Croydon University 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.

Tumor expression of the proliferation antigen Ki67 is widely used to assess the prognosis of cancer patients. A change in the expression of Ki67 after short-term exposure of patients to therapeutic agents is frequently used as a pharmacodynamic marker of efficacy, particularly among breast cancer patients before undergoing surgery. To determine the clinical significance of the level of tumor cell proliferation during endocrine therapy for breast cancer, we measured the expression of Ki67 in tumor biopsy samples taken before and after 2 weeks of presurgical treatment with anastrozole or tamoxifen or the combination of anastrozole plus tamoxifen in 158 patients with hormone receptor-positive primary disease. In a multivariable analysis, we found that higher Ki67 expression after 2 weeks of endocrine therapy was statistically significantly associated with lower recurrence-free survival (P = .004) whereas higher Ki67 expression at baseline was not. Larger baseline tumor size and lower estrogen receptor level after 2 weeks of treatment were also statistically significantly associated with poorer recurrence-free survival (P < .001 and P = .04, respectively). Our data indicate that measurements of tumor Ki67 level after short-term endocrine treatment may improve the prediction of recurrence-free survival by integrating the prognostic value of Ki67 level at baseline with changes in Ki67 level that are associated with treatment benefit.

In Brief Objective: To assess local recurrence, disease-free survival, and overall survival in magnetic resonance imaging (MRI)–predicted good prognosis tumors treated by surgery alone. Background: The MERCURY study reported that high-resolution MRI can accurately stage rectal cancer. The routine policy in most centers involved in the MERCURY study was primary surgery alone in MRI-predicted stage II or less and in MRI “good prognosis” stage III with selective avoidance of neoadjuvant therapy. Patients and Methods: Data were collected prospectively on all patients included in the MERCURY study who were staged as MRI-defined “good” prognosis tumors. “Good” prognosis included MRI-predicted safe circumferential resection margins, with MRI-predicted T2/T3a/T3b (less than 5 mm spread from muscularis propria), regardless of MRI N stage. None received preoperative or postoperative radiotherapy. Overall survival, disease-free survival, and local recurrence were calculated. Results: Of 374 patients followed up in the MERCURY study, 122 (33%) were defined as “good prognosis” stage III or less on MRI. Overall and disease-free survival for all patients with MRI “good prognosis” stage I, II and III disease at 5 years was 68% and 85%, respectively. The local recurrence rate for this series of patients predicted to have a good prognosis tumor on MRI was 3%. Conclusions: The preoperative identification of good prognosis tumors using MRI will allow stratification of patients and better targeting of preoperative therapy. This study confirms the ability of MRI to select patients who are likely to have a good outcome with primary surgery alone. This study was a prospective, multi-centre, European study that recruited consecutive patients with rectal cancer. All patients underwent detailed preoperative assessment with high resolution MRI and have now been followed up for 5 years. Data is presented for patients identified to have good prognostic features on MRI.

BACKGROUND: Sirolimus-eluting stents reduce rates of restenosis and reintervention, as compared with uncoated stents. Data are limited regarding the safety and efficacy of such stents in primary percutaneous coronary intervention (PCI) for acute myocardial infarction with ST-segment elevation. METHODS: We performed a single-blind, multicenter, prospectively randomized trial to compare sirolimus-eluting stents with uncoated stents in primary PCI for acute myocardial infarction with ST-segment elevation. The trial included 712 patients at 48 medical centers. The primary end point was target-vessel failure at 1 year after the procedure, defined as target-vessel-related death, recurrent myocardial infarction, or target-vessel revascularization. A follow-up angiographic substudy was performed at 8 months among 174 patients from selected centers. RESULTS: The rate of the primary end point was significantly lower in the sirolimus-stent group than in the uncoated-stent group (7.3% vs. 14.3%, P=0.004). This reduction was driven by a decrease in the rate of target-vessel revascularization (5.6% and 13.4%, respectively; P<0.001). There was no significant difference between the two groups in the rate of death (2.3% and 2.2%, respectively; P=1.00), reinfarction (1.1% and 1.4%, respectively; P=1.00), or stent thrombosis (3.4% and 3.6%, respectively; P=1.00). The degree of neointimal proliferation, as assessed by the mean (+/-SD) in-stent late luminal loss, was significantly lower in the sirolimus-stent group (0.14+/-0.49 mm, vs. 0.83+/-0.52 mm in the uncoated stent group; P<0.001). CONCLUSIONS: Among selected patients with acute myocardial infarction, the use of sirolimus-eluting stents significantly reduced the rate of target-vessel revascularization at 1 year. (ClinicalTrials.gov number, NCT00232830 [ClinicalTrials.gov].).

