01). No other activity measure was associated with participation. CONCLUSIONS: Findings suggest that while activity capacity, capability and performance are related, activity is a poor predictor of participation. The strength of associations between constructs of activity, and activity and participation, however, are often small with wide confidence intervals, indicating that there is considerable uncertainty associated with effect estimates.

Evaluation of Hospital-wide Readmission Risk Calculator to Predict 30-Day Readmission in Neurocritical Care Patients.

BACKGROUND AND PURPOSE: Thirty-day hospital readmissions have been shown to be a measure of quality and result in higher mortality and increased costs. Readmissions are a target for hospitals and payers; thus, several centers have developed predictive readmission scores to identify high-risk patients. The purpose of this study was to evaluate the current hospital-wide readmission risk calculator and the ability of this tool to predict 30-day readmissions in the neurocritical care population. METHODS: A retrospective chart review was performed that included 340 consecutive patients admitted to our neuroscience critical care unit. Data including readmission scores, reason for admission, length of stay, and whether they were readmitted were recorded. RESULTS: After removing patients without readmission scores or who died at the end of the original admission, the records of N = 279 patients were analyzed. Patients were more likely to be readmitted if they were initially emergently hospitalized or if there was a history of malignancy. Readmitted patients had a longer original hospital length of stay. Furthermore, 65.8% of the patients who were given a "low risk" for readmission were readmitted within 30 days. CONCLUSIONS: This small set of data in a specific patient population found that the current risk prediction score was inaccurate in predicting readmission in the neuroscience intensive care unit population. Further evaluation is needed of a larger patient population to generalize these results for all neuroscience intensive care unit patients. To design an accurate readmission risk tool, centers should create unique readmission scores based on less heterogeneous patient populations.

Telomere length in the colon is related to colorectal adenoma prevalence.

Telomere length has been associated with risk of several cancers. However, studies of the relationship between telomere length and colorectal cancer risk have been inconsistent. This study examined the relationship between telomere length in normal colon tissue and the prevalence of colorectal adenoma, a precursor to colorectal cancer. This nested case-control study consisted of 85 patients aged 40 to 65 undergoing a screening colonoscopy: 40 cases with adenoma(s) detected at colonoscopy and 45 controls with normal colonoscopy. During the colonoscopy, two pinch biopsies of healthy, normal appearing mucosa were obtained from the descending colon. Relative telomere length (rTL) was quantified in DNA extracted from colon mucosa using quantitative real-time PCR. Logistic regression was used to assess the relationship between telomere length and adenoma prevalence and estimate odds ratios and 95% confidence intervals. rTL was significantly longer in colon tissue of individuals with adenomas compared to healthy individuals (p = 0.008). When rTL was categorized into quartiles according to the distribution of rTL among controls, individuals with the longest telomeres had increased odds of adenoma when compared to individuals with shortest telomeres (OR = 4.58, 95% CI: 1.19, 17.7). This study suggests that long telomeres in normal colon tissue are associated with increased colorectal cancer risk.

Multimodal Neuromonitoring in Neurocritical Care.

Neuromonitoring is important for patients with acute brain injury. The bedside neurologic examination is standard for neurologic monitoring; however, a clinical examination may not reliably detect subtle changes in intracranial physiology. Changes found during neurologic examinations are often late signs. The assessment of multiple physiological variables in real time can provide new clinical insights into treatment decisions. No single monitoring modality is ideal for all patients. Simultaneous assessment of cerebral hemodynamics, oxygenation, and metabolism, such as in multimodal monitoring, allows an innovative approach to individualized patient care.

Bulky DNA adduct levels in normal-appearing colon mucosa, and the prevalence of colorectal adenomas.

PURPOSE: Examine the association between bulky DNA adduct levels in colon mucosa and colorectal adenoma prevalence, and explore the correlation between adduct levels in leukocytes and colon tissue. METHODS: Bulky DNA adduct levels were measured using 32P-postlabelling in biopsies of normal-appearing colon tissue and blood donated by 202 patients. Multivariable logistic regression was used to examine associations between DNA adducts, and interactions of DNA adduct-DNA repair polymorphisms, with the prevalence of colorectal adenomas. Correlation between blood and tissue levels of DNA adducts was evaluated using Spearman's correlation coefficient. RESULTS: An interaction between bulky DNA adduct levels and XPA rs1800975 on prevalence of colorectal adenoma was observed. Among individuals with lower DNA repair activity, increased DNA adduct levels were associated with increased colorectal adenoma prevalence (OR = 1.41 per SD increase, 95%CI: 0.92-2.18). Conversely, among individuals with normal DNA activity, an inverse association was observed (OR = 0.60 per SD increase, 95%CI: 0.34-1.07). Blood and colon DNA adduct levels were inversely correlated (ρ = -0.20). CONCLUSIONS: Among genetically susceptible individuals, higher bulky DNA adducts in the colon was associated with the prevalence of colorectal adenomas. The inverse correlation between blood and colon tissue measures demonstrates the importance of quantifying biomarkers in target tissues.