King George 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.

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.

OBJECTIVES: To use multiple regression analysis to define the contribution of maternal variables that influence the measured concentration of free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), and the interaction between these covariates, in first-trimester biochemical screening for trisomy 21. METHODS: This was a multicenter study of prospective screening for trisomy 21 by a combination of fetal nuchal translucency thickness, and maternal serum free beta-hCG and PAPP-A at 11 + 0 to 13 + 6 weeks of gestation. In the pregnancies subsequently found to have trisomy 21 and in those with no obvious chromosomal abnormality, we used multiple regression analysis to account for pregnancy characteristics that influence the measured concentrations of free beta-hCG and PAPP-A. We fitted Gaussian distributions to the distribution of log multiples of the median (MoM) values in trisomy 21 and in unaffected pregnancies. RESULTS: There were 491 cases of trisomy 21 and 96 803 chromosomally normal pregnancies. Compared with values in Caucasian women, those who were parous, non-smokers and those who conceived spontaneously, PAPP-A was 57% higher in women of Afro-Caribbean origin, 3% higher in South Asians, 9% higher in East Asians, 2% higher in nulliparous women, 17% lower in smokers and 10% lower in those conceiving by in-vitro fertilization (IVF). Free beta-hCG was 12% higher in women of Afro-Caribbean origin, 9% lower in South Asians, 8% higher in East Asians, 2% higher in nulliparous women, 4% lower in smokers and 9% higher in those conceiving by IVF. In screening for trisomy 21 by maternal age and serum free beta-hCG and PAPP-A the estimated detection rate was 65% for a false-positive rate of 5%. CONCLUSIONS: In first-trimester biochemical screening for trisomy 21 it is essential to adjust the measured values of free beta-hCG and PAPP-A for maternal and pregnancy characteristics.

OBJECTIVE: To investigate the accuracy of intrapartum transvaginal digital examination in defining the position of the fetal head before instrumental delivery. PATIENTS AND METHODS: In 64 singleton pregnancies undergoing instrumental delivery the fetal head position was determined by transvaginal digital examination by the attending obstetrician. Immediately after or before the clinical examination, the fetal head position was determined by transabdominal ultrasound by a trained sonographer who was not aware of the clinical findings. The digital examination was considered to be correct if the fetal head position was within +/- 45 degrees of the ultrasound finding. The accuracy of the digital examination was examined in relation to maternal and fetal characteristics. RESULTS: Digital examination failed to define the correct fetal head position in 17 (26.6%) cases. In 12 of 17 (70.6%) errors the difference was >/= 90 degrees and in five (29.4%) the difference was between 45 degrees and 90 degrees. The accuracy of vaginal digital examination was 83% for occiput-anterior and 54% for occiput-lateral + occiput-posterior positions. Logistic regression analysis demonstrated significant independent contributions in explaining the variance in the accuracy of vaginal examination for the station of the fetal head, the position of the fetal head and the experience of the examining obstetrician. CONCLUSIONS: Digital examination during instrumental delivery fails to identify the correct fetal head position in about one quarter of cases.

OBJECTIVE: To investigate whether rituximab, an anti-B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögren's syndrome (SS). METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that included health economic analysis. Anti-Ro-positive patients with primary SS, symptomatic fatigue, and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally randomized to receive either intravenous (IV) placebo (250 ml saline) or IV rituximab (1,000 mg in 250 ml saline) in 2 courses at weeks 0, 2, 24, and 26, with pre- and postinfusion medication including corticosteroids. The primary end point was the proportion of patients achieving a 30% reduction in either fatigue or oral dryness at 48 weeks, as measured by visual analog scale. Other outcome measures included salivary and lacrimal flow rates, quality of life, scores on the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient Reported Index and EULAR Sjögren's Syndrome Disease Activity Index, symptoms of ocular and overall dryness, pain, globally assessed disease activity, and cost-effectiveness. RESULTS: All 133 patients who were randomized to receive placebo (n = 66) or rituximab (n = 67) were included in the primary analysis. Among patients with complete data, 21 of 56 placebo-treated patients and 24 of 61 rituximab-treated patients achieved the primary end point. After multiple imputation of missing outcomes, response rates in the placebo and rituximab groups were 36.8% and 39.8%, respectively (adjusted odds ratio 1.13 [95% confidence interval 0.50, 2.55]). There were no significant improvements in any outcome measure except for unstimulated salivary flow. The mean ± SD costs per patient for rituximab and placebo were £10,752 ± 264.75 and £2,672 ± 241.71, respectively. There were slightly more adverse events (AEs) reported in total for rituximab, but there was no difference in serious AEs (10 in each group). CONCLUSION: The results of this study indicate that rituximab is neither clinically effective nor cost-effective in this patient population.