BACKGROUND: Extramural vascular invasion (EMVI) is a poor prognostic feature in colorectal cancer. The accuracy of magnetic resonance imaging (MRI) in detecting EMVI and predicting relapse-free survival (RFS) was compared retrospectively with the histological reference standard. METHODS: Preoperative magnetic resonance images from patients diagnosed with rectal and sigmoid cancer were reviewed and an MRI-EMVI score (range 0 to 4) was assigned. Comparison was made with histology and clinical outcome. RESULTS: Some 142 patients with a median follow-up of 3.3 (range 0.9-5.7) years were reviewed. Histological EMVI was reported in a quarter of patients. The sensitivity and specificity of MRI detection of EMVI in 94 patients undergoing primary surgery were 62 and 88 per cent respectively. On univariable analysis, RFS at 3 years was 35 per cent for patients with an MRI-EMVI score of 3-4, compared with 74 per cent for those with a score of 0-2 (P < 0.001), similar to values in patients with positive and negative histological EMVI status respectively (34 versus 73.7 per cent; P < 0.001). CONCLUSION: High MRI-EMVI scores may help in predicting disease relapse.

BACKGROUND: It is uncertain whether subtotal abdominal hysterectomy results in better bladder, bowel, or sexual function than total abdominal hysterectomy. METHODS: We conducted a randomized, double-blind trial comparing total and subtotal abdominal hysterectomy in 279 women referred for hysterectomy because of benign disease; most of the women were premenopausal. The main outcomes were measures of bladder, bowel, and sexual function at 12 months. We also evaluated postoperative complications. RESULTS: The rates of urinary frequency (urination more than seven times during the day) were 33 percent in the subtotal-hysterectomy group and 31 percent in the total-hysterectomy group before surgery, and they fell to 24 percent and 20 percent, respectively, at 12 months (P=0.03 for the change over time within each group; P=0.84 for the interaction between the treatment assignment and time). The reduction in nocturia and stress incontinence and the improvement in bladder capacity were similar in the two groups. The frequency of bowel symptoms (as indicated by reported constipation and use of laxatives) and measures of sexual function (including the frequency of intercourse and orgasm and the rating of the sexual relationship with a partner) did not change significantly in either group after surgery. The women in the subtotal-hysterectomy group had a shorter hospital stay (5.2 days, vs. 6.0 in the total-hysterectomy group; P=0.04) and a lower rate of fever (6 percent vs. 19 percent, P<0.001). After subtotal abdominal hysterectomy, 7 percent of women had cyclical bleeding and 2 percent had cervical prolapse. CONCLUSIONS: Neither subtotal nor total abdominal hysterectomy adversely affects pelvic organ function at 12 months. Subtotal abdominal hysterectomy results in more rapid recovery and fewer short-term complications but infrequently causes cyclical bleeding or cervical prolapse.

OBJECTIVE: To determine whether serum concentrations of the cytokines tumour necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6), which regulate C reactive protein, are associated with cardiovascular risk factors and prevalent coronary heart disease. DESIGN: A population based cross sectional study. SUBJECTS AND METHODS: 198 men aged 50 to 69 years were part of a random population sample drawn from south London. Serum cytokine and C reactive protein concentrations were determined by enzyme linked immunosorbent assay. The presence of coronary heart disease was determined by Rose angina questionnaire and Minnesota coded electrocardiogram. RESULTS: Serum TNF alpha concentrations were positively related to body mass index and Helicobacter pylori infection, but inversely related to alcohol consumption. IL-6 concentrations were positively associated with smoking, symptoms of chronic bronchitis, age, and father having a manual occupation. TNF alpha was associated with increased IL-6 and triglycerides, and reduced high density lipoprotein cholesterol. IL-6 was associated with raised fibrinogen, sialic acid, and triglycerides. ECG abnormalities were independently associated with increases in IL-6 and TNF alpha, each by approximately 50% (P < 0.05 for TNF alpha, P < 0.1 for IL-6). The corresponding increases in men with an abnormal ECG or symptomatic coronary heart disease were 28% for TNF alpha and 36% for IL-6 (P = 0.14 for TNF alpha and P < 0.05 for IL-6). CONCLUSIONS: This study confirms that many of the phenomena with which C reactive protein is associated, are also associated with serum levels of cytokine, which may be the mechanism.

