Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection.

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.

Whole Blood Program: Implementation in a Rural Trauma Center.

BACKGROUND: The balanced transfusion of blood components plays a leading role in traumatic hemostatic resuscitation. Yet, previous whole blood studies have only focused on urban trauma center settings. OBJECTIVE: To compare component vs whole blood therapy on wastage rates and mortality in the rural setting. METHODS: This study was a nonrandomized, retrospective, observational, single-center study on a cold-stored whole blood program implementation for adult massive transfusions from 2020 to 2022 at a Level II trauma center. Trauma registry data determined the facility's whole blood needs and facilitated sustainable blood supplies. Whole blood use protocols were established, and utilization and laboratory compliance for incompatible ABO antibody hemolysis was monitored and reviewed monthly at stakeholder and trauma services meetings. RESULTS: From 2018 to 2019, the facility initiated component therapy massive transfusions every 9 days (n = 41). Therefore, four units of low-titer, O-positive whole blood delivered fortnightly was determined to provide patient coverage and minimize wastage. Across the study time frame (2020-2022), there were n = 68 hemodynamically unstable patients, consisting of those receiving whole blood, n = 37, and patients receiving component therapy, n = 31. Mortality rates were significantly lower (p = .030) in the whole blood population (n = 3, 8%) compared to those solely receiving component therapy (n = 9, 29%). Wastage rates were constantly evaluated; in 2021, 43.4% was not utilized, and in 2022, this was reduced to 38.7%. Anecdotally, nurses appreciated the ease of administration and documentation of transfusing whole blood, as it negated ratio compliance. CONCLUSION: This evidence-based whole blood program provides vital care to severely injured trauma patients in a vast, rural region.

Genetic influences on epilepsy outcomes: A whole-exome sequencing and health care records data linkage study.

OBJECTIVE: This study was undertaken to develop a novel pathway linking genetic data with routinely collected data for people with epilepsy, and to analyze the influence of rare, deleterious genetic variants on epilepsy outcomes. METHODS: We linked whole-exome sequencing (WES) data with routinely collected primary and secondary care data and natural language processing (NLP)-derived seizure frequency information for people with epilepsy within the Secure Anonymised Information Linkage Databank. The study participants were adults who had consented to participate in the Swansea Neurology Biobank, Wales, between 2016 and 2018. DNA sequencing was carried out as part of the Epi25 collaboration. For each individual, we calculated the total number and cumulative burden of rare and predicted deleterious genetic variants and the total of rare and deleterious variants in epilepsy and drug metabolism genes. We compared these measures with the following outcomes: (1) no unscheduled hospital admissions versus unscheduled admissions for epilepsy, (2) antiseizure medication (ASM) monotherapy versus polytherapy, and (3) at least 1 year of seizure freedom versus <1 year of seizure freedom. RESULTS: We linked genetic data for 107 individuals with epilepsy (52% female) to electronic health records. Twenty-six percent had unscheduled hospital admissions, and 70% were prescribed ASM polytherapy. Seizure frequency information was linked for 100 individuals, and 10 were seizure-free. There was no significant difference between the outcome groups in terms of the exome-wide and gene-based burden of rare and deleterious genetic variants. SIGNIFICANCE: We successfully uploaded, annotated, and linked genetic sequence data and NLP-derived seizure frequency data to anonymized health care records in this proof-of-concept study. We did not detect a genetic influence on real-world epilepsy outcomes, but our study was limited by a small sample size. Future studies will require larger (WES) data to establish genetic variant contribution to epilepsy outcomes.

Research-ready data: the C-Surv data model.

Research-ready data (data curated to a defined standard) increase scientific opportunity and rigour by integrating the data environment. The development of research platforms has highlighted the value of research-ready data, particularly for multi-cohort analyses. Following stakeholder consultation, a standard data model (C-Surv) optimised for data discovery, was developed using data from 5 population and clinical cohort studies. The model uses a four-tier nested structure based on 18 data themes selected according to user behaviour or technology. Standard variable naming conventions are applied to uniquely identify variables within the context of longitudinal studies. The data model was used to develop a harmonised dataset for 11 cohorts. This dataset populated the Cohort Explorer data discovery tool for assessing the feasibility of an analysis prior to making a data access request. Data preparation times were compared between cohort specific data models and C-Surv.It was concluded that adopting a common data model as a data standard for the discovery and analysis of research cohort data offers multiple benefits.