Staphylococcus aureus is the most common cause of hospital-acquired bacteremia. From 1995 through 2000, data on age, sex, patient specialty at time of first bacteremia, primary and secondary sites of infection, delay in initiating antimicrobial therapy, and patient outcome were prospectively recorded for 815 patients with nosocomial S. aureus bacteremia. The proportion of patients whose death was attributable to methicillin-resistant S. aureus (MRSA) was significantly higher than that for methicillin-susceptible S. aureus (MSSA) (11.8% vs. 5.1%; odds ratio [OR], 2.49; 95% confidence interval [CI], 1.46-4.24; P<.001). After adjustment for host variables, the OR decreased to 1.72 (95% CI, 0.92-3.20; P=.09). There was no significant difference between rates of disseminated infection (7.1% vs. 6.2% for MRSA-infected patients and MSSA-infected patients, respectively; P=.63), though the rate of death due to disseminated infection was significantly higher than death due to uncomplicated infection (37% vs. 10% for MRSA-infected patients [P<.001] and 37% vs. 3% for MSSA-infected patients [P<.001]). There was a strong statistical trend toward death due to nosocomial MRSA infection and bacteremia, compared with MSSA.

OBJECTIVE: To investigate the accuracy of intrapartum transvaginal digital examination in defining the position of the fetal head. PATIENTS AND METHODS: In 496 singleton pregnancies in labor at term, the fetal head position was determined by routine transvaginal digital examination by the attending midwife or obstetrician. Immediately before or after the clinical examination, the fetal head position was determined using transabdominal ultrasound by an appropriately trained sonographer who was not aware of the clinical findings. The digital examination was considered to be correct if the fetal head position was within 45 degrees of the ultrasound finding. The accuracy of the digital examination was examined in relation to maternal characteristics and the progress of labor. RESULTS: The position of the fetal head was determined by ultrasound examination in all 496 cases examined. Digital examination failed to define the fetal head position in 166 (33.5%) cases and, in 330 cases where the position was determined, the findings of the digital and sonographic examinations were in agreement in only 163 (49.4%) cases. The rate of correct identification of the fetal position by digital examination increased with cervical dilatation, from 20.5% at 3-4 cm to 44.2% at 8-10 cm, and was higher if the examination was carried out by an obstetrician than a midwife (50% versus 30%) and if there was absence rather than presence of caput (33% versus 25%). CONCLUSIONS: Routine digital examination during labor fails to identify the correct fetal position in the majority of cases.

BACKGROUND: Low levels of pregnancy associated plasma protein-A (PAPP-A) have been previously shown to be associated with pregnancies that subsequently develop pre-eclampsia. The objective of this study was to establish the relative risk for pre-eclampsia at various PAPP-A levels as an aid to counselling and follow up of pregnancies. METHODS: Maternal serum PAPP-A and free ss-human chorionic gonadotropin (ss-hCG) levels at 11 to 13 weeks of gestation from 224 singleton pregnancies that subsequently developed pre-eclampsia were compared to those from 47,770 normal singleton pregnancies resulting in live births after 37 weeks with birth weight greater than or equal to the 10th centile of normal for gestation. In all cases, the measured PAPP-A and free ss-hCG levels were expressed as multiple of the median (MoM). The association between metabolite levels and the incidence of pre-eclampsia was assessed by comparing the relative incidence at a number of MoM cut-offs and at various centiles. At various marker levels, the likelihood ratio for pre-eclampsia was also calculated. RESULTS: In the pre-eclampsia group the median PAPP-A MoM was significantly reduced (0.772 MoM, p < 0.0001) whilst the median free beta-hCG MoM was not different from controls (0.981 MoM, p = 0.26). With decreasing levels of PAPP-A, the likelihood ratio for pre-eclampsia increased. At the 5th centile of normal (PAPP-A MoM 0.415) the odds ratio was increased 4-fold and at this cut-off 15% of cases of pre-eclampsia would be identified. CONCLUSIONS: The graphical presentation of a likelihood ratio curve for pre-eclampsia at any PAPP-A MoM level is likely to be useful in counselling women with low levels of PAPP-A and a normal karyotype. Use of low levels of PAPP-A for selecting women for further follow-up with uterine artery Doppler may further improve the clinical discrimination.