Injection of 5-hydroxytryptophan into mice produces a characteristic head-twitch. For a given period of observation this response may be assessed quantitatively either by observing the proportion of mice showing at least one head-twitch (a quantal response) or by counting the number of head-twitches for each mouse (a graded response). A method, based on the quantal response, of investigating the effect of centrally acting compounds on the head-twitch response is described. Evidence is presented that the head-twitches are due to a central action of 5-hydroxytryptamine formed by decarboxylation of 5-hydroxytryptophan. Head-twitches are potentiated by monoamine oxidase inhibitors and by phenytoin. Antagonists tested include an inhibitor of decarboxylase, antagonists of 5-hydroxytryptamine, some antihistamines, major tranquillizers and analgesic and sympathomimetic drugs. Drugs which neither potentiate nor inhibit the response include barbiturates and minor tranquillizers. The method may be valuable in the preliminary examination of compounds likely to have a central action.

OBJECTIVES: To establish the true prevalence of clinically recognisable and occult obstetric anal sphincter injuries (OASIS). DESIGN: Prospective interventional study. SETTING: Busy district general hospital. SAMPLE: Two hundred and fifty-four women having their first vaginal delivery over a 12-month period were invited. Two hundred and forty-one (95%) participated and 208 (86%) attended follow up. METHODS: Women had a clinical examination at delivery by the accoucheur and repeated by an experienced research fellow immediately after delivery. All identified OASIS were verified and repaired by the duty specialist registrar or consultant. Endoanal ultrasound was performed immediately postpartum prior to suturing and repeated seven weeks later. MAIN OUTCOME MEASURES: Prevalence of recognised and occult anal sphincter injuries. RESULTS: Fifty-nine (24.5%) women sustained OASIS. The prevalence of OASIS increased significantly from 11% to 24.5% when women were re-examined. Of these, 30 occurred in deliveries by midwives who missed 26 (87%) and 29 following deliveries by doctors who missed 8 (28%) injuries. All clinically apparent OASIS were also identified on endoanal ultrasound. In addition, three (1.2%) women had an occult anal sphincter injury. Two of these occult sphincter injuries were isolated to the internal anal sphincter (IAS) and would not usually be clinically detectable. CONCLUSIONS: OASIS occur more frequently than previously reported. Many remain undiagnosed and are subsequently classified as occult when identified on anal endosonography. Genuine occult injuries are rare. Training in perineal anatomy and recognition of OASIS needs to be enhanced in order to increase detection of OASIS and minimise the risk of consequent anal incontinence.

Viral hepatitis is one of the major public health concerns around the world but until recently it has drawn little attention or funding from global health policymakers. Every year 1.4 million people die from viral hepatitis-related cirrhosis and liver cancer. However, the majority of the infected population are unaware of their condition. This population have significant obstacles to overcome such as lack of awareness, vulnerability, increased migration, disease stigma, discrimination, as well as poor health resources, conflict in policy development and program implementation. Despite implementing infection control measures over the last few decades eradication or significant disease reduction remains elusive. This study aims to present the current global prevalence status and examines potential elimination strategies. The information for this research were obtained through a systematic review, published scientific literatures, the official websites of various government organisations, international public health organisations and internationally recognised regulatory bodies over a period of 40 years between 1978 and 2018.

