Royal London Hospital

Alphaxalone-alphadolone (Althesin), diluted and administered as a controlled infusion, was used as a sedative for 30 patients in an intensive therapy unit. This technique allowed rapid and accurate control of the level of sedation. It had three particularly useful applications: it provided "light sleep," allowed rapid variation in the level of sedation, and enabled repeated assessment of the central nervous system.Sedation was satisfactory for 86% of the total time, and no serious complications were attributed to the use of the drug. Furthermore, though alphaxalone-alphadolone was given for periods up to 20 days there was no evidence of tachyphylaxis or delay in recovery time.

BACKGROUND: Methods of classifying chronic obstructive pulmonary disease (COPD) depend largely upon spirometric measurements but disability is only weakly related to measurements of lung function. With the increased use of pulmonary rehabilitation, a need has been identified for a simple and standardised method of categorising disability in COPD. This study examined the validity of the Medical Research Council (MRC) dyspnoea scale for this purpose. METHODS: One hundred patients with COPD were recruited from an outpatient pulmonary rehabilitation programme. Assessments included the MRC dyspnoea scale, spirometric tests, blood gas tensions, a shuttle walking test, and Borg scores for perceived breathlessness before and after exercise. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ) and Chronic Respiratory Questionnaire (CRQ). The Nottingham Extended Activities of Daily Living (EADL) score and Hospital Anxiety and Depression (HAD) score were also measured. RESULTS: Of the patients studied, 32 were classified as having MRC grade 3 dyspnoea, 34 MRC grade 4 dyspnoea, and 34 MRC grade 5 dyspnoea. Patients with MRC grades 1 and 2 dyspnoea were not included in the study. There was a significant association between MRC grade and shuttle distance, SGRQ and CRQ scores, mood state and EADL. Forced expiratory volume in one second (FEV1) was not associated with MRC grade. Multiple logistic regression showed that the determinants of disability appeared to vary with the level of disability. Between MRC grades 3 and 4 the significant covariates were exercise performance, SGRQ and depression score, whilst between grades 4 and 5 exercise performance and age were the major determinants. CONCLUSIONS: The MRC dyspnoea scale is a simple and valid method of categorising patients with COPD in terms of their disability that could be used to complement FEV1 in the classification of COPD severity.

<h3>Importance</h3> Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. <h3>Objective</h3> To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. <h3>Evidence Review</h3> We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. <h3>Findings</h3> In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs). <h3>Conclusions and Relevance</h3> The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.

INTRODUCTION: The SCARE Guidelines were published in 2016 to provide a structure for reporting surgical case reports. Since their publication, SCARE guidelines have been widely endorsed by authors, journal editors, and reviewers, and have helped to improve reporting transparency of case reports across a range of surgical specialties. In order to encourage further progress in reporting quality, the SCARE guidelines must themselves be kept up to date. We completed a Delphi consensus exercise to update the SCARE guidelines. METHODS: A Delphi consensus exercise was undertaken. All members of the previous Delphi group were invited to participate, in addition to researchers who have previously studied case reports, and editors from the International Journal of Surgery Case Reports. The expert group was sent an online questionnaire where they were asked to rate their agreement with proposed changes to each of the 24 items. RESULTS: 56 people agreed to participate and 45 (80%) invitees completed the survey which put forward modifications to the original guideline. The collated responses resulted in modifications. There was high agreement amongst the expert group. CONCLUSION: A modified and improved SCARE checklist is presented, after a Delphi consensus exercise was completed. The SCARE 2018 Statement: Updating Consensus Surgical CAse REport (SCARE) Guidelines.

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.

Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene-environment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein-Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of 'pre-symptomatic MS' being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

Diagnostic karyotype provides the framework for risk-stratification schemes in acute myeloid leukemia (AML); however, the prognostic significance of many rare recurring cytogenetic abnormalities remains uncertain. We studied the outcomes of 5876 patients (16-59 years of age) who were classified into 54 cytogenetic subgroups and treated in the Medical Research Council trials. In multivariable analysis, t(15;17)(q22;q21), t(8;21)(q22;q22), and inv(16)(p13q22)/t(16;16)(p13;q22) were the only abnormalities found to predict a relatively favorable prognosis (P < .001). In patients with t(15;17) treated with extended all-trans retinoic acid and anthracycline-based chemotherapy, additional cytogenetic changes did not have an impact on prognosis. Similarly, additional abnormalities did not have a significant adverse effect in t(8;21) AML; whereas in patients with inv(16), the presence of additional changes, particularly +22, predicted a better outcome (P = .004). In multivariable analyses, various abnormalities predicted a significantly poorer outcome, namely abn(3q) (excluding t(3;5)(q25;q34)), inv(3)(q21q26)/t(3;3)(q21;q26), add(5q)/del(5q), -5, -7, add(7q)/del(7q), t(6;11)(q27;q23), t(10;11)(p11 approximately 13;q23), other t(11q23) (excluding t(9;11)(p21 approximately 22;q23) and t(11;19)(q23;p13)), t(9;22)(q34;q11), -17, and abn(17p). Patients lacking the aforementioned favorable or adverse aberrations but with 4 or more unrelated abnormalities also exhibited a significantly poorer prognosis (designated "complex" karyotype group). These data allow more reliable prediction of outcome for patients with rarer abnormalities and may facilitate the development of consensus in reporting of karyotypic information in clinical trials involving younger adults with AML. This study is registered at http://www.isrctn.org as ISRCTN55678797 and ISRCTN17161961.

