Kingston Hospital

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.

Abstract Background : There is a need for a generic, short, and easy‐to‐use assessment measure for common presentations of psychological distress in UK primary care mental health settings. This paper sets out the development of the CORE‐10 in response to this need. Method : Items were drawn from the CORE‐OM and 10 items were selected according to a combination of usefulness, coverage of item clusters, and statistical procedures. Three CORE‐OM datasets were employed in the development phase: (1) a primary care sample, (2) a sample from an MRC platform trial of enhanced collaborative care of depression in primary care, and (3) a general population sample derived from the Office of National Statistics Psychiatric Morbidity Follow‐up survey. A fourth dataset comprising a sample from an occupational health setting was used to evaluate the CORE‐10 in its standalone format. Results : The internal reliability (alpha) of the CORE‐10 was .90 and the score for the CORE‐10 correlated with the CORE‐OM at .94 in a clinical sample and .92 in a non‐clinical sample. The clinical cut‐off score for general psychological distress was 11.0 with a reliable change index (90% CI) of 6. For depression, the cut‐off score for the CORE‐10 was 13 and yielded sensitivity and specificity values of .92 (CI=.83–1.0) and 0.72 (CI=.60–.83) respectively. Conclusion : The CORE‐10 is an acceptable and feasible instrument that has good psychometric properties and is practical to use with people presenting with common mental health problems in primary care settings.

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.

BACKGROUND: Previous prospective cohort studies have shown that angiogenic factors have a high diagnostic accuracy in women with suspected pre-eclampsia, but we remain uncertain of the effectiveness of these tests in a real-world setting. We therefore aimed to determine whether knowledge of the circulating concentration of placental growth factor (PlGF), an angiogenic factor, integrated with a clinical management algorithm, decreased the time for clinicians to make a diagnosis in women with suspected pre-eclampsia, and whether this approach reduced subsequent maternal or perinatal adverse outcomes. METHODS: We did a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial in 11 maternity units in the UK, which were each responsible for 3000-9000 deliveries per year. Women aged 18 years and older who presented with suspected pre-eclampsia between 20 weeks and 0 days of gestation and 36 weeks and 6 days of gestation, with a live, singleton fetus were invited to participate by the clinical research team. Suspected pre-eclampsia was defined as new-onset or worsening of existing hypertension, dipstick proteinuria, epigastric or right upper-quadrant pain, headache with visual disturbances, fetal growth restriction, or abnormal maternal blood tests that were suggestive of disease (such as thrombocytopenia or hepatic or renal dysfunction). Women were approached individually, they consented for study inclusion, and they were asked to give blood samples. We randomly allocated the maternity units, representing the clusters, to blocks. Blocks represented an intervention initiation time, which occurred at equally spaced 6-week intervals throughout the trial. At the start of the trial, all units had usual care (in which PlGF measurements were also taken but were concealed from clinicians and women). At the initiation time of each successive block, a site began to use the intervention (in which the circulating PlGF measurement was revealed and a clinical management algorithm was used). Enrolment of women continued for the duration of the blocks either to concealed PlGF testing, or after implementation, to revealed PlGF testing. The primary outcome was the time from presentation with suspected pre-eclampsia to documented pre-eclampsia in women enrolled in the trial who received a diagnosis of pre-eclampsia by their treating clinicians. This trial is registered with ISRCTN, number 16842031. FINDINGS: Between June 13, 2016, and Oct 27, 2017, we enrolled and assessed 1035 women with suspected pre-eclampsia. 12 (1%) women were found to be ineligible. Of the 1023 eligible women, 576 (56%) women were assigned to the intervention (revealed testing) group, and 447 (44%) women were assigned to receive usual care with additional concealed testing (concealed testing group). Three (1%) women in the revealed testing group were lost to follow-up, so 573 (99%) women in this group were included in the analyses. One (<1%) woman in the concealed testing group withdrew consent to follow-up data collection, so 446 (>99%) women in this group were included in the analyses. The median time to pre-eclampsia diagnosis was 4·1 days with concealed testing versus 1·9 days with revealed testing (time ratio 0·36, 95% CI 0·15-0·87; p=0·027). Maternal severe adverse outcomes were reported in 24 (5%) of 447 women in the concealed testing group versus 22 (4%) of 573 women in the revealed testing group (adjusted odds ratio 0·32, 95% CI 0·11-0·96; p=0·043), but there was no evidence of a difference in perinatal adverse outcomes (15% vs 14%, 1·45, 0·73-2·90) or gestation at delivery (36·6 weeks vs 36·8 weeks; mean difference -0·52, 95% CI -0·63 to 0·73). INTERPRETATION: We found that the availability of PlGF test results substantially reduced the time to clinical confirmation of pre-eclampsia. Where PlGF was implemented, we found a lower incidence of maternal adverse outcomes, consistent with adoption of targeted, enhanced surveillance, as recommended in the clinical management algorithm for clinicians. Adoption of PlGF testing in women with suspected pre-eclampsia is supported by the results of this study. FUNDING: National Institute for Health Research.