BACKGROUND: There is much interest in reported associations between serum C-reactive protein and incident ischaemic heart disease. It is uncertain what this association represents. We aimed to assess the effect of confounding from a number of different sources in the Caerphilly Prospective Heart Disease Study and in particular whether the low grade inflammation indicated by C-reactive protein may be the mechanism whereby non-circulating risk factors may influence pathogenesis of ischaemic heart disease. METHODS: Plasma specimens collected during 1979-83 from 1395 men with sufficient sample remaining were assayed for serum C-reactive protein by ELISA. Subsequent mortality and incident ischaemic heart disease events were ascertained from death certificates, hospital records and electrocardiographic changes at 5-yearly follow-up examinations. RESULTS: There was a positive association between C-reactive protein and incident ischaemic heart disease (P<0.005) mainly with fatal disease (P<0.002). There was also a positive association with all-cause mortality (P<0.0001). C-reactive protein was significantly associated with a number of non-circulating risk factors including body mass index (P<0.0001), smoking (P<0.0001), low forced expiratory volume in 1 s (P<0.0001), height (P=0.025), low childhood social class (P=0.014) and age (P=0.036). C-reactive protein was also associated positively with circulating risk factors including viscosity, leukocyte count, fibrinogen (all P<0.0001) and insulin (P=0.0058). After adjustment for non-circulating risk factors the association with all-incident ischaemic heart disease and ischaemic heart disease death became non-significant, but the association with all-cause mortality remained (P=0.033). Further adjustment for fibrinogen however removed any hint of an increasing trend in odds for all three outcomes. CONCLUSION: C-reactive protein levels are raised in association with a variety of established cardiovascular risk factors. Neither C-reactive protein nor the systemic inflammation it represents appears to play a direct role in the development of ischaemic heart disease.

PURPOSE: Neoadjuvant (preoperative) therapy for breast cancer may allow for the development of intermediate markers of treatment benefit, thereby circumventing the need for efficacy trials of adjuvant therapy, which require much larger patient numbers and longer follow-up. The aim of this study--as part of the Immediate Preoperative "Arimidex" (anastrozole), Tamoxifen, or Arimidex Combined with Tamoxifen (IMPACT) trial (n = 330)--was to test the hypotheses that changes in Ki-67 after 2 weeks and/or 12 weeks: (i) differed between treatments, (ii) predicted clinical tumor response, and/or (iii) may predict long-term outcome differences between treatments in adjuvant therapy. EXPERIMENTAL DESIGN: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared these same agents in the adjuvant setting. Biomarkers were measured in biopsy specimens taken before and after 2 and 12 weeks of treatment. RESULTS: Suppression of the proliferation marker Ki-67 after 2 and 12 weeks was significantly greater with anastrozole than with tamoxifen (P = 0.004 and P < 0.001) but was similar between tamoxifen and the combination (P = 0.600 and P = 0.912). This result closely parallels that seen for the relative recurrence-free survival with the treatments after a median follow-up of 31 months in the ATAC trial in 9,366 patients. Against expectations, apoptosis was not increased in any of the treatment arms. CONCLUSIONS: The data indicate that short-term changes in proliferation in the neoadjuvant setting may be able to predict outcome during adjuvant use of the same treatments. If this can be confirmed, these findings could lead to a profound change in approaches to drug development in breast cancer. The data indicate that estrogen is not an important survival factor for human breast cancer cells.

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.

BACKGROUND: Anal sphincter injury during childbirth - obstetric anal sphincter injuries (OASIS) - are associated with significant maternal morbidity including perineal pain, dyspareunia (painful sexual intercourse) and anal incontinence, which can lead to psychological and physical sequelae. Many women do not seek medical attention because of embarrassment. The two recognised methods for the repair of damaged external anal sphincter (EAS) are end-to-end (approximation) repair and overlap repair. OBJECTIVES: To compare the effectiveness of overlap repair versus end-to-end repair following OASIS in reducing subsequent anal incontinence, perineal pain, dyspareunia and improving quality of life. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2013) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing different techniques of immediate primary repair of EAS following OASIS. DATA COLLECTION AND ANALYSIS: Trial quality was assessed independently by all authors. MAIN RESULTS: Six eligible trials, of variable quality, involving 588 women, were included. There was considerable heterogeneity in the outcome measures, time points and reported results. Meta-analyses showed that there was no statistically significant difference in perineal pain (risk ratio (RR) 0.08, 95% confidence interval (CI) 0.00 to 1.45, one trial, 52 women), dyspareunia (average RR 0.77, 95% CI 0.48 to 1.24, two trials, 151 women), flatus incontinence (average RR 1.14, 95% CI 0.58 to 2.23, three trials, 256 women) between the two repair techniques at 12 months. However, it showed a statistically significant lower incidence of faecal urgency (RR 0.12, 95% CI 0.02 to 0.86, one trial, 52 women), and lower anal incontinence score (standardised mean difference (SMD) -0.70, 95% CI -1.26 to -0.14, one trial, 52 women) in the overlap group. The overlap technique was also associated with a statistically significant lower risk of deterioration of anal incontinence symptoms over 12 months (RR 0.26, 95% CI 0.09 to 0.79, one trial, 41 women). There was no significant difference in quality of life. At 36 months follow-up, there was no difference in flatus incontinence (average RR 1.12, 95% CI 0.63 to 1.99, one trial, 68 women) or faecal incontinence (average RR 1.01, 95% CI 0.34 to 2.98, one trial, 68 women). AUTHORS' CONCLUSIONS: The data available show that at one-year follow-up, immediate primary overlap repair of the external anal sphincter compared with immediate primary end-to-end repair appears to be associated with lower risks of developing faecal urgency and anal incontinence symptoms. At the end of 36 months there appears to be no difference in flatus or faecal incontinence between the two techniques. However, since this evidence is based on only two small trials, more research evidence is needed in order to confirm or refute these findings.