Journal Article SENSORY DISTURBANCES FROM CEREBRAL LESIONS Get access HENRY HEAD, M.D., F.R.S., HENRY HEAD, M.D., F.R.S. Physician London HospitalGreenwich Search for other works by this author on: Oxford Academic PubMed Google Scholar GORDON HOLMES, M.D. GORDON HOLMES, M.D. Assistant Physician National Hospital Queen Square, and to the Seamen's HospitalGreenwich Search for other works by this author on: Oxford Academic PubMed Google Scholar Brain, Volume 34, Issue 2-3, November 1911, Pages 102–254, https://doi.org/10.1093/brain/34.2-3.102 Published: 01 November 1911

This new diagnostic consensus guideline is a joint project of the European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR] that now merges the former ECCO-ESGAR Imaging Guideline and the former ECCO Endoscopy Guideline, also including laboratory parameters. It has been drafted by 30 ECCO and ESGAR members from 17 European countries. All the authors recognize th e work of and are grateful to previous ECCO and ESGAR members who contributed tocreating the earlier consensus guidelines on imaging and endoscopy. The former guidelines have been condensed into this new diagnostic consensus guideline which consists of two papers: the first detailing assessment at initial diagnosis, to monitor treat ment and for the detection of complications; the second dealing with the available scoring systems and general considerations regarding the different diagnostic tools. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, an open call for participants was made, with ECCO participants selected by the Guidelines’ Committee of ECCO [known as GuiCom] on the basis of their publication record and a personal statement and ESGAR participants nominated by ESGAR. The following working parties were established: diagnostics at initial diagnosis, diagnostics for monitoring treatment in patients with known IBD, diagnostics for the detect ion of complications, scores for IBD, and general principles and technical aspects. Provisional guideline statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds. The first voting round introduced a more comprehensive voting procedure, in which each Guidelines participants voted on all statements by explicitly reviewing those statements together with their respective supporting text and references. The second voting round included optional national representative participation of ECCO’s 36 member countries and ESGAR’s 28 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine [www.cebm.net]. The ECCO statements were finalized by the authors at a face-to-face meeting in Barcelona in October 2017 and represent consensus with agreement of at least 80% of the present participants. Consensus statements are intended to be read in context with their qualifying comments and not in isolation. The supporting text was then finalised under the direction of each working group leader [SV, TK, GF, VA, EC], before being integrated by the consensus leaders [CM, JS, AS].

beta-Lactamases are the commonest single cause of bacterial resistance to beta-lactam antibiotics. Numerous chromosomal and plasmid-mediated types are known and may be classified by their sequences or phenotypic properties. The ability of a beta-lactamase to cause resistance varies with its activity, quantity, and cellular location and, for gram-negative organisms, the permeability of the producer strain. beta-Lactamases sometimes cause obvious resistance to substrate drugs in routine tests; often, however, these enzymes reduce susceptibility without causing resistance at current, pharmacologically chosen breakpoints. This review considers the ability of the prevalent beta-lactamases to cause resistance to widely used beta-lactams, whether resistance is accurately reflected in routine tests, and the extent to which the antibiogram for an organism can be used to predict the type of beta-lactamase that it produces.

BACKGROUND: Traumatic coagulopathy is thought to be caused primarily by fluid administration and hypothermia. METHODS: A retrospective study was performed to determine whether coagulopathy resulting from the injury itself is a clinically important entity in severely injured patients. RESULTS: One thousand eight hundred sixty-seven consecutive trauma patients were reviewed, of whom 1,088 had full data sets. Median Injury Severity Score was 20, and 57.7% had an Injury Severity Score > 15; 24.4% of patients had a significant coagulopathy. Patients with an acute coagulopathy had significantly higher mortality (46.0% vs. 10.9%; chi2, p < 0.001). The incidence of coagulopathy increased with severity of injury, but was not related to the volume of intravenous fluid administered (r2 = 0.25, p < 0.001). CONCLUSION: There is a common and clinically important acute traumatic coagulopathy that is not related to fluid administration. This is a marker of injury severity and is related to mortality. A coagulation screen is an important early test in severely injured patients.

A classification of anal fistulas is presented, which is the result of an analysis of 400 cases treated over the past 15 years, based on the pathogenesis of the disease and the normal muscular anatomy of the pelvic floor. Four main types were found but numerous variations of each occur, which are described. It is hoped that this will alert the surgeon to the various complex situations that he may encounter.