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.

Congenital cytomegalovirus (cCMV) is the most common congenital infection in the developed world. Reported prevalence varies between cohorts but is approximately 7 per 1000 births.1 About half of cytomegalovirus (CMV)-infected babies with clinically detectable disease at birth are destined to have significant impairments in their development, and cCMV infection is implicated in approximately 25% of all children with sensorineural hearing loss (SNHL).1,2 Meta-analysis shows that although long-term sequelae, especially SNHL, are more common in those with clinically detectable disease at birth, they are also found in 13% of those without clinical features attributable to CMV on initial examination.1 Despite the significant long-term impact of cCMV infection, there is limited evidence on which to base many treatment decisions in clinical practice. In an era of enhanced perinatal screening, fetuses and newborns are increasingly tested for CMV after abnormalities were detected during routine ultrasonography or maternal serology. Furthermore, otherwise “asymptomatic”, congenitally CMV-infected, newborns are being identified after detection of SNHL through newborn hearing screening programs. Because of earlier diagnosis, babies with cCMV now presenting to pediatricians differ from those primarily included in clinical trials of treatment reported in the literature. A symposium was convened during the 2015 conference of the European Society of Paediatric Infectious Diseases to discuss the current management of cCMV. In attendance were clinicians from throughout Europe, many of whom are involved in policy for cCMV for their region/country. This article summarizes the discussions at this meeting alongside the evidence informing them. A balanced perspective of the controversies in this area is presented and areas of consensus highlighted. Finally, where evidence is lacking, suggestions are made for future research efforts to address areas of unmet medical need. The authors acknowledge the coexisting need for studies on the management of babies with symptoms consistent with cCMV, but in whom this diagnosis cannot be firmly established, and of those with symptomatic postnatal CMV infection; this article does not, however, address these groups. The internationally accepted GRADE system for evaluating evidence has been used to illustrate points where relevant (Table 1).3TABLE 1.: Grade System of Evaluating Evidence3DEFINITIONS OF SYMPTOMATIC DISEASE Classically, cCMV infection is categorized as “symptomatic” or “asymptomatic” at birth. Differing definitions and opinions on what constitutes “symptomatic” CMV infection, however, makes interpreting the literature challenging. Indeed, some of the largest cohort studies include babies with SNHL at birth in the group described as being “asymptomatic” because no “clinically apparent disease” was detectable during newborn examination.4 In modern healthcare systems, whereby cCMV is increasingly detected through screening for other conditions, alongside increased accessibility of investigations, such as magnetic resonance imaging (MRI), the traditional dichotomy between clinically “apparent” and “inapparent” disease is becoming less meaningful. Table 2 summarizes the accepted clinical features of cCMV disease with those symptoms detectable on newborn examination listed separately to those detectable only if specific investigations are conducted, for example, when cCMV is already suspected.5–8TABLE 2.: Possible Signs and Symptoms in Children With Congenital CMV5–8Full Consensus Within This Expert Group Was That 1. For the purposes of research and publication, newborns identified as having cCMV disease after abnormal clinical examination at birth (such as microcephaly, small for gestational age (SGA), widespread petechiae, hepatosplenomegaly) should be differentiated from those babies identified through screening or investigation for other disorders, for example, those tested for CMV after known/likely maternal infection or abnormal newborn hearing screening. This differentiation would allow for more accurate assessment of the prognostic value of individual manifestations of “symptomatic” disease on longer-term outcomes as already shown in other publications.9 2. “Symptomatic” cCMV should be considered as “severe,” “moderate” or “mild” disease. a. “Mild” disease includes those with isolated (1 or 2 at most), otherwise, clinically insignificant or transient findings, such as petechiae, mild hepatomegaly or splenomegaly or biochemical/hematologic abnormalities (such as thrombocytopenia, anemia, leukopenia, borderline raised liver enzyme abnormalities or conjugated hyperbilirubinemia) or SGA (defined as weight for gestational age <−2 standard deviations) without microcephaly. b. “Severe” disease includes those with central nervous system (CNS) involvement (abnormal neurologic or ophthalmologic examination, microcephaly or neuroimaging consistent with cCMV disease [such as calcifications, moderate to severe ventriculomegaly, cysts, white matter changes, cerebral or cerebellar hypoplasia, hippocampal dysplasia, neuronal migration abnormalities])10 or with life-threatening disease. The Majority Agreed That 2b. “Severe” disease also includes babies with evidence of severe single-organ disease (including those with clinically significant liver enzyme abnormalities [liver “failure”] and marked hepatosplenomegaly) or those with significant multiorgan involvement. Babies with transient or otherwise clinically insignificant abnormalities (ie, the babies are not “sick”) that resolve spontaneously over a few weeks are not included in this group even if these abnormalities are multiple. 2c. A further group exists that may be considered to have “moderate” disease. This group is heterogeneous and includes, for example, those with persistent (eg, more than 2 weeks duration) abnormalities of hematologic/biochemical indices or more than 2 “mild” disease manifestations (as listed earlier). Because of lack of evidence, full consensus could not be reached on how to approach this group, and treatment decisions are currently made on a case by case basis. Development of a validated clinical scoring system for disease severity at presentation and risk of sequelae would be beneficial for both counseling parents and informing treatment decisions. 3. Defining CNS involvement a. It remains uncertain whether some, nonspecific findings detected on cranial ultrasound (CrUSS) and MRI (particularly isolated lenticulostriatal vasculopathy [LSV]) constitute clinically significant CNS disease. LSV has been detected in 0.4%–5.8% of all neonates undergoing an ultrasound, and only 5% has been associated with cCMV.11,12 Some have suggested isolated LSV as a marker of risk for SNHL.11 Others have found only more extensive neuroimaging abnormalities to be of prognostic value.13,14 The majority at this meeting would not consider LSV in isolation to be a notable CNS manifestation of disease. It is suggested that neuroradiologic abnormalities not known to be clearly associated with CMV disease and adverse outcomes are discussed with a suitably experienced neuroradiologist, particularly, if the results of these discussions might influence treatment decisions. b. The exact pathophysiology of SNHL is not clear but is likely secondary to infection and degradation of sensory structures within the inner ear.15,16 It is therefore debated whether isolated SNHL should truly be considered a CNS manifestation of infection and, as a consequence, whether such children should be considered comparable to those with CNS disease included in published clinical trials. No studies have addressed this specific population, but a nonrandomized cohort study observing the effects of valganciclovir in isolated SNHL is in progress (clinicaltrials.gov NCT02005822). The majority of experts at this meeting would categorize babies with isolated, confirmed SNHL in the “severe”/CNS group because bilateral SNHL is not only associated