Northampton General Hospital NHS Trust

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

OBJECTIVES: Rising demand for emergency and urgent care services is well documented, as are the consequences, for example, emergency department (ED) crowding, increased costs, pressure on services, and waiting times. Multiple factors have been suggested to explain why demand is increasing, including an aging population, rising number of people with multiple chronic conditions, and behavioral changes relating to how people choose to access health services. The aim of this systematic mapping review was to bring together published research from urgent and emergency care settings to identify drivers that underpin patient decisions to access urgent and emergency care. METHODS: Systematic searches were conducted across Medline (via Ovid SP), EMBASE (via Ovid), The Cochrane Library (via Wiley Online Library), Web of Science (via the Web of Knowledge), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; via EBSCOhost). Peer-reviewed studies written in English that reported reasons for accessing or choosing emergency or urgent care services and were published between 1995 and 2016 were included. Data were extracted and reasons for choosing emergency and urgent care were identified and mapped. Thematic analysis was used to identify themes and findings were reported qualitatively using framework-based narrative synthesis. RESULTS: Thirty-eight studies were identified that met the inclusion criteria. Most studies were set in the United Kingdom (39.4%) or the United States (34.2%) and reported results relating to ED (68.4%). Thirty-nine percent of studies utilized qualitative or mixed research designs. Our thematic analysis identified six broad themes that summarized reasons why patients chose to access ED or urgent care. These were access to and confidence in primary care; perceived urgency, anxiety, and the value of reassurance from emergency-based services; views of family, friends, or healthcare professionals; convenience (location, not having to make appointment, and opening hours); individual patient factors (e.g., cost); and perceived need for emergency medical services or hospital care, treatment, or investigations. CONCLUSIONS: We identified six distinct reasons explaining why patients choose to access emergency and urgent care services: limited access to or confidence in primary care; patient perceived urgency; convenience; views of family, friends, or other health professionals; and a belief that their condition required the resources and facilities offered by a particular healthcare provider. There is a need to examine demand from a whole system perspective to gain better understanding of demand for different parts of the emergency and urgent care system and the characteristics of patients within each sector.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

The Silver-Russell syndrome (SRS) is characterised by severe intrauterine growth retardation, with a preserved head circumference, leading to a lean body habitus and short stature. Facial dysmorphism and asymmetry are considered typical features of the syndrome, although the range of phenotypic variance is unknown. Fifty seven subjects varying in age from 0.84 to 35.01 years, in whom the diagnosis of SRS had been considered definite or likely, were re-evaluated in a combined clinical and molecular study by a single observer (SMP). In 50 patients the clinical findings complied with a very broad definition of SRS. Notable additional findings included generalised camptodactyly seen in 11 (22%), many with distal arthrogryposis. Thirteen of the 25 males required genital surgery for conditions including hypospadias and inguinal hernia. Fourteen (36.8%) subjects above school age have received a statement of special educational needs. Molecular genetic analysis was performed in 42 subjects and has identified maternal uniparental disomy of chromosome 7 in four. The phenotype was generally milder with birth weights for one patient above and three below -2 SD from the mean. Two children had classical facial dysmorphic features, and two had a milder facial phenotype. Of relevance to the possible molecular mechanism underlying this condition, none of the four disomic patients had significant asymmetry.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

Abstract The association between tumor Epstein-Barr virus (EBV) status and clinical outcome in Hodgkin lymphoma (HL) is controversial. This population-based study assessed the impact of EBV status on survival in age-stratified cohorts of adults with classic HL (cHL). Data from 437 cases were analyzed with a median follow-up of 93 months. Overall survival (OS) was significantly better for EBV-negative compared with EBV-positive patients (P &amp;lt; .001), with 5-year survival rates of 81% and 66%, respectively; disease-specific survival (DSS) was also greater for EBV-negative patients (P = .03). The impact of EBV status varied with age at diagnosis. In patients aged 16 to 34 years, EBV-associated cases had a survival advantage compared with EBV-negative cases, but differences were not statistically significant (P = .21). Among patients 50 years or older, EBV positivity was associated with a significantly poorer outcome (P = .003). Excess deaths occurred in EBV-positive patients with both early- and advanced-stage disease. In multivariate analysis of OS in the older patients, EBV status retained statistical significance after adjusting for the effects of sex, stage, and B symptoms (P = .01). Impaired immune status may contribute to the development of EBV-positive cHL in older patients, and strategies aimed at boosting the immune response should be investigated in the treatment of these patients. (Blood. 2005;106:2444-2451)