BACKGROUND: Fabry's disease, lysosomal alpha-galactosidase A deficiency, results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. METHODS: We evaluated the safety and effectiveness of recombinant alpha-galactosidase A in a multicenter, randomized, placebo-controlled, double-blind study of 58 patients who were treated every 2 weeks for 20 weeks. Thereafter, all patients received recombinant alpha-galactosidase A in an open-label extension study. The primary efficacy end point was the percentage of patients in whom renal microvascular endothelial deposits of globotriaosylceramide were cleared (reduced to normal or near-normal levels). We also evaluated the histologic clearance of microvascular endothelial deposits of globotriaosylceramide in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. RESULTS: In the double-blind study, 20 of the 29 patients in the recombinant alpha-galactosidase A group (69 percent) had no microvascular endothelial deposits of globotriaosylceramide after 20 weeks, as compared with none of the 29 patients in the placebo group (P<0.001). Patients in the recombinant alpha-galactosidase A group also had decreased microvascular endothelial deposits of globotriaosylceramide in the skin (P<0.001) and heart (P<0.001). Plasma levels of globotriaosylceramide were directly correlated with clearance of the microvascular deposits. After six months of open-label therapy, all patients in the former placebo group and 98 percent of patients in the former recombinant alpha-galactosidase A group who had biopsies had clearance of microvascular endothelial deposits of globotriaosylceramide. The incidence of most treatment-related adverse events was similar in the two groups, with the exception of mild-to-moderate infusion reactions (i.e., rigors and fever), which were more common in the recombinant alpha-galactosidase A group. IgG seroconversion occurred in 88 percent of patients who received recombinant alpha-galactosidase A. CONCLUSIONS: Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabry's disease, reversing the pathogenesis of the chief clinical manifestations of this disease.

Importance: The increasing burden due to cancer and other noncommunicable diseases poses a threat to human development, which has resulted in global political commitments reflected in the Sustainable Development Goals as well as the World Health Organization (WHO) Global Action Plan on Non-Communicable Diseases. To determine if these commitments have resulted in improved cancer control, quantitative assessments of the cancer burden are required. Objective: To assess the burden for 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus. Evidence Review: Cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) were evaluated for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods. Levels and trends were analyzed over time, as well as by the Sociodemographic Index (SDI). Changes in incident cases were categorized by changes due to epidemiological vs demographic transition. Findings: In 2016, there were 17.2 million cancer cases worldwide and 8.9 million deaths. Cancer cases increased by 28% between 2006 and 2016. The smallest increase was seen in high SDI countries. Globally, population aging contributed 17%; population growth, 12%; and changes in age-specific rates, -1% to this change. The most common incident cancer globally for men was prostate cancer (1.4 million cases). The leading cause of cancer deaths and DALYs was tracheal, bronchus, and lung cancer (1.2 million deaths and 25.4 million DALYs). For women, the most common incident cancer and the leading cause of cancer deaths and DALYs was breast cancer (1.7 million incident cases, 535 000 deaths, and 14.9 million DALYs). In 2016, cancer caused 213.2 million DALYs globally for both sexes combined. Between 2006 and 2016, the average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories, and the average annual age-standardized death rates decreased within that timeframe in 143 of 195 countries or territories. Conclusions and Relevance: Large disparities exist between countries in cancer incidence, deaths, and associated disability. Scaling up cancer prevention and ensuring universal access to cancer care are required for health equity and to fulfill the global commitments for noncommunicable disease and cancer control.

BACKGROUND: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. METHODS: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. FINDINGS: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. INTERPRETATION: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. FUNDING: Medical Research Council.

The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).

Importance: Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported. Objective: To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab. Design, Setting, and Participants: In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites. Interventions: Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death. Main Outcomes and Measures: The primary end point was overall survival (OS). Results: A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs. Conclusions and Relevance: Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types. Trial Registration: ClinicalTrials.gov Identifier: NCT02017717.

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.

Ghrelin is a novel growth hormone-releasing peptide, originally identified in the rat stomach as the endogenous ligand for the growth hormone secretagogue-receptor (GHS-R1a). Ghrelin is involved in the regulation of GH release, but it has recently been suggested that ghrelin may have other actions, including effects on appetite, carbohydrate metabolism, heart, kidney, pancreas, gonads, and cell proliferation. The distribution of ghrelin, its functional receptor (type 1a) and the unspliced, non-functional GHS-R type 1b mRNA expression was investigated in various human tissues using classical and real-time reverse transcription and polymerase chain reaction. GHS-R1a was predominantly expressed in the pituitary and at much lower levels in the thyroid gland, pancreas, spleen, myocardium and adrenal gland. In contrast, ghrelin was found in the stomach, other parts of the gut and, indeed, in all the tissues studied (adrenal gland, atrium, breast, buccal mucosa, esophagus, Fallopian tube, fat tissue, gall bladder, human lymphocytes, ileum, kidney, left colon, liver, lung, lymph node, muscle, muscle, myocardium, ovary, pancreas, pituitary, placenta, prostate, right colon, skin, spleen, testis, thyroid, and vein). GHS-R1b expression was also widespread in all tissues studied. The significance of the widespread tissue distribution of ghrelin remains to be determined. These data suggest that ghrelin might have widespread physiological effects via different, partly unidentified, subtypes of the GHS-R in endocrine and non-endocrine tissues.