with likely long-term impairments but was also included in the criteria for recruitment in the only randomized controlled trials (RCTs) in cCMV. However, consensus was not reached because the spectrum of hearing loss is wide, and treatment of isolated SNHL has not been evaluated in any RCTs. WHEN SHOULD TESTING FOR CONGENITAL CMV BE CONSIDERED? Indications for testing for cCMV are based on the presence of one or more of the most frequently observed clinical features (Table 3).17 Unfortunately, predictive values for each of these features are not available.TABLE 3.: Clinical Features That Should Lead to Testing for Congenital CMVFull Consensus Within This Expert Group Was That Testing for cCMV Should be Performed in 1. Fetuses with ultrasound/MRI imaging consistent with cCMV disease (by appropriately timed antenatal testing of amniotic fluid).18 (Quality C, Level 1) 2. Newborns where there is a maternal history of suspected primary CMV infection during pregnancy. If antenatal testing of amniotic fluid has been conducted, it is suggested that cCMV infection should still be confirmed at birth because both false-positive and -negative results have been reported.18 (Quality C, Level 1) 3. Newborns with signs/symptoms consistent with cCMV disease (see Table 2; including those with findings consistent with cCMV on antenatal imaging). (Quality B, Strength 1) 4. Children with confirmed SNHL.16 Systems need to be established to ensure testing for cCMV occurs, where possible, in the first 21 days of life because dried blood spot (DBS) are not always readily available for testing (see below). (Quality B, Strength 1) The Majority Agreed That 5. Newborns who are SGA should not routinely be tested. Studies in SGA newborns have shown the prevalence of cCMV to be 0%–5.2%.19–22 However, the majority of studies report a prevalence of 1.4%–1.8%, which is not significantly higher than the prevalence of cCMV in the general population. Therefore, evidence is insufficient to justify screening all newborns with isolated SGA for cCMV. None of these studies distinguish between asymmetrical (with normal head circumference) and symmetrical SGA, but when head circumference was mentioned, most SGA babies with cCMV had microcephaly (head circumference <−2 standard deviations).21,22 Because of this, and the poor prognostic outcome of children with cCMV and microcephaly, many present at this meeting test those babies with symmetrical SGA but not those with preserved head growth.14(Quality C, Strength 2) 6. Prematurity. Evidence that premature babies have a higher incidence of cCMV is limited.20,23 Testing extremely premature babies (<28 weeks gestational age) at birth does, however, assist in differentiating between congenital and postnatal infection. This may be very helpful in guiding the management of these babies that are particularly vulnerable to symptomatic postnatal infection. However, consensus was not reached regarding practice in this area, with cost being a factor among other considerations.24 (Quality C, Strength 2) 7. Testing of babies born to mothers who are known to be CMV seropositive at the establishment of pregnancy. Although maternal nonprimary CMV infection is known to be important when considering the overall burden of cCMV disease, testing all babies born to these women, particularly in populations with high maternal seroprevalence, is tantamount to universal neonatal screening.25,26 Identifying women with nonprimary CMV who are at highest risk of transmitting infection to their fetus remains elusive. It was agreed that individual case discussion and local policy should therefore dictate practice in this area. Further research is clearly needed. LABORATORY DIAGNOSIS OF CONGENITAL CMV INFECTION Testing for cCMV using CMV polymerase chain reaction (PCR) in urine is highly reliable: sensitivity is 100% and specificity 99%.27 One negative urine specimen in a neonate is therefore sufficient to exclude infection, and repeat sampling is not necessary. After 21 days, a urine positive for CMV could be because of CMV acquired postnatally from, for example, passage through the birth canal or through breast milk. As CMV PCR techniques are becoming more sensitive, earlier testing, before the age of 14 days, is recommended.27 CMV PCR testing of saliva is an alternative and is easy to perform. Samples should be taken immediately before feeding in breastfed newborns, and confirmed with urine, as false-positive results have been reported.28–31 PCR assay of neonatal DBS can be performed retrospectively in an attempt to diagnose cCMV after the first 21 days of life. is in but is highly on the techniques used and the being a negative DBS PCR be used to exclude a diagnosis of Consensus Within This Expert Group Was That 1. Testing for cCMV should be performed using a CMV PCR of urine within 21 days of birth but within 14 days of birth (Quality B, Strength 2. PCR testing can be an but a positive should be confirmed using urine (Quality B, Strength 3. After the age of 21 days, CMV PCR of DBS can be used to diagnose cCMV sensitivity is and a negative test cannot be used to exclude a diagnosis of cCMV (Quality B, Strength A DIAGNOSIS OF CONGENITAL CMV INFECTION After a diagnosis of cCMV infection has been investigations are to the of disease and to assist with discussions regarding and Consensus Within This Expert Group Was That 1. The investigations are in any in whom a diagnosis of cCMV is for the manifestations of disease (Table blood liver (Quality Strength 1) testing some screening such as are not sufficient to central hearing loss in (Quality Strength 1) (Quality Strength 1) 2. If imaging to is to be MRI is the neuroimaging MRI can be performed in neonates without the need for and both highly and of the of which (Quality C, Strength 1) 3. MRI should be performed in babies with clinically detectable neurologic findings or The Majority Agreed That 4. MRI should be performed in any babies with cCMV and evidence of CMV disease (see Table (Quality C, Strength 1) 5. CMV PCR should be performed in blood at studies have shown the of CMV to be associated with long-term and this may be when evaluating babies without any other manifestations of cCMV CMV PCR should not, however, be used to cCMV infection the of CMV in blood has been described even in babies with severe cCMV (Quality C, Strength 2) 6. of fluid No current evidence examination of as of routine Studies have shown detectable CMV in and such as a poor However, have shown no prognostic value from in the clinical Despite this lack of evidence, there was a majority that although a area of for future should not be performed routinely in babies with cCMV infection (Quality C, Strength a Agreed That 7. MRI should be performed in all Although there is no evidence that MRI prognostic to in those without evidence of CMV disease at birth, some that it is to MRI in all babies because can be identified as with (Quality Strength No are currently for the treatment of cCMV. Although many case and cohort studies have reported on treatment for cCMV, there are results from only 2 The first of these studies evaluated treatment in neonates of gestational age weeks and clinically apparent disease in the newborn with evidence of CNS disease (including microcephaly, abnormal indices for hearing and hearing and outcomes were but there was significant loss to A more to treatment with valganciclovir and included babies with any evidence of symptomatic (including cCMV babies however, had isolated, mild clinical and in the treatment group had isolated SNHL A on both hearing and outcomes was shown with the treatment The treatment of hearing outcomes most in those with CNS involvement. of was only however, for hearing as to hearing is of and only for CNS involvement. the of some features of cCMV disease in published alongside the of hearing loss and in SNHL reported in cCMV, it is even more to any regarding treatment from Clinical trials to not, evidence on which to base treatment decisions for many of the presenting to clinicians in clinical