OBJECTIVE The FreeStyle Libre (FSL) flash glucose-monitoring device was made available on the U.K. National Health Service (NHS) drug tariff in 2017. This study aims to explore the U.K. real-world experience of FSL and the impact on glycemic control, hypoglycemia, diabetes-related distress, and hospital admissions. RESEARCH DESIGN AND METHODS Clinicians from 102 NHS hospitals in the U.K. submitted FSL user data, collected during routine clinical care, to a secure web-based tool held within the NHS N3 network. The t and Mann-Whitney U tests were used to compare the baseline and follow-up HbA1c and other baseline demographic characteristics. Linear regression analysis was used to identify predictors of change in HbA1c following the use of FSL. Within-person variations of HbA1c were calculated using . RESULTS Data were available for 10,370 FSL users (97% with type 1 diabetes), age 38.0 (±18.8) years, 51% female, diabetes duration 16.0 (±49.9) years, and BMI of 25.2 (±16.5) kg/m2 (mean [±SD]). FSL users demonstrated a −5.2 mmol/mol change in HbA1c, reducing from 67.5 (±20.9) mmol/mol (8.3%) at baseline to 62.3 (±18.5) mmol/mol (7.8%) after 7.5 (interquartile range 3.4–7.8) months of follow-up (n = 3,182) (P &amp;lt; 0.0001). HbA1c reduction was greater in those with initial HbA1c ≥69.5 mmol/mol (&amp;gt;8.5%), reducing from 85.5 (±16.1) mmol/mol (10%) to 73.1 (±15.8) mmol/mol (8.8%) (P &amp;lt; 0.0001). The baseline Gold score (score for hypoglycemic unawareness) was 2.7 (±1.8) and reduced to 2.4 (±1.7) (P &amp;lt; 0.0001) at follow-up. A total of 53% of those with a Gold score of ≥4 at baseline had a score &amp;lt;4 at follow-up. FSL use was also associated with a reduction in diabetes distress (P &amp;lt; 0.0001). FSL use was associated with a significant reduction in paramedic callouts and hospital admissions due to hypoglycemia and hyperglycemia/diabetic ketoacidosis. CONCLUSIONS We show that the use of FSL was associated with significantly improved glycemic control and hypoglycemia awareness and a reduction in hospital admissions.

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and are currently used as supportive therapy for multiple myeloma (MM). However, the exact clinical role of bisphosphonates in MM remains unclear. OBJECTIVES: This update of the first review published in 2002. We have also analyzed observational studies targeting osteonecrosis of jaw (ONJ). SEARCH STRATEGY: We searched the literature using the methods outlined in the previous review. We also searched observational studies or case reports examining ONJ. SELECTION CRITERIA: We selected RCTs with a parallel design related to the use of bisphosphonate in myeloma. We also selected observational studies or case reports examining bisphosphonates related to ONJ. DATA COLLECTION AND ANALYSIS: We have reported pooled data using either hazard ratio or risk ratio and, when appropriate, as absolute risk reduction and the number needed to treat to prevent or to cause a pathological event. We have assessed statistical heterogeneity and reported I(2) statistic. MAIN RESULTS: This review includes 17 trials with 1520 patients analyzed in bisphosphonates groups, and 1490 analyzed in control groups. In comparison with placebo/no treatment, the pooled analysis demonstrated the beneficial effect of bisphosphonates on prevention of pathological vertebral fractures (RR= 0.74 (95% CI: 0.62 to 0.89), P = 0.001), total skeletal related events (SREs) (RR= 0.80 (95% CI: 0.72 to 0.89), P < 0.0001) and on amelioration of pain (RR = 0.75 (95% CI: 0.60 to 0.95), P = 0.01). We found no significant effect of bisphosphonates on overall survival (OS), progression-free survival (PFS), hypercalcemia or on the reduction of non-vertebral fractures. The indirect meta-analyses did not find the superiority of any particular type of bisphosphonate over others. Only two RCTs reported ONJ. The identified observational studies suggested that ONJ may be a common event (range: 0% to 51%). AUTHORS' CONCLUSIONS: Adding bisphosphonates to the treatment of MM reduces pathological vertebral fractures, SREs and pain but not mortality. Assuming the baseline risk of 20% to 50% for vertebral fracture without treatment, we estimate that between eight and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming the baseline risk of 31% to 76% for pain amelioration without treatment, we estimate that between five to 13 MM patients should be treated to reduce pain in one patient. Also, with the baseline risk of 35% to 86% for SREs without treatment, we estimate that between six and 15 MM patients should be treated to prevent SRE(s) in one patient. No bisphoshphonate appears to be superior to others.