Biodegradable temporising matrix: use of negative pressure wound therapy shows a significantly higher success rate.

OBJECTIVE: The purpose of this case series was to evaluate the efficacy of a synthetic biodegradable temporising matrix (BTM; PolyNovo Biomaterials Pty Ltd, Australia) and compare the outcome of BTM patients with and without negative pressure wound therapy (NPWT). METHOD: A retrospective chart review was conducted on patients admitted with deep full-thickness burns, traumatic or complex wound injuries treated with BTM. Electronic medical records and images were evaluated by a team of clinical professionals. Endpoints included: the measure of successful BTM integration; and comparison between patients treated with and without NPWT. Additional measures were BTM total surface area, BTM sites, timeliness of BTM application and any complications. RESULTS: A total of 28 patients were evaluated and 23 (82.1%) demonstrated overall successful BTM integration. Patients treated with BTM in conjunction with NPWT (n=16) demonstrated a significantly higher (p=0.046) integration rate compared to patients treated without NPWT (n=12) (93.8% versus 58.3%, respectively). Patients treated with BTM with NPWT continued to successfully integrate and sustain favourable outcomes despite the presence of severe infection or the development of haematomas. CONCLUSION: A significantly higher integration rate was demonstrated when BTM was used in conjunction with NPWT. The results of this study further support the efficacy of successful integration of BTM as a replacement for tissue loss in the treatment of deep, full-thickness burns, traumatic and complex wound injuries, and particularly favourable outcomes with the use of NPWT. To the best of our knowledge, this is the first reported case series comparing the clinical outcomes of BTM with and without the use of NPWT.

ATTAC! Development of a Novel Advanced Trauma Team Application Course.

BACKGROUND: Although existing trauma nurse courses provide basic education, advanced courses with simulation experiences that enhance team leadership, communication, and workflows are lacking. OBJECTIVE: To design and implement the Advanced Trauma Team Application Course (ATTAC) to promote advanced skills for nurses and respiratory therapists with varied experience and skill levels. METHODS: Trauma nurses and respiratory therapists were selected to participate based on years of experience and the novice to expert nurse model. Two nurses from each level (excluding novice) participated, ensuring a diverse cohort to promote development and mentorship. The 11-module course was presented over 12 months. A five-question survey was employed at the end of each module to self-evaluate assessment skills, communication skills, and comfort for trauma patient care. Participants rated skills and comfort on a "0-10" scale, with 0 being "not at all" to 10 being "extensively." RESULTS: The pilot course was conducted from May 2019 to May 2020 at a Level II trauma center in the Northwest United States. Nurses reported ATTAC improved assessment skills, team communication, and comfort in caring for trauma patients (mean = 9.4; 95% CI [9.0, 9.8]; scale of 0-10). Participants indicated scenarios closely mimicked real-world situations; concept application commenced directly following each session. CONCLUSION: This novel approach to advanced trauma education promotes development of advanced skills that enable nurses to anticipate needs rather than being reactive, engage in critical thinking, and adapt to rapidly changing patient conditions.

Bringing Trauma Education to the Frontier: Overcoming Distance Barriers Utilizing a Virtual Platform.

BACKGROUND: The American College of Surgeons and state regulations mandate that trauma facilities offer trauma-specific continuing education throughout the region they serve. These requirements come with unique challenges when serving a rural and sparsely populated state. A novel approach to providing education was necessitated by the coronavirus disease 2019 pandemic, travel distance, and limited local specialists. OBJECTIVE: The purpose of this article is to describe the development of a virtual educational program used to improve access to quality trauma education and decrease barriers to obtaining continuing education hours inherent in the region. METHODS: This article describes the development and implementation of the Virtual Trauma Education program, which provided one free continuing education hour per month from October 2020 to October 2021. The program reached more than 2,000 viewers and established a method to provide continuous monthly educational offerings throughout the region. RESULTS: After the Virtual Trauma Education program implementation, monthly educational attendance increased from an average of 55 to 190. Viewership data indicate that trauma education across our region is far more robust, available, and accessible using a virtual platform. With more than 2,000 views from October 2020 to October 2021, Virtual Trauma Education offerings have spread far beyond regional borders, reaching 25 states and 169 communities. CONCLUSION: Virtual Trauma Education delivers easily accessible trauma education and is a program that has proven its sustainability.