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 ).

Aims During the COVID-19 pandemic, many patients continue to require urgent surgery for hip fractures. However, the impact of COVID-19 on perioperative outcomes in these high-risk patients remains unknown. The objectives of this study were to establish the effects of COVID-19 on perioperative morbidity and mortality, and determine any risk factors for increased mortality in patients with COVID-19 undergoing hip fracture surgery. Methods This multicentre cohort study included 340 COVID-19-negative patients versus 82 COVID-19-positive patients undergoing surgical treatment for hip fractures across nine NHS hospitals in Greater London, UK. Patients in both treatment groups were comparable for age, sex, body mass index, fracture configuration, and type of surgery performed. Predefined perioperative outcomes were recorded within a 30-day postoperative period. Univariate and multivariate analysis were used to identify risk factors associated with increased risk of mortality. Results COVID-19-positive patients had increased postoperative mortality rates (30.5% (25/82) vs 10.3% (35/340) respectively, p &lt; 0.001) compared to COVID-19-negative patients. Risk factors for increased mortality in patients with COVID-19 undergoing surgery included positive smoking status (hazard ratio (HR) 15.4 (95% confidence interval (CI) 4.55 to 52.2; p &lt; 0.001) and greater than three comorbidities (HR 13.5 (95% CI 2.82 to 66.0, p &lt; 0.001). COVID-19-positive patients had increased risk of postoperative complications (89.0% (73/82) vs 35.0% (119/340) respectively; p &lt; 0.001), more critical care unit admissions (61.0% (50/82) vs 18.2% (62/340) respectively; p &lt; 0.001), and increased length of hospital stay (mean 13.8 days (SD 4.6) vs 6.7 days (SD 2.5) respectively; p &lt; 0.001), compared to COVID-19-negative patients. Conclusion Hip fracture surgery in COVID-19-positive patients was associated with increased length of hospital stay, more admissions to the critical care unit, higher risk of perioperative complications, and increased mortality rates compared to COVID-19-negative patients. Risk factors for increased mortality in patients with COVID-19 undergoing surgery included positive smoking status and multiple (greater than three) comorbidities. Cite this article: Bone Joint J 2020;102-B(9):1136–1145.

OBJECTIVE: To investigate if occiput posterior delivery is the consequence of persistence of an initial occiput posterior position or malrotation from an initial occiput anterior or transverse position. METHODS: This was a cross-sectional study involving transabdominal sonography to determine fetal occipital position in 918 singleton pregnancies with cephalic presentation in active labor at 37-42 weeks of gestation. The relationship between occipital position in labor and at delivery was examined. RESULTS: The occiput was posterior in 33.0% (149/452), 33.9% (101/298) and 19.0% (32/168) of fetuses at the respective cervical dilatations of 3-5, 6-9 and 10 cm and this persisted at delivery in 21.5% (32/149), 31.7% (32/101) and 43.8% (14/32) of cases. In 70% (32/46), 91% (32/35) and 100% (14/14) of occiput posterior deliveries there was persistence from this position at 3-5, 6-9 and 10 cm of cervical dilation. CONCLUSIONS: The majority of occiput posterior positions during labor rotate to the anterior position even at 10 cm of cervical dilatation. However, the vast majority of occiput posterior positions at delivery are a consequence of persistence of this position during labor rather than malrotation from an initial occiput anterior or transverse position.