BACKGROUND: Locally advanced cervical cancer is treated with chemoradiotherapy (standard of care), but many patients still relapse and die from metastatic disease. We investigated chemoradiotherapy with or without induction chemotherapy to determine whether induction chemotherapy improves both progression-free survival and overall survival. METHODS: for 6 weeks) followed by standard cisplatin-based chemoradiotherapy. Stratification factors were recruiting site, stage, nodal status, three-dimensional conformal radiotherapy or intensity modulated radiotherapy, age, tumour size, and histology (squamous vs non-squamous). Primary endpoints were progression-free survival and overall survival within the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01566240, and EUDRACT, 2011-001300-35. FINDINGS: Between Nov 8, 2012, and Nov 17, 2022, 500 eligible patients were enrolled and randomly assigned to the chemoradiotherapy alone group (n=250) or the induction chemotherapy with chemoradiotherapy group. Of 500 patients, 354 (70%) had stage IIB disease and 56 (11%) stage IIIB disease. Pelvic lymph nodes were positive in 215 (43%) patients. 230 (92%) patients who received induction chemotherapy had at least five cycles. Median interval between induction chemotherapy and chemoradiotherapy was 7 days. Four or more cycles of cisplatin were given to 212 (85%) participants in the induction chemotherapy with chemoradiotherapy group and to 224 (90%) of participants in the chemoradiotherapy alone group. 462 (92%) participants received external beam radiotherapy and brachytherapy with a median overall treatment time of 45 days. After a median follow-up of 67 months, 5-year progression-free survival rates were 72% in the induction chemotherapy with chemoradiotherapy group and 64% in the chemoradiotherapy alone group with a hazard ratio (HR) of 0·65 (95% CI 0·46-0·91, p=0·013). 5-year overall survival rates were 80% in the induction chemotherapy with chemoradiotherapy group and 72% in the chemoradiotherapy alone group, with an HR of 0·60 (95% CI 0·40-0·91, p=0·015). Grade 3 or greater adverse events were reported in 147 (59%) of 250 individuals in the induction chemotherapy with chemoradiotherapy group versus 120 (48%) of 250 individuals in the chemoradiotherapy alone group. INTERPRETATION: Short-course induction chemotherapy followed by chemoradiotherapy significantly improves survival of patients with locally advanced cervical cancer. FUNDING: Cancer Research UK and University College London-University College London Hospitals Biomedical Research Centre.

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.

BACKGROUND: The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all-cause 30-day readmissions and complications in a prospective population-based cohort. METHODS: Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all-cause 30-day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two-level hierarchical structure with patients (level 1) nested within hospitals (level 2). RESULTS: Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. CONCLUSION: Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics.

