Royal Shrewsbury 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.

The psychiatric morbidity associated with mastectomy was assessed in 75 women by following them up from the time they presented with suspected breast cancer to one year after the operation. Fifty women with benign breast disease served as controls. Throughout the follow-up period the incidence of psychiatric problems was higher among the women who had undergone mastectomy. One year after surgery 19 (25%) of these women compared with only 5 (10%) of the controls needed treatment for anxiety or depression or both, and 16 (33%) compared with 3 (8%) respectively had moderate or severe sexual difficulties. Altogether 29 patients in the mastectomy group (39%) and six of the controls (12%) had serious anxiety, depression, or sexual difficulties. Of the eight women in the mastectomy group who sought help for their problems, only two felt that the help given had been appropriate. The inability to recognise and treat these emotional disturbances is a common and serious problem. Monitoring by specially trained nurses and social workers might help to identify them earlier and even reduce them.

These evidence-based guidelines have been produced after a literature review of the treatment and prophylaxis of methicillin-resistant Staphylococcus aureus (MRSA) infection. The guidelines were further informed by antibiotic susceptibility data on MRSA from the UK. Recommendations are given for the treatment of common infections caused by MRSA, elimination of MRSA from carriage sites and prophylaxis of surgical site infection. There are several antibiotics currently available that are suitable for use in the management of this problem and potentially useful new agents are continuing to emerge.

BACKGROUND: The erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation. METHODS: An individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention. RESULTS: The analysis included 2783 patients, with 14 245 person-years of follow-up (median 5·5 years). Early (0-6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0·61, 95 per cent c.i. 0·42 to 0·89; P = 0·010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 0·40, 95 per cent c.i. 0·22 to 0·74). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 5·16, 1·49 to 17·89; P = 0·010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P = 0·022) in the period from 6 months to 4 years after randomization. CONCLUSION: The early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5 years, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle : brachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM (Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (Anévrysme de l'aorte abdominale, Chirurgie versus Endoprothèse), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575.

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: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 μg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

PURPOSE Previous studies of hypofractionated adjuvant whole-breast radiotherapy for early breast cancer established a 15- or 16-fraction (fr) regimen as standard. The FAST Trial (CRUKE/04/015) evaluated normal tissue effects (NTE) and disease outcomes after 5-fr regimens. Ten-year results are presented. METHODS Women ≥ 50 years of age with low-risk invasive breast carcinoma (pT1-2 pN0) were randomly assigned to 50 Gy/25 fr (5 weeks) or 30 or 28.5 Gy in 5 once-weekly fr of 6.0 or 5.7 Gy. The primary end point was change in photographic breast appearance at 2 and 5 years; secondary end points were physician assessments of NTE and local tumor control. Odds ratios (ORs) from longitudinal analyses compared regimens. RESULTS A total of 915 women were recruited from 18 UK centers (2004-2007). Five-year photographs were available for 615/862 (71%) eligible patients. ORs for change in photographic breast appearance were 1.64 (95% CI, 1.08 to 2.49; P = .019) for 30 Gy and 1.10 (95% CI, 0.70 to 1.71; P = .686) for 28.5 Gy versus 50 Gy. α/β estimate for photographic end point was 2.7 Gy (95% CI, 1.5 to 3.9 Gy), giving a 5-fr schedule of 28 Gy (95% CI, 26 to 30 Gy) estimated to be isoeffective with 50 Gy/25 fr. ORs for any moderate/marked physician-assessed breast NTE (shrinkage, induration, telangiectasia, edema) were 2.12 (95% CI, 1.55 to 2.89; P &lt; .001) for 30 Gy and 1.22 (95% CI, 0.87 to 1.72; P = .248) for 28.5 Gy versus 50 Gy. With 9.9 years median follow-up, 11 ipsilateral breast cancer events (50 Gy: 3; 30 Gy: 4; 28.5 Gy: 4) and 96 deaths (50 Gy: 30; 30 Gy: 33; 28.5 Gy: 33) have occurred. CONCLUSION At 10 years, there was no significant difference in NTE rates after 28.5 Gy/5 fr compared with 50 Gy/25 fr, but NTE were higher after 30 Gy/5 fr. Results confirm the published 3-year findings that a once-weekly 5-fr schedule of whole-breast radiotherapy can be identified that appears to be radiobiologically comparable for NTE to a conventionally fractionated regimen.

Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long-term outlook. Median follow-up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse-free survival was 16 years. After relapse (n = 79) or non-response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse-free survival was 11 years. After third-line therapy (n = 23), 50% achieved CR and median relapse-free survival was 6.5 years. However, CRs were equally durable, whether after first, second or third-line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 x 10(9)/l before treatment had the longest relapse-free survival (P < 0.0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan.