practice. Table on which should be treatment after a risk discussion with the This and associated areas where consensus was discussion the treatment of babies with less severe cCMV disease and whether the shown in the treatment was sufficient to justify such a of Although clinical findings such as SGA and have been shown in cohorts to risk for SNHL, more of that these findings in isolation are associated with outcomes in babies presenting without other manifestations of symptomatic on the or of symptoms treatment remains and it is therefore that clinicians discuss treatment and with an in this of Consensus Within This Expert Group Was That 1. Babies with evidence of CNS disease should treatment (Quality Strength should be for (Quality B, Strength 2. Babies with no findings consistent with CMV disease should not treatment because no evidence exists to treatment in this group (Quality Strength to 3. Babies with evidence of life-threatening disease or severe single-organ disease or multiorgan involvement should Although evidence is particularly for life-threatening disease, consensus was that treatment should be considered in this group (Quality B, Strength Consensus could not be reached on of treatment in this 4. valganciclovir is now the of should be used in babies to or where is uncertain (Quality Strength The Majority Agreed That 5. Babies with “mild” cCMV disease (as should not No studies have clearly addressed treatment in this present at this meeting would not, babies with or 2 isolated or clinically manifestations of disease (Quality C, Strength 6. Babies with “moderate” cCMV disease (as earlier). Evidence for babies with but not manifestations of disease (including without significantly raised liver is It that these are discussed on a with a with of babies with cCMV (such as a disease (Quality B, Strength 7. of isolated The majority at this meeting would include SNHL at birth in their for treatment because this was in the criteria for treatment in RCTs. Furthermore, the of treatment is in hearing than hearing with outcomes reported in studies (with likely was not, however, and it is that no have addressed treatment in this group of babies who are now identified through newborn hearing screening C, Strength and Although valganciclovir is now treatment in most it is currently whether valganciclovir areas as as where should be (eg, CNS or inner because no studies have the 2 In those with severe disease, particularly if is by some in of treatment can be (Quality C, Strength in without CNS In those in whom the is taken to the majority would for However, there was no consensus on this in of the shown for treatment in the only (Quality B, Strength babies than of children has not been addressed in any although it is that the is also not evidence case of small of babies the newborn have reported Babies found to have SNHL after hearing screening at birth not have a diagnosis of cCMV confirmed the of for No consensus was reached on how it might be to treatment in this or in the of hearing are currently evaluating the of treatment in children with cCMV and SNHL (clinicaltrials.gov and which may this for the newborn Strength OF of the less babies to the effects of currently available is frequently observed during treatment in This is reported less with valganciclovir than with with during the first of with no increased observed after weeks in those randomized to treatment with in the only evaluating The of valganciclovir also the burden of and risk of and central observed during treatment with has been reported in to of those with and in a In the most study of treatment with liver was but this was clinically significant when with In all abnormal and after effects have not been evaluated in neonates with or studies the risk of and Although this has not been observed in to parents should be these particularly when considering treatment in those in which has not been clearly No adverse long-term effects have been in a small cohort of babies in neonatal studies and to OF Table summarizes a for babies for cCMV. are based on the and from the published and to are no to however, have a when is a (eg, in those with or where there are treatment Consensus Within This Expert Group Was That treatment is babies should have weight and to of (see Table Strength 1) treatment is parents should be both the known and effects of treatment with current (Quality Strength for no published Although there are of treatment no cohorts have been to this to be evaluated in during life. possible, children treatment be a to a Agreed That Some report to assist in decisions regarding and detection of however, most experts at this meeting not this is not by any and of after treatment is with no with long-term outcomes (Quality Strength If is after it is suggested that parents are of the that be detectable and that this is of Table summarizes of babies with cCMV and The for is based on long-term studies of SNHL in is suggested during the first 2 of life because this is the of highest risk for of hearing loss and a for detection of SNHL during this is also most likely to long-term should however, because in hearing throughout (Quality B, Strength is suggested at and 2 of age with This is not, however, routinely in all and there is no in this group, although detection of impairments is agreed to be is at children can in those with clinically detectable disease at birth, but not in those because in has been observed in this group (Quality C, Strength should be for where these (see cCMV are not parents of children with hearing loss may from for those with hearing FOR Clinical trials treatment of those with more manifestations of clinically detectable disease at birth and those with isolated Clinical studies of antenatal to of infection and cCMV disease infection is to cCMV should it clear how those included were identified (ie, babies presenting with clinically detected babies identified through antenatal or postnatal screening including hearing screening or after further investigation of such as thrombocytopenia, found when blood sampling is performed for other Development of clinical to categorize severity of disease and babies with findings of and associated outcomes to assist counseling of Studies of particularly and value with to long-term impairments particularly in those without clinically detectable disease at birth through studies cCMV Clinical trials of alternative treatment and when It that a of treatment be beneficial in babies with such clinical manifestations of disease and likely burden and The of both and of long-term outcomes would of future and more accurate counseling and children treatment should be in a to for any long-term effects of of risk for maternal particularly, in those mothers with known to CMV As at the this article the consensus of a group of with a in cCMV. It that of practice is based on limited but areas where there is consensus have shown cost of screening at birth for cCMV, although these are by the raised in this article regarding of of treatment and agreed treatment in It be to address many of the research raised through the significant and long-term alongside in such studies when treatment is being more accurate on disease manifestations and treatment outcomes in alongside maternal however, treatment as shown very for the management of This a approach to initial definitions of and which is currently being addressed by a of clinicians with an in this area through both and European such as Paediatric European for of Infectious the European Congenital CMV and European Society of Paediatric Infectious Diseases and European Society for Clinical It should also be that this article on postnatal of diagnosis and is an associated and need for alongside and to address in of antenatal It is that through such progress be made in infection and disease in newborns and children with cCMV. The children and their who have for and who on a to and consistent including those parents who are involved with other parents through local or including not CMV