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

The myelodysplastic syndromes (MDS) are a heterogeneous group of malignant haematopoietic disorders characterized by dysplastic changes in one or more cell lineages, ineffective haematopoiesis and a variable predilection to development of acute myeloid leukaemia (AML) (Swerdlow et al, 2008). The incidence of MDS is approximately 4/100 000 population/year, but it is predominantly a disease of the elderly with an incidence of > 30/100 000/year over the age of 70 years. Patients with suspected MDS should be assessed by a haematologist. As MDS is considered a rare or ‘orphan’ malignancy, patients should always be given the opportunity to be reviewed by a regional or national haematologist with a specific interest in MDS. All patients with a diagnosis of MDS must be discussed at a multi-disciplinary meeting (MDT), which should include allogeneic stem cell transplant representation. All patients diagnosed with MDS should be reported to the National Cancer Registry via the MDT, and to MDS-specific registries if appropriate. The diagnosis of MDS should be considered in patients with otherwise unexplained cytopenias(s). The minimum clinical assessment and laboratory investigation of a patient with possible MDS are shown in Table 1. Selected patients may require further investigations (Table 2). It is important to consider alternative diagnoses and reactive causes of marrow dysplasia. The initial assessment of a patient with unexplained cytopenias(s) may not confirm a diagnosis of MDS. In the absence of significant (>10%) marrow dysplasia or a clonal cytogenetic abnormality, a definitive diagnosis of MDS and distinction from other causes of cytopenia may be difficult. The term ‘idiopathic cytopenia of unknown origin’ may be used for patients with sustained (>6 months) cytopenia who do not fulfil the criteria for the diagnosis of MDS and where there is no other identifiable cause for the cytopenias (Valent et al, 2012). Such patients should be observed (with repeat marrow examination if necessary), as some may subsequently develop overt MDS. A blood film analysis and bone marrow examination for characteristic morphological features of dysplasia are both necessary for the diagnosis, classification and prognostic evaluation of MDS. This should be performed by a haematologist or haemato-pathologist. Blood film examination should include assessment of red cell, platelet and white cell morphology for features of dysplasia (Swerdlow et al, 2008; Bain et al, 2010). Bone marrow examination should include an assessment of May-Grünwald Giemsa (or equivalent) stained smears for myeloid, megakaryocyte and erythroid maturation, with identification of dysplasia if present. 500 nucleated cells and at least 30 megakaryocytes should, where possible, be evaluated and the percentage of blasts enumerated. Dysplastic features should be present in at least 10% of cells of the relevant lineage (myeloid, erythroid or megakaryocytic) (Swerdlow et al, 2008; Vardiman et al, 2009; Bain et al, 2010) (Evidence levels 2B,C). An iron stain (Prussian Blue/Perls stain) should be performed on all marrow aspirates to assess iron stores and to identify the presence and quantity of ring sideroblasts, which should be at least 15% of the total erythroblasts to be diagnostic of refractory anaemia with ring sideroblasts (RARS) or refractory anaemia with multilineage dysplasia + ring sideroblasts (RCMD-RS). A trephine biopsy (decalcified and paraffin-embedded or plastic embedded) including reticulin staining should be performed in all patients as it contributes significantly to the assessment of patients with MDS. It can provide information regarding cellularity and fibrosis, aiding the identification of hypocellular MDS and overlap myelodysplastic/myeloproliferative syndromes (Bennett & Orazi, 2009). If the aspirate is dilute, CD34+ staining of an adequate trephine biopsy specimen may allow assessment of bone marrow blast percentage. In patients with hypocellular marrows, the diagnosis of MDS requires dysplasia in the myeloid and/or megakaryocytic series, as erythroid dysplasia is common in aplastic anaemia. (Evidence levels 2B,C). Cytogenetic analysis should be performed on all patients with suspected MDS to confirm the diagnosis, inform management options and provide prognostic information. Cytogenetic analysis should be performed on at least 25 metaphases and should be reported in accordance with the International System for Human Cytogenetic Nomenclature Recommendations (Schaffer et al, 2009). Identification of clonal chromosomal abnormalities has become essential for the application of international prognostic scoring systems [such as the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R)]. A new comprehensive cytogenetic scoring system has been incorporated into the IPSS-R (Schanz et al, 2012). In addition, identification of a specific cytogenetic abnormality may provide a marker for assessing response to therapy. In patients where conventional marrow cytogenetic analysis is not possible (‘dry tap’) or has failed, fluorescence in situ hybridization analysis of bone marrow or peripheral blood films for selected cytogenetic anomalies (for instance monosomy 7, deletion of 5q, trisomy 8) may help provide diagnostic and prognostic evaluation (Evidence levels 2B,C). Despite on-going advances in molecular genetics, the classification of MDS currently remains largely based upon morphological examination with incorporation of limited genetic information. The diagnosis and classification of MDS should be based on the World Health Organization Classification (WHO, 2008 revision) (Swerdlow et al, 2008), which has superseded the former French-American-British (FAB) Classification (Bennett et al, 1982). The specific WHO classification subtype should be identified for each patient and included in the marrow aspirate report (Table 3). Due consideration should be given to the MDS/Myeloproliferative Neoplasm (MPN) category, which now includes chronic myelomonocytic leukaemia (CMML), MDS/MPN neoplasms (unclassifiable), and the provisional entity RARS with thrombocytosis (RARS-T) (Swerdlow et al, 2008). Adult patients with >20% blasts are now classified as having AML, although those with between 20 and 30% blasts were included in the IPSS. MDS secondary to prior cytotoxic therapy is classified as a separate entity by the WHO Classification (therapy-related myeloid neoplasms). Refractory cytopenias with unilineage dysplasia (RCUD) Refractory anaemia (RA) Refractory neutropenia (RN) Refractory or or rare blasts 10% of the cells of the lineage are dysplastic blasts of the erythroid are ring sideroblasts blasts dysplasia blasts of erythroid are ring sideroblasts or rare blasts in of cells in or more myeloid and/or erythroid and/or blasts ring sideroblasts or multilineage dysplasia dysplasia in 10% in myeloid cell but cytogenetic abnormality with blasts in peripheral blood with or platelet or rare blasts to megakaryocytes with blasts cytogenetic abnormality The of as analysis and has to the identification of in cells of patients with some of which may prognostic et al, 2009; et al, Identification by new of of cells with may help in clonal and disease et al, are with the ring et al, in other as and in analysis but prognostic in analysis has not been in et al, et al, analysis be incorporated into diagnostic or prognostic evaluation of patients with MDS but provide important information in the (Evidence levels 2B,C). is not for the diagnosis of MDS. is no specific diagnostic of MDS. anomalies may the diagnosis but should be in with morphological and cytogenetic (Evidence levels 2B,C). are on myeloid, and erythroid lineages, of et al, and CD34+ lineage Recommendations for of including for cell and been with of of for analysis et al, 2009; et al, et al, in the IPSS has been an important for assessing the of patients with MDS et al, prognostic been the important of which are cytogenetic (Table more prognostic information (Schanz et al, 2012). The IPSS has the of clinical with to by analysis of MDS patients not with the IPSS-R used the as the IPSS marrow and the IPSS-R has been to further by more cytogenetic of blast and of cytopenias (Table et al, 2012). This new scoring system has IPSS-R and has the prognostic to and in patients with MDS (Table A to the IPSS-R can be via the MDS This should be the scoring system for It should be the IPSS-R is not to be a scoring and can provide a at The WHO Prognostic Scoring System the WHO diagnosis, IPSS cytogenetic criteria and and the IPSS et al, allow an of at the disease for MDS largely the IPSS as are by the IPSS MDS includes patients with IPSS and MDS includes those with IPSS It remains IPSS-R patients should be into or As patients should be considered for management by clinical and and by patient and can be to response to therapy in to the which should be used to in all but not to therapy. all patients should be into clinical and/or Registry to information the and of MDS to National clinical are currently and MDS patients can be including and is to the management of MDS blood are a stem cell transplant or with cell is given to of et al, The for from patient to patient to as chronic disease and no for a can be red cell to including iron and the development of red cell should be given to red cell in patients who are and is for patients who are for a stem cell and for the management of including the assessment and management of possible are and are to In addition, the National for Health and for the and management of in patients are et al, 2012). The of may be considered in patients with who there is the of as in patients therapy for et al, there is no to should be given to all patients with The of platelet is to the management of in platelet may be of in patients but there is no to in patients not with platelet for in Blood The of as a in may be but should be shown in patients with disease or is some for the of in selected in of in the platelet et al, et al, The has been evaluated in a an et al, 2010). The of blast cell in patients It remains if into an in disease were and platelet in the currently be clinical The diagnosis of MDS is to the patient and It can be a diagnosis for the patient to and there are options and to All patients should be by the with in MDS. The MDS is a for all both at diagnosis and is patient information should be with at least on an et al, Patients by the IPSS as or and by the IPSS-R as and a The clinical in MDS patients to the of cytopenias and the to An for the management of MDS can be in 1. A chronic red cell for MDS patients in iron Patients with ineffective those with a of The to be and are for in in patients with predominantly erythroid disease RARS and et al, A may not iron is an of in stem cell et al, is by other iron for iron therapy are based upon The of red cell may be but it is is more relevant for total et al, et al, can be used to and iron but the with red cell has not been in MDS et al, et al, 2008; et al, is no to a for iron therapy in MDS and A of patients haematopoiesis on iron to for patients are all and limited et al, 2010). Despite there is in national and international for iron therapy in selected MDS patients et al, is the for iron therapy in MDS therapy is or The used for are MDS patients of of patients shown a in and iron over of therapy but remains et al, 2012). of all patients of to The and has a to the for for with and remains the therapy of as there is the of clinical it is and if although to is but not in patients et al, and therapy been used to the anaemia of MDS for over 20 and the et al, the of other has been Despite the in the of there are to the of in MDS to the in et al, 2010). are to at least there may be a for to therapy et al, 2008; et al, and in for et al, et al, not in the by et the to the of not been by include or not there is a significant in and for to to patients on red cell of in MDS are now The of patients who are to a of to are and not significantly the et al, et al, et al, The for response to should be used et al, et al, The and for with