We have identified a t(8;9)(p21-23;p23-24) in seven male patients (mean age 50, range 32-74) with diverse hematologic malignancies and clinical outcomes: atypical chronic myeloid leukemia/chronic eosinophilic leukemia (n = 5), secondary acute myeloid leukemia (n = 1), and pre-B-cell acute lymphoblastic leukemia (n = 1). Initial fluorescence in situ hybridization studies of one patient indicated that the nonreceptor tyrosine kinase Janus-activated kinase 2 (JAK2) at 9p24 was disrupted. Rapid amplification of cDNA ends-PCR identified the 8p22 partner gene as human autoantigen pericentriolar material (PCM1), a gene encoding a large centrosomal protein with multiple coiled-coil domains. Reverse transcription-PCR and fluorescence in situ hybridization confirmed the fusion in this case and also identified PCM1-JAK2 in the six other t(8;9) patients. The breakpoints were variable in both genes, but in all cases the chimeric mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2. Reciprocal JAK2-PCM1 mRNA was not detected in any patient. We conclude that human autoantigen pericentriolar material (PCM1)-JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1-JAK2 disease are attractive candidates for targeted signal transduction therapy.

A literature review was performed to clarify available information which influences decisions whether to advise a young adult patient to undergo surgery for a severely displaced acromioclavicular dislocation. Twenty-four papers were retrieved yielding 1172 patients of whom the mean followup for the 833 surgically treated patients was 43.7 months and not surgically treated was 60.4 months. Of the 24 papers, only five reported surgical and conservative outcomes; two of these papers used prospective randomized methodology and three used nonrandomized methodology. Fourteen papers reported surgical outcome only and five papers reported conservative outcome only. Overall, 88% of surgically treated patients and 87% of nonsurgically treated patients had a satisfactory outcome. Complications most commonly listed were (surgically treated versus nonsurgically treated): need for further surgery (59% versus 6%), infection (6% versus 1%), and deformity (3% versus 37%). Return to activity was no quicker with surgery. Pain was not any more common without surgery. Range of movement was more frequently normal or near normal without surgery (95% versus 86% if surgically treated) and so was strength (92% versus 87%). Meta-analysis of the four studies including data from surgical and conservative therapy showed on significant benefit from surgery. Power studies suggest that to show a statistically significant benefit from surgery, large studies would be required, which, given the relative incidence of these injuries, would probably be multicenter and therefore vulnerable to methodologic difficulties. There does not seem to be any reason to recommend an operative procedure to a patient with a Rockwood et al Type III injury based on the evidence currently available.