White blood cell (WBC) count is a known risk factor for atherosclerotic vascular disease in adult women. Polycystic ovary syndrome (PCOS) is potentially a risk factor for atherosclerosis and cardiovascular disease. The aim of the present study was to investigate leukocyte count in PCOS. One hundred and fifty PCOS women matched for age and body mass index with 150 healthy women were enrolled. WBC count, C-reactive protein, and a complete anthropometrical, metabolic, and hormonal evaluation were performed in both groups. Serum insulin, glucose level, and lipid profile were also measured in each subject. WBC count was significantly higher (P < 0.0001) in PCOS with (interquartile range in parentheses) 7260 (393) cells/mm(3), compared with controls with 5220 (210) cells/mm(3). C-reactive protein levels were significantly increased (P < 0.0001) in PCOS with 2 (1) mg/liter compared with healthy women with 0.7 (0.8) mg/liter. In both groups, there was a significant (P < 0.0001) linear correlation between WBC count and homeostasis model assessment score (PCOS, r = 0.94; controls, r = 0.91). Multiple linear regression analysis showed that other hormone levels are not predictors of leukocyte count both in PCOS and control women. In conclusion, our data demonstrate that PCOS women have an increased WBC count that correlates with homeostasis model assessment values.

Abstract Rationale The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non–idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17–2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of &amp;lt;80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05–2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39−3.71). Conclusions Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