but is for with The is used as shown in Table therapy should be considered for MDS patients with an IPSS of or who fulfil the criteria for response and Patients with MDS in not to be considered for therapy with of and the of and stem cell which require red cell should with or The for is 30 000 for et al, If there is no response at the can be to or 30 000 for a further The for should be or et al, et al, 2008). The can be in to a of for a further of et al, are erythroid to the of to are et al, et al, et al, 2009). the of to is not as as used in of and is but there is of with to an response of in RARS et al, et al, 2009). It is the should be with from the in should be given as to approximately the white cell if or the white cell in the of clinical a of in to in is appropriate. of is a and of the has therapy of diagnosis response and the of to of et al, 2010). As a of therapy should be the of therapy to or the of et al, et al, the response criteria used were in other criteria for response used in the of response et al, are as of > and in and but remains Patients who a erythroid response been shown to a of response those who a erythroid response months) et al, patients who a erythroid response the of should be to the the If the response is at iron should be but common in MDS patients with in patients with anaemia. The of in MDS patients to has been at in one et al, and the of in significantly in patients with as or to therapy if the or if there is a in the can be with of the of to be a of in at least some patients with MDS. include a incidence of abnormalities cytotoxic et al, and of cells et al, is an overlap between MDS and aplastic anaemia. provide the for which are now an and for a of therapy should be considered in patients stem cell The response to in MDS patients is approximately et al, et al, In to aplastic a response to with age in MDS patients et al, 2008), although patient are The initial therapy be in patients with hypocellular bone marrow is and in patients with and been patients a response if et al, and presence of a has not been a for response et al, et al, 2008). with is with a in patients with aplastic anaemia et al, and in MDS should be to patients must be as an in with therapy. The of is as In aplastic anaemia there is for a and in patients with with et al, et al, for and in MDS is should be et al, and for at least to the Blood and must be of at of response is years. In the absence of it is to therapy response is A of should be but may in a of in which the should be in an to a further may a response although red cell is the may a for patients with of or a hypocellular bone is for and a response et al, not been The is characterized by a refractory in with characteristic megakaryocytes and erythroid It has a with a of at least but patients are and the at is approximately patients with MDS can the features or with as blasts and cytogenetic for in MDS with include and cytogenetic of are bone marrow blast and et al, 2012). of MDS to in the to in patients International criteria et al, et al, 2008). et the response of MDS with to the a of in a in patients with MDS to et al, Patients with the characteristic deletion an response to in patients with and patients with other cytogenetic This to a et al, and patients with deletion were with given for or in a of of patients were with a to response of although some patients to to a The were neutropenia and of et reported the of the in and MDS with which of for in a or for with The in in of patients with with in the group and in the with a of to Cytogenetic were in and of the In a platelet to response to patients with on in the for the of with IPSS or but it to in based on a of to This reviewed in a by the MDS who patients with for in a et al, 2012). patients to the of the The to a group of patients with who for the of with and not are in a some the of in patients with et al, reported an of secondary with in et al, 2012). This to limited to and chronic leukaemia from the of in MDS is not reported in The for for Human has now a for for the of patients with anaemia to or MDS with an deletion cytogenetic abnormality other options are or This is the which includes all patients with and IPSS of the of cytogenetic Patients with and/or bone marrow cells by a and largely to to This may be an to consider in the to et al, can be considered where on an Selected patients with and IPSS may be for allogeneic stem cell include patients who to those or patients with not considered for et al, 2010). is the with for MDS. all patients with diagnosed MDS should be discussed at a and the of allogeneic should be patient for is an important of and the to transplant patients with disease the of disease the of a transplant and the of As of the of should the disease In of an transplant are the patients with MDS a those with disease et al, et al, et al, 2010). for disease is to be if patients are at a with disease of and prior to the of et al, et al, et al, 2009). are the from et which the of disease for patients with IPSS and analysis not include patients with or patients with and not into In prognostic as red cell bone marrow and molecular abnormalities which were not included in the IPSS and a more for a given IPSS are currently for the of patients allogeneic are not considered in the or in the IPSS is some red cell can transplant et al, 2010). age not a on transplant but the are with age should be into assessing MDS patients for The et al, and the for Blood and et al, both been for MDS and shown to and et al, et al, 2009; et al, 2010). is not of assessed by has been with a and of allogeneic and et al, et al, 2008). the the prognostic of may be to of iron has been et al, and it remains to iron in patients who allogeneic This is a largely to the patient age and the of to The is 20 et al, and is at diagnosis, as patients and/or patients with disease may be considered for an allogeneic stem cell transplant at the As not incorporated in the incorporated in the alternative prognostic may be as the et al, and cytogenetic abnormalities should be into et al, A prognostic has been which a cytogenetic white blood cell for with a and This has been on of and to be in clinical patients a of for et al, include for and of or clinical are no specific to to in the performed in et al, is to alternative as specific in are is now by the for on the of patients included in the et al, 2009). in et al, et al, et al, 2012). a by the for Health Cancer MDS limited but with a of et al, 2012). has reported in but remains by the et al, et al, et al, 2008; et al, 2008; et al, A a response in a including 10% response and bone marrow response et al, patients on were to a to in the of et al, 2012). The of has not been in all patients and can be for the or in clinical may be considered for selected patients et al, if et al, 2008). transplant can in term for selected patients et al, although reported term significantly and are Patients with MDS IPSS or IPSS-R a to of to and a of et al, the for patients for therapy should be at the of the disease to Patients should be given the opportunity to in clinical given allogeneic is the therapy with should a patient is a possible transplant at diagnosis and the disease with the transplant is to and An for the management of MDS can be in patients with IPSS of age is and with an allogeneic transplant a for et al, In patients with has been to be for et al, of patients with MDS may to over with which for the presence of disease et al, The IPSS and the et al, The which from in to in et al, 2008). In age not disease or et al, et al, 2010). patient consideration include and the which in transplant et al, patients with disease and the of a transplant to be the possible from with significantly is is et al, of with for group of patients with a incidence of acute and at the of of which remains the for et al, et al, et al, et al, 2008; et al, et al, 2012). the from are to those with et al, from a is not or if there is a to bone marrow is an in et al, should be given to alternative from blood or clinical stem cell for MDS is not of clinical et al, 2010). disease at the of transplant significantly et al, 2009; et al, it to to prior to patients with bone marrow blasts or or where the of significant as are hypocellular marrow or reticulin a to to transplant should be patients with blasts and may from initial therapy to This can be by The is to a cytogenetic response and/or the blast percentage to The of in those patients an of but a abnormality is As the of marrow and is in MDS AML, it is to identify a prior to if An of therapy is to identify those patients with in the is Such patients should be considered for therapy or as et al, in MDS and both with and et al, et al, 2012). Such are of interest but As be as a to transplant in MDS of clinical those patients not for can be used in an to disease response and patients should be into clinical where The of are the if is and the of been reported of term in patients with MDS and an et al, patients are in AML, is months) and of marrow and more et al, et al, et al, et al, et al, 2010). of patients over the age of with MDS or an of 10% and an to in of the patients et al, to those with a who a of those with a abnormalities or a of The of for MDS et al, it is cytogenetic are to in patients with as there is no to in be et al, 2009). of as and an alternative to in MDS. do not a by the may a and are in the elderly and those with The of are the it is an based with a of with a response of and a with is to the of the et al, 2009). The of should be to clinical has been by et al, and the as a for patients not for with MDS or and with blasts and Patients should be for a minimum of The is which is for by a of The for the of in patient from the et al, 2009). This with significantly to conventional or et al, 2009). in with of patients to on the conventional In a analysis of the elderly patients the significantly to conventional 15% is the of in patients with and MDS et al, 2010). has been shown to be in all cytogenetic with conventional patients with a of with for conventional et al, 2009). patients with monosomy or 7, or as of a with to a over those with conventional et al, 2009). The of is unknown but therapy for as as a response is is patients a significant in with those having at least of the et al, of therapy for disease should be at the patient and It is patients a bone marrow assessment (for morphology and prior to the disease has not and at the of the should there be there is of disease for include given for no for further of given on a or a given for et al, 2009). been predominantly in but The is a alternative to the and is as the alternative to the for the of can be in the by et In selected patients who a with a and an in the of a should be of in MDS been et al, et al, used given for of patients and but to significant in patients has in MDS. may been by the a significant of patients or of The patients with 20 for as for a of et al, 2009). response + marrow response to criteria et al, of red cell and platelet to the response in the were of patients were the of the the has in both and the of over in the therapy in MDS. therapy be considered for a and rare group of those with an of blasts in a hypocellular marrow with a for no alternative therapy is and/or appropriate. The of patients with of et al, a but for a patients are Patients not for the and information in is to be and at the of to the the for the for the of The for in on an to it remains the at to if the has been or The the the The group selected to be of myelodysplastic (MDS) Recommendations are based on of the and to the The group the which subsequently revised with by of the of the for in The reviewed by a of approximately the and the for were incorporated where appropriate. of and of been assessed the of Recommendations and for assessing the of and of The of is to provide with on the management of patients with MDS. The may not be to patient and in all patient may an alternative All the to the of The to and been in of and/or from and/or In addition, has for for for & and for and and no of interest to of all can be by the