BACKGROUND: Biliary tract infection is a common cause of bacteraemia and is associated with high morbidity and mortality. Few papers describe blood culture isolates, underlying structural abnormalities and clinical outcomes in patients with bacteraemia. AIMS: To determine the proportion of bacteraemias caused by biliary tract infection and to describe patient demographics, underlying structural abnormalities and clinical outcomes in patients with bacteraemia. DESIGN: Prospective cohort study. METHODS: Biliary tract infection that caused bacteraemia was defined as a compatible clinical syndrome and a blood culture isolate consistent with ascending cholangitis. Patients aged 16 years and over were included in the study. From June 2003 to May 2005, demographic and clinical data were collected prospectively on all adult patients with bacteraemia. Radiological and endoscopic retrograde cholangiopancreatography findings were collected retrospectively. RESULTS: In 49 patients, the biliary tract was the site of infection for 39/592 (6.6%) community-acquired and 19/466 (4.1%) hospital-acquired episodes of bacteraemia. Three patients had mixed bacteraemias, and four had recurrent bacteraemia. The proportion of patients presenting with a structural abnormality was 34/49 (69%), and, of these structural abnormalities, 18/34 (53%) were pre-existing or newly diagnosed malignancies. Gram-negative organisms caused 55/58 (95%) episodes of bacteraemia. The most common Gram-negative organisms were Escherichia coli (34/55; 62%) and Klebsiella pneumoniae (14/55; 26%). Of the E coli isolates, 6/34 (18%) were extended spectrum beta-lactamase producers or multiply drug resistant. Thirty-day mortality was 7/49 (14%). There was no difference in time taken to administer an effective antibiotic to survivors and non-survivors (0.86 vs 1.05 days, respectively, p = 0.92). Of the seven who died, four died from septic shock within 48 h of admission caused by "susceptible" Gram-negative organisms. Two others died from disseminated malignancy. CONCLUSIONS: The proportion of bacteraemias caused by biliary tract infection was 5.5%. The most common infecting organisms were E coli and K pneumoniae. There was a strong association with choledocholithiasis and malignancies, both pre-existing and newly diagnosed. Death was uncommon but when it occurred was often caused by septic shock within 48 h of presentation.

OBJECTIVE: To examine the distribution of first-trimester biochemical markers of aneuploidy in twin pregnancies, and to assess whether there are differences in the distributions between monochorionic and dichorionic twins. METHODS: Maternal serum-free beta-hCG and PAPP-A were measured between 11 + 0 and 13 + 6 weeks as part of a routine first-trimester screening program in conjunction with fetal nuchal translucency (NT) performed at two sites. Data from twin pregnancies were extracted from the fetal databases along with information on the chorionicty. The individual marker concentrations were expressed as weight corrected, ethnicity corrected, smoking corrected and IVF corrected MoM using data from singleton pregnancies as the reference. The overall medians were compared to those in singleton pregnancies and between monochorionic and dichorionic twins. RESULTS: Data was available from 1914 sets of twins. Of these, 1214 had information with respect to chorionicity, with 1024 being dichorionic and 190 being monochorionic. The overall median weight corrected, ethnicity corrected, smoking corrected and IVF corrected MoM amongst twin pregnancies were 2.023 for free beta-hCG (sd log(10) MoM = 0.2611 and 2.121 for PAPP-A (sd log(10) MoM = 0.2255) -- both medians were significantly greater than the medians in singleton pregnancies (1.00 MoM). In the case of monochorionic and dichorionic twins the median weight corrected, ethnicity corrected, smoking corrected and IVF corrected, free beta-hCG MoM's were not significantly different (1.983 v 2.041), however for PAPP-A the median weight corrected, ethnicity corrected, smoking corrected and IVF corrected MoM in monochorionic twins was significantly lower than in dichorionic twins (1.756 v 2.250) whilst the sd log(10) MoM's were not significantly different (0.2185 v 0.2167). CONCLUSION: Screening in twin pregnancies requires adjustment of the calculated MoM to account for the presence of two fetuses. In general, for free beta-hCG, this should be by dividing the observed corrected MoM by 2.023. For PAPP-A two different factors are required - 2.192 in dichorionic twins and 1.788 in monochorionic twins.

OBJECTIVE: To establish an algorithm for first-trimester combined screening for trisomy 21 with biochemical testing from 7 to 14 weeks' gestation and ultrasound testing at 11-13 weeks. METHODS: This was a multicenter study of 886 pregnancies with trisomy 21 and 222 475 unaffected pregnancies with measurements of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 7-14 weeks' gestation. Multiple regression modeling of log-transformed marker values was used to produce log multiples of the median (MoM) values for PAPP-A and free β-hCG. The models included terms for the center attended and the machine used for biochemical analysis, gestational age, maternal racial origin, maternal weight, smoking status and method of conception. Bivariate Gaussian distributions were fitted to log MoM PAPP-A and log MoM free β-hCG in trisomy 21 and in unaffected pregnancies. In each case the patient-specific risk for trisomy 21 was estimated by multiplying the individual maternal age-related risk with the likelihood ratio (LR) for fetal nuchal translucency (NT) according to the mixture model and the combined LR for maternal serum free β-hCG and PAPP-A. Estimates of detection rates for trisomy 21 and false-positive rates were calculated for combined screening with measurements of NT at 12 weeks together with measurements of free β-hCG and PAPP-A from 8 to 13 weeks. RESULTS: In trisomy 21 pregnancies the mean log MoM free β-hCG increased linearly with gestation between 7 and 14 weeks, whereas the relation between log MoM PAPP-A and gestation was fitted by a quadratic equation such that the maximum separation between trisomy 21 and unaffected pregnancies occurs at 9-10 weeks. At a false-positive rate of 3% the detection rate of combined screening at 12 weeks was 86% and this increased to 90% by biochemical testing at 9 weeks and ultrasound scanning at 12 weeks. The detection rate increased to 92% by measuring PAPP-A at 9 weeks and free β-hCG at the time of the scan at 12 weeks. CONCLUSION: The performance of first-trimester biochemical screening for trisomy 21 is best at 9-10 weeks rather than at 7-8 or 11-14 weeks.