Redondovirus Diversity and Evolution on Global, Individual, and Molecular Scales.

Redondoviridae is a newly established family of circular Rep-encoding single-stranded (CRESS) DNA viruses found in the human ororespiratory tract. Redondoviruses were previously found in ∼15% of respiratory specimens from U.S. urban subjects; levels were elevated in individuals with periodontitis or critical illness. Here, we report higher redondovirus prevalence in saliva samples: four rural African populations showed 61 to 82% prevalence, and an urban U.S. population showed 32% prevalence. Longitudinal, limiting-dilution single-genome sequencing revealed diverse strains of both redondovirus species (Brisavirus and Vientovirus) in single individuals, persistence over time, and evidence of intergenomic recombination. Computational analysis of viral genomes identified a recombination hot spot associated with a conserved potential DNA stem-loop structure. To assess the possible role of this site in recombination, we carried out in vitro studies which showed that this potential stem-loop was cleaved by the virus-encoded Rep protein. In addition, in reconstructed reactions, a Rep-DNA covalent intermediate was shown to mediate DNA strand transfer at this site. Thus, redondoviruses are highly prevalent in humans, found in individuals on multiple continents, heterogeneous even within individuals and encode a Rep protein implicated in facilitating recombination. IMPORTANCERedondoviridae is a recently established family of DNA viruses predominantly found in the human respiratory tract and associated with multiple clinical conditions. In this study, we found high redondovirus prevalence in saliva from urban North American individuals and nonindustrialized African populations in Botswana, Cameroon, Ethiopia, and Tanzania. Individuals on both continents harbored both known redondovirus species. Global prevalence of both species suggests that redondoviruses have long been associated with humans but have remained undetected until recently due to their divergent genomes. By sequencing single redondovirus genomes in longitudinally sampled humans, we found that redondoviruses persisted over time within subjects and likely evolve by recombination. The Rep protein encoded by redondoviruses catalyzes multiple reactions in vitro, consistent with a role in mediating DNA replication and recombination. In summary, we identify high redondovirus prevalence in humans across multiple continents, longitudinal heterogeneity and persistence, and potential mechanisms of redondovirus evolution by recombination.

Genomic evidence for shared common ancestry of East African hunting-gathering populations and insights into local adaptation.

Anatomically modern humans arose in Africa ∼300,000 years ago, but the demographic and adaptive histories of African populations are not well-characterized. Here, we have generated a genome-wide dataset from 840 Africans, residing in western, eastern, southern, and northern Africa, belonging to 50 ethnicities, and speaking languages belonging to four language families. In addition to agriculturalists and pastoralists, our study includes 16 populations that practice, or until recently have practiced, a hunting-gathering (HG) lifestyle. We observe that genetic structure in Africa is broadly correlated not only with geography, but to a lesser extent, with linguistic affiliation and subsistence strategy. Four East African HG (EHG) populations that are geographically distant from each other show evidence of common ancestry: the Hadza and Sandawe in Tanzania, who speak languages with clicks classified as Khoisan; the Dahalo in Kenya, whose language has remnant clicks; and the Sabue in Ethiopia, who speak an unclassified language. Additionally, we observed common ancestry between central African rainforest HGs and southern African San, the latter of whom speak languages with clicks classified as Khoisan. With the exception of the EHG, central African rainforest HGs, and San, other HG groups in Africa appear genetically similar to neighboring agriculturalist or pastoralist populations. We additionally demonstrate that infectious disease, immune response, and diet have played important roles in the adaptive landscape of African history. However, while the broad biological processes involved in recent human adaptation in Africa are often consistent across populations, the specific loci affected by selective pressures more often vary across populations.

Making the Most of Big Data in Plastic Surgery: Improving Outcomes, Protecting Patients, Informing Service Providers.