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterised by recurrent painful boils in flexural sites, such as the axillae and groin, that affects about 1% of the population, with onset in early adulthood. OBJECTIVES: To assess the effects of interventions for HS in people of all ages. SEARCH METHODS: We searched the following databases up to 13 August 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 7, 2015), MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We also searched five trials registers and handsearched the conference proceedings of eight dermatology meetings. We checked the reference lists of included and excluded studies for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of all interventions for hidradenitis suppurativa. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and methodological quality and performed data extraction. Our primary outcomes were quality of life, measured by a validated dermatology-specific scale, and adverse effects of the interventions. MAIN RESULTS: Twelve trials, with 615 participants, met our inclusion criteria. The median number of participants in each trial was 27, and median trial duration was 16 weeks. The included studies were conducted over a 32-year time period, from 1983 to 2015. A single RCT that was underpowered to detect clinically meaningful differences investigated most interventions.There were four trials of anti-TNF-α (tumour necrosis factor-alpha) therapies, which included etanercept, infliximab, and adalimumab. Adalimumab 40 mg weekly improved the Dermatology Life Quality Index (DLQI) score in participants with moderate to severe HS by 4.0 points relative to placebo (95% confidence interval (CI) -6.5 to -1.5 points), an effect size approximately equal to the DLQI minimal clinically important difference. We reduced the evidence quality to 'moderate' because the effect size was based on the results of only one study. In a meta-analysis of two studies with 124 participants, standard dose adalimumab 40 mg every other week was ineffective compared with placebo (moderate quality evidence). In a smaller study of 38 participants, of whom only 33 provided efficacy data, infliximab 5 mg/kg treatment improved DLQI by 8.4 DLQI points after eight weeks. Etanercept 50 mg twice weekly was well tolerated but ineffective.In a RCT of 200 participants, no difference was found in surgical complications (week one: risk ratio (RR) 0.78, 95% CI 0.58 to 1.05, moderate quality evidence) or risk of recurrence (after three months: RR 0.96, 95% CI 0.68 to 1.34, moderate quality evidence) in those randomised to receive a gentamicin-collagen sponge prior to primary closure compared with primary closure alone.RCTs of other interventions, including topical clindamycin 1% solution; oral tetracycline; oral ethinylestradiol 50 mcg with either cyproterone acetate 50 mg or norgestrel 500 mcg; intense pulsed light; neodymium-doped yttrium aluminium garnet (Nd:YAG) laser; methylene blue gel photodynamic therapy; and staphage lysate, were relatively small studies, preventing firm conclusions due to imprecision. AUTHORS' CONCLUSIONS: Many knowledge gaps exist in RCT evidence for HS. Moderate quality evidence exists for adalimumab, which improves DLQI score when 40 mg is given weekly, twice the standard psoriasis dose. However, the 95% confidence interval includes an effect size of only 1.5 DLQI points, which may not be clinically relevant, and the safety profile of weekly dosing has not been fully established. Infliximab also improves quality of life, based on moderate quality evidence.More RCTs are needed in most areas of HS care, particularly oral treatments and the type and timing of surgical procedures. Outcomes should be validated, ideally, including a minimal clinically important difference for HS.