BACKGROUND: Incontinence of stool and flatus are frequent complications of childbirth. We examined the prevalence and possible causes of these adverse outcomes in a large cohort of women. METHODS: We studied 949 pregnant women who gave birth in 5 hospitals in 1995/96 in the province of Quebec. These women, participants in a randomized controlled trial of prenatal perineal massage, completed a self-administered questionnaire 3 months after giving birth. RESULTS: Three months after delivery 29 women (3.1%) reported incontinence of stool, and 242 (25.5%) had involuntary escape of flatus. Incontinence of stool was more frequent among women who delivered vaginally and had third- or fourth-degree perineal tears than among those who delivered vaginally and had no anal sphincter tears (7.8% v. 2.9%). Forceps delivery (adjusted risk ratio [RR] 1.45, 95% confidence interval [CI] 1.01-2.08) and anal sphincter tears (adjusted RR 2.09, 95% CI 1.40-3.13) were independent risk factors for incontinence of flatus or stool or both. Anal sphincter injury was strongly and independently associated with first vaginal birth (RR 39.2, 95% CI 5.4-282.5), median episiotomy (adjusted RR 9.6, 95% CI 3.2-28.5), forceps delivery (adjusted RR 12.3, 95% CI 3.0-50.4) and vacuum-assisted delivery (adjusted RR 7.4, 95% CI 1.9-28.5) but not with birth weight (adjusted RR for nirth weight 4000 g or more: 1.4, 95% CI 0.6-3.0) or length of the second stage of labour (adjusted RR for second stage 1.5 hours or longer compared with less than 0.5 hours: 1.2, 95% CI 0.5-2.7). INTERPRETATION: Anal incontinence is associated with forceps delivery and anal sphincter laceration. Anal sphincter laceration is strongly predicted by first vaginal birth, median episiotomy, and forceps or vacuum delivery but not by birth weight or length of the second stage of labour.

The present study investigated: (1) perception of genetic risk and, (2) the psychological effects of genetic counselling in women with a family history of breast cancer. Using a prospective design, with assessment pre- and post-genetic counselling at clinics and by postal follow-up at 1, 6 and 12 months, attenders at four South London genetic clinics were assessed. Participants included 282 women with a family history of breast cancer. Outcome was measured in terms of mental health, cancer-specific distress and risk perception. High levels of cancer-specific distress were found pre-genetic counselling, with 28% of participants reporting that they worried about breast cancer 'frequently or constantly' and 18% that worry about breast cancer was 'a severe or definite problem'. Following genetic counselling, levels of cancer-specific distress were unchanged. General mental health remained unchanged over time (33% psychiatric cases detected pre-genetic counselling, 27% at 12 months after genetic counselling). Prior to their genetics consultation, participants showed poor knowledge of their lifetime risk of breast cancer since there was no association between their perceived lifetime risk (when they were asked to express this as a 1 in x odds ratio) and their actual risk, when the latter was calculated by the geneticist at the clinic using the CASH model. In contrast, women were more accurate about their risk of breast cancer pre-genetic counselling when this was assessed in broad categorical terms (i.e. very much lower/very much higher than the average woman) with a significant association between this rating and the subsequently calculated CASH risk figure (P = 0.001). Genetic counselling produced a modest shift in the accuracy of perceived lifetime risk, expressed as an odds ratio, which was maintained at 12 months' follow-up. A significant minority failed to benefit from genetic counselling; 77 women continued to over-estimate their risk and maintain high levels of cancer-related worry. Most clinic attenders were inaccurate in their estimates of the population risk of breast cancer with only 24% able to give the correct figure prior to genetic counselling and 36% over-estimating this risk. There was some improvement following genetic counselling with 62% able to give the correct figure, but this information was poorly retained and this figure had dropped to 34% by the 1-year follow-up. The study showed that women attending for genetic counselling are worried about breast cancer, with 34% indicating that they had initiated the referral to the genetic clinic themselves. This anxiety is not alleviated by genetic counselling, although women reported that it was less of a problem at follow-up. Women who continue to over-estimate their risk and worry about breast cancer are likely to go on seeking unnecessary screening if they are not reassured.

Surgical management of pelvic floor disorders depends on a comprehensive understanding of the structural integrity and function of the pelvic floor. For visualizing this region, ultrasonography has emerged as a procedure that is relatively easy to perform, cost-effective and widely available. In this review, pelvic floor ultrasonography, including two-dimensional (2D), three-dimensional (3D) and 4D imaging as well as transvaginal, endoanal and transperineal techniques, is discussed from a global and multicompartmental perspective, rather than using a compartmentalized approach. The role of the different sonographic modalities in the major disorders of the pelvic floor-urinary and fecal incontinence, pelvic organ prolapse and obstructed defecation syndrome-is evaluated critically.