ABSTRACT: In medicine, "big data" refers to the interdisciplinary analysis of high-volume, diverse clinical and lifestyle information on large patient populations. Recent advancements in data storage and electronic record keeping have enabled the expansion of research in this field. In the United Kingdom, Big data has been highlighted as one of the government's "8 Great Technologies," and the Medical Research Council has invested more than £100 million since 2012 in developing the Health Data Research UK infrastructure. The recent Royal College of Surgeons Commission of the Future of Surgery concluded that analysis of big data is one of the 4 most likely avenues to bring some of the most innovative changes to surgical practice in the 21st century.In this article, we provide an overview of the nascent field of big data analytics in plastic and highlight how it has the potential to improve outcomes, increase safety, and aid service planning.We outline the current resources available, the emerging role of big data within the subspecialties of burns, microsurgery, skin and breast cancer, and how these data can be used. We critically review the limitations and considerations raised with big data, offer suggestions regarding database optimization, and suggest future directions for research in this exciting field.

IFCC Interim Guidelines on Biochemical/Hematological Monitoring of COVID-19 Patients.

Routine biochemical and hematological tests have been reported to be useful in the stratification and prognostication of pediatric and adult patients with diagnosed coronavirus disease (COVID-19), correlating with poor outcomes such as the need for mechanical ventilation or intensive care, progression to multisystem organ failure, and/or death. While these tests are already well established in most clinical laboratories, there is still debate regarding their clinical value in the management of COVID-19, particularly in pediatrics, as well as the value of composite clinical risk scores in COVID-19 prognostication. This document by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 provides interim guidance on: (A) clinical indications for testing, (B) recommendations for test selection and interpretation, (C) considerations in test interpretation, and (D) current limitations of biochemical/hematological monitoring of COVID-19 patients. These evidence-based recommendations will provide practical guidance to clinical laboratories worldwide, underscoring the contribution of biochemical and hematological testing to our collective pandemic response.

The Dementias Platform UK (DPUK) Data Portal.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

Paradoxical response of intracranial pressure to shunt valve setting adjustments.

BACKGROUND: The hydrodynamics of cerebrospinal fluid shunts have been described in vitro; however, knowledge on the response of intracranial pressure (ICP) to valve settings adjustments in vivo is limited. This study describes the effect of adjusting the shunt valve setting on ICP in a cohort of patients with complex symptom management. METHOD: Single-centre retrospective observational study. Patients who underwent ICP-guided valve setting adjustments during 24-h continuous ICP monitoring, between 2014 and 2019, were included. Patients with suspected shunt malfunction were excluded. Median night ICP before and after the valve adjustments were compared (Δ night ICP). The responses of ICP to valve adjustment were divided into 3 different groups as follows: expected, paradoxical and no response. The frequency of the paradoxical response and its potential predicting factors were investigated. RESULTS: Fifty-one patients (37 females, 14 males, mean age 38 years) receiving 94 valve setting adjustments met the study inclusion criteria. Patients' underlying conditions were most commonly hydrocephalus (47%) or idiopathic intracranial hypertension (43%). The response of ICP to valve setting adjustments was classified as 'expected' in 54 cases (57%), 'paradoxical' in 17 cases (18%) and 'no effect' (Δ night ICP < 1 mmHg) in 23 cases (24%). There was a significant correlation between the Δ night ICP and the magnitude of valve setting change in both the investigated valves (Miethke ProGAV, p = 0.01 and Medtronic Strata, p = 0.02). CONCLUSIONS: Paradoxical ICP changes can occur after shunt valve setting adjustments. This observation should be taken into account when performing ICP-guided valve adjustments and is highly relevant for the future development of "smart" shunt systems.

Analysis of clinical benefit, harms, and cost-effectiveness of screening women for abdominal aortic aneurysm.