AIMS: The epidemiological and pathological features of Hodgkin lymphoma (HL) are complex. The Epstein-Barr virus (EBV) is consistently associated with a proportion of cases, and these cases are thought to represent a distinct aetiological subgroup of HL. The aim of the present analysis was to determine the age and sex specific incidence of EBV associated and non-associated HL, analysed separately, using data derived from a population based study-the Scotland and Newcastle epidemiological study of Hodgkin's disease (SNEHD). This study also provided a unique opportunity to evaluate accuracy in the current diagnosis and classification of HL. METHODS: SNEHD analysed consecutive cases of HL diagnosed in the study area between 1993 and 1997. Diagnostic biopsy material was retrieved, EBV status of tumours was determined, and histological review was performed. RESULTS: In total, 622 cases were eligible for the study, and EBV studies and histopathological review were performed on biopsy material from 537 and 549 cases, respectively. Accuracy in the overall diagnosis of HL and classification of nodular sclerosis HL was good, but diagnosis of HL in the elderly and classification of other subtypes was less reliable. One third of classic HL cases were EBV associated, and age specific incidence curves for EBV associated and non-associated cases were distinct. CONCLUSIONS: Comparison of age specific incidence curves for EBV associated and non-associated HL supports the hypothesis that these are two distinct aetiological entities. Accuracy in the diagnosis of HL is generally good, but certain subgroups of cases continue to present diagnostic difficulties.