The objective of this study was to analyse associations between sexualised substance use (chemsex), STI diagnoses and sexual behaviour among gay bisexual and other men who have sex with men accessing sexual health clinics to better inform clinical pathways. A retrospective case notes review was undertaken following the introduction of more detailed and holistic profomas for all gay bisexual and other men who have sex with men attending two London sexual health clinics between 1 June 2014 and 31 January 2015. Chemsex status was documented for 655/818. Overall, 30% disclosed recreational drug use of whom 113 (57%) disclosed chemsex and 27 (13.5%) injecting drugs. HIV-positive gay bisexual and other men who have sex with men were more likely to disclose chemsex (AOR 6.68; 95% CI 3.91-11.42; p < 0.001). Those disclosing chemsex had a higher incidence of acute bacterial STIs (AOR 2.83 CI 1.79-4.47; p < 0.001), rectal STIs (AOR 3.10 CI 1.81-5.32; p < 0.001) or hepatitis C (AOR 15.41 CI 1.50-158.17; p = 0.021). HIV incidence in the study period was 1.8% (chemsex) vs. 0.9% (no chemsex) (p = 0.61). Chemsex was associated with having more sexual partners, transactional sex, group sex, fisting, sharing sex toys, injecting drug use, higher alcohol consumption and the use of 'bareback' sexual networking applications (p < 0.004). Chemsex participants were also more likely to have accessed post-exposure prophylaxis for HIV in the study period and report sex with a discordant HIV or hepatitis C-infected partner (p < 0.001). Chemsex disclosure is associated with higher risk-taking behaviours, acute bacterial STIs, rectal STIs and hepatitis C incidence. HIV incidence was higher but not significantly so in the study period. Chemsex disclosure in sexual health clinics should prompt an opportunity for prevention, health promotion and wellbeing interventions.

Bowel function was assessed in 51 subjects: 10 women and seven men who habitually consumed an omnivorous, vegetarian, or vegan diet. The subjects on these diets had a mean intake of fibre of 23 g, 37 g, and 47 g respectively. Mean transit times were variable and not significantly different between the groups. Vegans, however, had a greater frequency of defecation and passed softer stools. All measurements of bowel function were significantly correlated with total dietary fibre. As dietary fibre increased mean transit time decreased, stool frequency increased and the stools became softer. Men produced a greater quantity of softer, less formed faeces than women. During the luteal phase of the menstrual cycle women excreted harder stools and had a significantly longer mean transit time. The finding that mean transit time was more highly correlated with faecal form than any of the other bowel function measurements could be of practical importance.