BACKGROUND: A third of deaths in the UK from ruptured abdominal aortic aneurysm (AAA) are in women. In men, national screening programmes reduce deaths from AAA and are cost-effective. The benefits, harms, and cost-effectiveness in offering a similar programme to women have not been formally assessed, and this was the aim of this study. METHODS: We developed a decision model to assess predefined outcomes of death caused by AAA, life years, quality-adjusted life years, costs, and the incremental cost-effectiveness ratio for a population of women invited to AAA screening versus a population who were not invited to screening. A discrete event simulation model was set up for AAA screening, surveillance, and intervention. Relevant women-specific parameters were obtained from sources including systematic literature reviews, national registry or administrative databases, major AAA surgery trials, and UK National Health Service reference costs. FINDINGS: AAA screening for women, as currently offered to UK men (at age 65 years, with an AAA diagnosis at an aortic diameter of ≥3·0 cm, and elective repair considered at ≥5·5cm) gave, over 30 years, an estimated incremental cost-effectiveness ratio of £30 000 (95% CI 12 000-87 000) per quality-adjusted life year gained, with 3900 invitations to screening required to prevent one AAA-related death and an overdiagnosis rate of 33%. A modified option for women (screening at age 70 years, diagnosis at 2·5 cm and repair at 5·0 cm) was estimated to have an incremental cost-effectiveness ratio of £23 000 (9500-71 000) per quality-adjusted life year and 1800 invitations to screening required to prevent one AAA-death, but an overdiagnosis rate of 55%. There was considerable uncertainty in the cost-effectiveness ratio, largely driven by uncertainty about AAA prevalence, the distribution of aortic sizes for women at different ages, and the effect of screening on quality of life. INTERPRETATION: By UK standards, an AAA screening programme for women, designed to be similar to that used to screen men, is unlikely to be cost-effective. Further research on the aortic diameter distribution in women and potential quality of life decrements associated with screening are needed to assess the full benefits and harms of modified options. FUNDING: UK National Institute for Health Research Health Technology Assessment programme.

Morphological suitability for endovascular repair, non-intervention rates, and operative mortality in women and men assessed for intact abdominal aortic aneurysm repair: systematic reviews with meta-analysis.

BACKGROUND: Prognosis for women with abdominal aortic aneurysm might be worse than the prognosis for men. We aimed to systematically quantify the differences in outcomes between men and women being assessed for repair of intact abdominal aortic aneurysm using data from study periods after the year 2000. METHODS: In these systematic reviews and meta-analysis, we identified studies (randomised, cohort, or cross-sectional) by searching MEDLINE, Embase, CENTRAL, and grey literature published between Jan 1, 2005, and Sept 2, 2016, for two systematic reviews and Jan 1, 2009, and Sept 2, 2016, for one systematic review. Studies were included if they were of both men and women, with data presented for each sex separately, with abdominal aortic aneurysms being assessed for aneurysm repair by either endovascular repair (EVAR) or open repair. We conducted three reviews based on whether studies reported the proportion morphologically suitable (within manufacturers' instructions for use) for EVAR (EVAR suitability review), non-intervention rates (non-intervention review), and 30-day mortality (operative mortality review) after intact aneurysm repair. Studies had to include at least 20 women (for the EVAR suitability review), 20 women (for the non-intervention review), and 50 women (for the operative mortality review). Studies were excluded if they were review articles, editorials, letters, or case reports. For the operative review, studies were also excluded if they only provided hazard ratios or only reported in-hospital mortality. We assessed the quality of the studies using the Newcastle-Ottawa scoring system, and contacted authors for the provision of additional data if needed. We combined results across studies by random-effects meta-analysis. This study is registered with PROSPERO, number CRD42016043227. FINDINGS: Five studies assessed the morphological eligibility for EVAR (1507 men, 400 women). The overall pooled proportion of women eligible (34%) for EVAR was lower than it was in men (54%; odds ratio [OR] 0·44, 95% CI 0·32-0·62). Four single-centre studies reported non-intervention rates (1365 men, 247 women). The overall pooled non-intervention rates were higher in women (34%) than men (19%; OR 2·27, 95% CI 1·21-4·23). The review of 30-day mortality included nine studies (52 018 men, 11 076 women). The overall pooled estimate for EVAR was higher in women (2·3%) than in men (1·4%; OR 1·67, 95% CI 1·38-2·04). The overall estimate for open repair also was higher in women (5·4%) than in men (2·8%; OR 1·76, 95% CI 1·35-2·30). INTERPRETATION: Compared with men, a smaller proportion of women are eligible for EVAR, a higher proportion of women are not offered intervention, and operative mortality is much higher in women for both EVAR and open repair. The management of abdominal aortic aneurysm in women needs improvement. FUNDING: National Institute for Health Research (UK).

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors.

BACKGROUND: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. METHODS: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. FINDINGS: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59-1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69-0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76-0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39-0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. INTERPRETATION: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. FUNDING: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.

Pulsatile versus non-pulsatile tinnitus in idiopathic intracranial hypertension.