There is increasing research exploring depression in carers of people with dementia. This study explored the relation of entrapment, shame and guilt to depression in a group of 70 carers of those with dementia. As in other studies the experience of entrapment in the role was highly related to depression. Moreover, experiences of shame relating to self-criticism, other people's expectations and the fear of their criticism were significantly related to depression, entrapment and guilt. Guilt however, as focused on the fears of harming others, letting others down and sense of responsibility, was not associated with depression or entrapment. Depression in carers may relate in part to feeling trapped in a role but also being vulnerable to criticism and feelings of inadequacy in that role. In this study, degree of behavioural disturbance/dependence was not found to be significantly associated with any of the research variables.

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

OBJECTIVES: To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren's syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. METHODS: Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0-11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. RESULTS: 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were -1.2 (95% CI -2.1 to -0.3; P=0.0099) and -1.2 (95% CI -2.0 to -0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. CONCLUSIONS: We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. TRIAL REGISTRATION NUMBER: 65360827, 2010-021430-64; Results.

OBJECTIVE: To estimate the difference between levels of the two biochemical markers pregnancy-associated plasma protein-A (PAPP-A) and maternal serum free β-human chorionic gonadotropin (free β-hCG) in twin pregnancies relative to singleton pregnancies and establish an improved screening procedure for chromosomal abnormalities such as trisomy 21 in twin pregnancies. METHODS: 4843 unaffected and 47 trisomy 21-affected twin pregnancies were included in the study. Chorionicity-specific medians were generated for PAPP-A and free β-hCG from gestational ages 8 to 14 weeks. Multiple of the median values for each of the biochemical markers were calculated. Detection rates and false-positive rates were estimated for screening tests incorporating nuchal translucency and maternal age, with and without biochemistry. RESULTS: Medians for the two biochemical markers for monochorionic and dichorionic twins in unaffected pregnancies show a gestational age-specific increase relative to singleton medians. Allowing for gestation and chorionicity, twin pregnancies affected with trisomy 21 had higher levels of free β-hCG and lower levels of PAPP-A. Adding biochemistry into the risk assessment using a fixed risk cut-off of 1 in 100 increased the detection rate for fetal trisomy 21 in dizygotic twin pregnancies from 78 to 90%, and decreased the false-positive rate from 8.0 to 5.9%. CONCLUSION: Generation of chorionicity-specific medians for the biochemical markers and their use in risk assessment can improve the performance of first-trimester screening for chromosomal abnormalities in twins to a level comparable with that in singleton pregnancies.

This article, a product of the two authors' multicultural experiences, contrasts British and Japanese families in order to examine the applicability of the Western model of family therapy to Japanese families and therapists. Areas where the Western model is incompatible are identified, and modifications to fit the Japanese indigenous model are suggested. The most significant difference in value systems between the two cultures is the Japanese preference for connectedness. The Japanese person is seen as a part of the embedded interconnectedness of relationships, whereas British norms prioritize separateness and clear boundaries in relationships, individuality, and autonomy. This value orientation is manifested in the Japanese language, hierarchical nature of the family structure, the family life cycle, and the implicit communication style. Systemic thinking, which deals with the pattern of relationships, is valid for all families regardless of cultural differences. But therapists should note that the preferred direction of change for Japanese families in therapy, is toward a process of integration--how a person can be effectively integrated into the given system--rather than a process of differentiation. An authoritative therapist style, the use of individual sessions, silence, and other nonverbal techniques are relevant to bringing about the desired change toward better integration of the individual with his or her networks.