The value of fibrinolytic enhancement with an anabolic steroid (stanozolol) combined with elastic stockings in treating venous lipodermatosclerosis was assessed in a six-month double-blind cross-over trial. Thirty-four legs of 23 patients in whom other treatments had failed were studied. The patients were randomly divided into two groups who were treated with either stanozolol plus elastic stockings or placebo plus elastic stockings for three months, and then vice versa. Treatment with or without stanozolol caused the area of lipodermatosclerosis to decrease, but the rate of healing when patients took stanozolol was double that when they took the placebo, and this was assumed to be biologically important. Stanozolol also reduced the incidence of extravascular fibrin detected in skin biopsy specimens. The elastic stocking with placebo produced significant decreases in leg volume, ankle circumference, and skin thickness. Stanozolol is valuable in treating intractable lipodermatosclerosis, giving relief of pain and reducing induration, inflammation, tenderness, and pigmentation.

OBJECTIVE: To evaluate the efficacy of ultrasound guided dry needling and autologous blood injection for the treatment of patellar tendinosis. DESIGN: Prospective cohort study. SETTING: Hospital/clinic based. PATIENTS: 47 knees in 44 patients (40 men, 7 women, mean age 34.5 years, age range 17 to 54 years) with refractory tendinosis underwent sonographic examination of the patellar tendon following referral with a clinical diagnosis of patellar tendinosis (mean symptom duration 12.9 months). INTERVENTIONS: Ultrasound guided dry needling and injection of autologous blood into the site of patellar tendinosis was performed on two occasions four weeks apart. MAIN OUTCOME MEASURES: Pre- and post-procedure Victorian Institute of Sport Assessment scores (VISA) were collected to assess patient response to treatment. Follow up ultrasound examination was done in 21 patients (22 knees). RESULTS: Therapeutic intervention led to a significant improvement in VISA score: mean pre-procedure score = 39.8 (range 8 to 72) v mean post procedure score = 74.3 (range 29 to 100), p<0.001; mean follow up 14.8 months (range 6 to 22 months). Patients were able to return to their sporting interests. Follow up sonographic assessment showed a reduction in overall tendon thickness and in the size of the area of tendinosis (hypoechoic/anechoic areas within the proximal patellar tendon). A reduction was identified in interstitial tears within the tendon substance. Neovascularity did not reduce significantly or even increased. CONCLUSIONS: Dry needling and autologous blood injection under ultrasound guidance shows promise as a treatment for patients with patellar tendinosis.

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 ).

OBJECTIVE: To determine whether suboptimal management in hospital could contribute to poor outcome in children admitted with meningococcal disease. DESIGN: Case-control study of childhood deaths from meningococcal disease, comparing hospital care in fatal and non-fatal cases. SETTING: National statistics and hospital records. SUBJECTS: All children under 17 years who died from meningococcal disease (cases) matched by age with three survivors (controls) from the same region of the country. MAIN OUTCOME MEASURES: Predefined criteria defined optimal management. A panel of paediatricians blinded to the outcome assessed case records using a standardised form and scored patients for suboptimal management. RESULTS: We identified 143 cases and 355 controls. Departures from optimal (per protocol) management occurred more frequently in the fatal cases than in the survivors. Multivariate analysis identified three factors independently associated with an increased risk of death: failure to be looked after by a paediatrician, failure of sufficient supervision of junior staff, and failure of staff to administer adequate inotropes. Failure to recognise complications of the disease was a significant risk factor for death, although not independently of absence of paediatric care (P = 0.002). The odds ratio for death was 8.7 (95% confidence interval 2.3 to 33) with two failures, increasing with multiple failures. CONCLUSIONS: Suboptimal healthcare delivery significantly reduces the likelihood of survival in children with meningococcal disease. Improved training of medical and nursing staff, adherence to published protocols, and increased supervision by consultants may improve the outcome for these children and also those with other life threatening illnesses.

The effect of powdered ginger root was compared with metoclopramide and placebo. In a prospective, randomised, double-blind trial the incidence of postoperative nausea and vomiting was measured in 120 women presenting for elective laparoscopic gynaecological surgery on a day stay basis. The incidence of nausea and vomiting was similar in patients given metoclopramide and ginger (27% and 21%) and less than in those who received placebo (41%). The requirement for postoperative antiemetics was lower in those patients receiving ginger. The requirements for postoperative analgesia, recovery time and time until discharge were the same in all groups. There was no difference in the incidence of possible side effects such as sedation, abnormal movement, itch and visual disturbance between the three groups. Zingiber officinale is an effective and promising prophylactic antiemetic, which may be especially useful for day case surgery.

UNLABELLED: Supernumerary teeth can present in various forms and in any region of the mandible or maxilla, but have a predisposition for the anterior maxilla. They can cause a variety of complications in the developing dentition. This article reviews the epidemiology, clinical features, diagnosis and options for the management of supernumerary teeth. CLINICAL RELEVANCE: Early diagnosis and appropriate management can minimize the potential complications caused by supernumerary teeth. Dental practitioners should be aware of their clinical signs and the treatment options.