INTRODUCTION: Tinnitus is a symptom commonly associated with idiopathic intracranial hypertension (IIH) that can have a profound effect on quality of life. We aim to determine tinnitus symptom response after dural venous sinus stenting (DVSS) or CSF diversion with a shunt, in patients with both pulsatile (PT) and non-pulsatile tinnitus (NPT). METHODS: Single-centre cohort of IIH patients (2006-2016) who underwent 24-h ICP monitoring (ICPM). An un-paired t test compared ICP and pulse amplitude (PA) values in IIH patients with PT vs. NPT. RESULTS: We identified 59 patients with IIH (56 F:3 M), mean age 32.5 ± 9.49 years, 14 of whom suffered from tinnitus. Of these 14, seven reported PT and seven reported NPT. Patients with tinnitus had a mean 24-h ICP and PA of 9.09 ± 5.25 mmHg and 6.05 ± 1.07 mmHg respectively. All 7 patients with PT showed symptom improvement or resolution after DVSS (n = 4), secondary DVSS (n = 2) or shunting (n = 1). In contrast, of the 7 with NPT, only 1 improved post intervention (DVSS), despite 2 patients having shunts and 5 having DVSS. CONCLUSIONS: NPT and PT were equally as common in our group of IIH patients. DVSS appears to be an effective management option for IIH patients with a clear history of pulsatile tinnitus. However, non-pulsatile tinnitus was more persistent and did not respond well to either DVSS or CSF diversion.

Impact of duplicate CT scan rate after implementation of transfer image repository system at a level 1 trauma center.

PURPOSE: The regionalization of trauma in the USA results in frequent transfers of patients from a primary hospital ED to a higher level trauma facility. While many hospitals have a Picture Archive Communication System (PACS) which captures digital radiological images, these are often not available to the receiving institution resulting in duplicate imaging. The state of Arkansas instituted a trauma image repository (TIR) in July 2013. We examined whether implementation of this repository would impact CT scan duplication in the trauma system. METHODS: This was a retrospective analysis of trauma patients transferred from outlying hospitals in Arkansas and Missouri to a single level 1 trauma hospital in Missouri between July 2012 and June 2015. We compared the duplicate CT rate for patients transferred from Arkansas and Missouri hospitals before and after the repository was implemented for Arkansas. RESULTS: Prior to implementation (July 2012-June 2013) of Arkansas TIR, duplicate CT rates were similar for patients transferred from Arkansas (11.5% ± 2.8) or Missouri (16.3% ± 7.5). Following implementation (July 2013-June 2014), the duplicate CT rate for patients transferred from Arkansas was significantly lower (Arkansas = 10.1% vs. Missouri 16.2%; CI 95%, p = 0.02), and significance continued (Arkansas = 9.0% vs. Missouri = 17.8%; CI 95%, p = 0.02) during follow-up (July 2014-June 2015). CONCLUSION: Fewer patients received duplicated scans within the Arkansas as compared with the Missouri-based trauma referral systems regardless of Injury Severity Scores (ISS). Our findings suggest that TIR adoption coupled with PACS improved transferability of radiographic studies and could improve patient care while reducing costs in trauma transfers.

Bias due to participant overlap in two-sample Mendelian randomization.

Mendelian randomization analyses are often performed using summarized data. The causal estimate from a one-sample analysis (in which data are taken from a single data source) with weak instrumental variables is biased in the direction of the observational association between the risk factor and outcome, whereas the estimate from a two-sample analysis (in which data on the risk factor and outcome are taken from non-overlapping datasets) is less biased and any bias is in the direction of the null. When using genetic consortia that have partially overlapping sets of participants, the direction and extent of bias are uncertain. In this paper, we perform simulation studies to investigate the magnitude of bias and Type 1 error rate inflation arising from sample overlap. We consider both a continuous outcome and a case-control setting with a binary outcome. For a continuous outcome, bias due to sample overlap is a linear function of the proportion of overlap between the samples. So, in the case of a null causal effect, if the relative bias of the one-sample instrumental variable estimate is 10% (corresponding to an F parameter of 10), then the relative bias with 50% sample overlap is 5%, and with 30% sample overlap is 3%. In a case-control setting, if risk factor measurements are only included for the control participants, unbiased estimates are obtained even in a one-sample setting. However, if risk factor data on both control and case participants are used, then bias is similar with a binary outcome as with a continuous outcome. Consortia releasing publicly available data on the associations of genetic variants with continuous risk factors should provide estimates that exclude case participants from case-control samples.