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. METHODS AND RESULTS: Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. CONCLUSIONS: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

ABSTRACT Nonmotor symptoms (NMS) are an important prodromal feature of Parkinson's disease (PD). However, their frequency, treatment rates, and impact on health‐related quality of life (HRQoL) in the early motor phase is unclear. Rates of NMS in enriched at‐risk populations, such as first‐degree PD relatives, have not been delineated. We assessed NMS in an early cohort of PD, first‐degree PD relatives and control subjects to address these questions. In total, 769 population‐ascertained PD subjects within 3.5 years of diagnosis, 98 first‐degree PD relatives, and 287 control subjects were assessed at baseline across the following NMS domains: (1) neuropsychiatric; (2) gastrointestinal; (3) sleep; (4) sensory; (5) autonomic; and (6) sexual. NMS were much more common in PD, compared to control subjects. More than half of the PD cases had hyposmia, pain, fatigue, sleep disturbance, or urinary dysfunction. NMS were more frequent in those with the postural instability gait difficulty phenotype, compared to the tremor dominant (mean total number of NMS 7.8 vs. 6.2; P &lt; 0.001). PD cases had worse HRQoL scores than controls (odds ratio: 4.1; P &lt; 0.001), with depression, anxiety, and pain being stronger drivers than motor scores. NMS were rarely treated in routine clinical practice. First‐degree PD relatives did not significantly differ in NMS, compared to controls, in this baseline study. NMS are common in early PD and more common in those with postural instability gait difficulty phenotype or on treatment. Despite their major impact on quality of life, NMS are usually under‐recognized and untreated. © 2015 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

Abstract: Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.