The repair of massive rotator cuff tears can be very challenging. Different surgical techniques are described in the literature, including debridement of the cuff with subacromial decompression, attempts at direct partial repair, various tendon transfers, shoulder hemiarthroplasty, reversed shoulder arthroplasty and allograft augmentation. Following favourable published evidence of the use of porcine dermal collagen implants, Permacol (Tissue Science Laboratories, Hampshire, UK, now known as Collagen Repair Patch, Zimmer, Warsaw, Ind) as a bridging device to repair massive defects, we used it in four of our patients. However, we have seen with great concern that in all four cases, the grafts failed between 3-6 months after a promising early postoperative period. We report on these 4 cases giving clinical, radiographic and histological findings. We conclude that although Permacol has man obvious advantages, it should not be used to bridge irreparable massive rotator cuff tears.

BACKGROUND: Alcohol misuse is common in people attending emergency departments (EDs) and there is some evidence of efficacy of alcohol screening and brief interventions (SBI). This study investigated the effectiveness of SBI approaches of different intensities delivered by ED staff in nine typical EDs in England: the SIPS ED trial. METHODS AND FINDINGS: Pragmatic multicentre cluster randomized controlled trial of SBI for hazardous and harmful drinkers presenting to ED. Nine EDs were randomized to three conditions: a patient information leaflet (PIL), 5 minutes of brief advice (BA), and referral to an alcohol health worker who provided 20 minutes of brief lifestyle counseling (BLC). The primary outcome measure was the Alcohol Use Disorders Identification Test (AUDIT) status at 6 months. Of 5899 patients aged 18 or more presenting to EDs, 3737 (63·3%) were eligible to participate and 1497 (40·1%) screened positive for hazardous or harmful drinking, of whom 1204 (80·4%) gave consent to participate in the trial. Follow up rates were 72% (n = 863) at six, and 67% (n = 810) at 12 months. There was no evidence of any differences between intervention conditions for AUDIT status or any other outcome measures at months 6 or 12 in an intention to treat analysis. At month 6, compared to the PIL group, the odds ratio of being AUDIT negative for brief advice was 1·103 (95% CI 0·328 to 3·715). The odds ratio comparing BLC to PIL was 1·247 (95% CI 0·315 to 4·939). A per protocol analysis confirmed these findings. CONCLUSIONS: SBI is difficult to implement in typical EDs. The results do not support widespread implementation of alcohol SBI in ED beyond screening followed by simple clinical feedback and alcohol information, which is likely to be easier and less expensive to implement than more complex interventions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 93681536.

OBJECTIVES: The aim of the study was to analyse associations between chemsex and new HIV and sexually transmitted infection (STI) diagnoses among gay, bisexual and other men who have sex with men (GBMSM) accessing sexual health clinics. METHODS: A retrospective case note review was carried out for all GBMSM attending two London sexual health clinics between 1 June 2014 and 31 July 2015. RESULTS: Chemsex status was documented for 1734 of 1840 patients. Overall, 27.1% (n = 463) disclosed current recreational drug use, of whom 286 (16.5%) disclosed chemsex participation and 74 of 409 (18.1%) injected drugs. GBMSM who were already HIV positive were more likely to disclose chemsex participation [adjusted odds ratio (AOR) 2.55; 95% confidence interval (CI) 1.89-3.44; P < 0.001]. Those disclosing chemsex participation had higher odds of being newly diagnosed with HIV infection (AOR 5.06; 95% CI 2.56-10.02; P < 0.001), acute bacterial STIs (AOR 3.94; 95% CI 3.00-5.17; P < 0.001), rectal STIs (AOR 4.45; 95% CI 3.37-6.06; P < 0.001) and hepatitis C (AOR 9.16; 95% CI 2.31-36.27; P = 0.002). HIV-negative chemsex participants were also more likely to have accessed post-exposure prophylaxis for HIV in the study period and to report sex with a discordant HIV- or hepatitis C virus-infected partner (P < 0.001). CONCLUSIONS: Chemsex disclosure in sexual health settings is associated with higher rates of STI diagnoses, including HIV infection and hepatitis C. GBMSM attending sexual health services should therefore be assessed for chemsex participation and disclosure should prompt health promotion, harm minimization and wellbeing interventions.

Abstract Data are presented on survivorship and causes of death of 475 patients with rheumatioid arthritis, first seen betwen 1954 and 1966. The observed cumulative survival rate was lower than expected in each sex at each year of follow‐up, particularly in the later years. The adjusted rate was generally lower in males than in females. Eighteen of the 86 deaths due to known causes were attributed to infection, a significantly excessive proportion.