Objectives To systematically review the literature pertaining to the prevalence of depression and anxiety in patients with ovarian cancer as a function of treatment stage. Design Systematic review and meta-analysis. Participants 3623 patients with ovarian cancer from primary research investigations. Primary outcome measure The prevalence of depression and anxiety in patients with ovarian cancer as a function of treatment stage. Results We identified 24 full journal articles that met the inclusion criteria for entry into the meta-analysis resulting in a pooled sample size of 3623 patients. The meta-analysis of prevalence rates identified pretreatment, on-treatment and post-treatment depression prevalences of 25.34% (CI 22.79% to 28.07%), 22.99% (CI 19.85% to 26.46%) and 12.71% (CI 10.14% to 15.79%), respectively. Pretreatment, on-treatment and post-treatment anxiety prevalences were 19.12% (CI 17.11% to 21.30%), 26.23% (CI 22.30% to 30.56%) and 27.09% (CI 23.10% to 31.49%). Conclusions Our findings suggest that the prevalence of depression and anxiety in women with ovarian cancer, across the treatment spectrum, is significantly greater than in the healthy female population. With the growing emphasis on improving the management of survivorship and quality of life, we conclude that further research is warranted to ensure psychological distress in ovarian cancer is not underdiagnosed and undertreated.

The purpose of this study was to assess trends in technique and philosophy of face lifting, associated procedures, and the incidence and management of complications. Surveys were sent to 3800 members of the American Society of Plastic and Reconstructive Surgeons (ASPRS); 570 surveys (15 percent) were returned. Numerous very specific technique and philosophy questions were asked. Details of demographics, techniques, incidence of complications, management of complications, and basic philosophy are presented. Three basic conclusions can be gleaned from this study: (1) Surgeons perform more tried and true methods of aesthetic surgery, rather than the many new methods that seem to get the most attention in the media and at the meetings. (2) It seems that less-experienced surgeons tend to be generally more conservative in their approach to aesthetic surgery. (3) Complication rates reported by the plastic surgery community at large coincide with previous complication rates, as outlined in other nonsurvey studies. The authors expect to report additional data from the survey--on brow surgery (part II) and facility and ancillary procedures (part III)--in forthcoming publications.

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 ).

A relationship between migraine with aura and the presence of right-to-left shunts has been reported in two studies. Right-to-left shunts are also associated with some forms of decompression illness. While conducting research in divers with decompression illness, it was our impression that divers with a large shunt often had a history of migraine with aura in everyday life and after dives. Therefore we routinely asked all divers about migraine symptoms. The medical records of the last 200 individuals referred for investigation of decompression illness were reviewed to determine the association between right-to-left shunts and migraine aura after diving, and migraine in daily life unconnected with diving. Migraine with aura in daily life unconnected with diving occurred significantly more frequently in individuals who had a large shunt which was present at rest (38 of 80; 47.5%) compared with those who had a shunt which was smaller or only seen after a Valsalva manoeuvre (four of 40; 10%) or those with no shunt (11 of 80; 13.8%) (P<0.001). Hemiplegic migraine occurred in 10 divers, each of whom had a shunt that was present at rest; in eight of these cases the shunt was large. The prevalence of migraine without aura was similar in all groups. Post-dive migraine aura was significantly more frequent in individuals who had a large shunt present at rest (21 of 80; 26.3%) compared with those who had a shunt that was smaller or only seen after a Valsalva manoeuvre (five of 40; 12.5%) or no shunt (one of 80; 1.3%) (P<0.001). Thus individuals with a large right-to-left shunt have an increased prevalence of migraine with aura in daily life unconnected with diving, and they also have an increased incidence of migraine aura after dives, but only when the dives liberate venous bubbles. These data suggest the possibility that, in some individuals, right-to-left shunts have a role in the aetiology of migraine with aura. The observations suggest that paradoxical gas embolism may precipitate migraine with aura.

IMPORTANCE: The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT. OBJECTIVE: To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients. DESIGN, SETTING, AND PARTICIPANTS: Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011. EXPOSURES: Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry. MAIN OUTCOMES AND MEASURES: Failure-free survival (FFS) and overall survival. RESULTS: A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]). CONCLUSIONS AND RELEVANCE: Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer. METHODS: In NEAT, we compared four cycles of epirubicin followed by four cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) with six cycles of CMF alone. In the BR9601 trial, we compared four cycles of epirubicin followed by four cycles of CMF, with eight cycles of CMF alone every 3 weeks. The primary end points were relapse-free and overall survival. The secondary end points were adverse effects, dose intensity, and quality of life. RESULTS: The two trials included 2391 women with early breast cancer; the median follow-up was 48 months. Relapse-free and overall survival rates were significantly higher in the epirubicin-CMF groups than in the CMF-alone groups (2-year relapse-free survival, 91% vs. 85%; 5-year relapse-free survival, 76% vs. 69%; 2-year overall survival, 95% vs. 92%; 5-year overall survival, 82% vs. 75%; P<0.001 by the log-rank test for all comparisons). Hazard ratios for relapse (or death without relapse) (0.69; 95% confidence interval [CI], 0.58 to 0.82; P<0.001) and death from any cause (0.67; 95% CI, 0.55 to 0.82; P<0.001) favored epirubicin plus CMF over CMF alone. Independent prognostic factors were nodal status, tumor grade, tumor size, and estrogen-receptor status (P<0.001 for all four factors) and the presence or absence of vascular or lymphatic invasion (P=0.01). These factors did not significantly interact with the effect of epirubicin plus CMF. The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life. CONCLUSIONS: Epirubicin plus CMF is superior to CMF alone as adjuvant treatment for early breast cancer. (ClinicalTrials.gov number, NCT00003577 [ClinicalTrials.gov].).

A retrospective analysis of 260 completed intrauterine insemination (IUI) cycles was used in an attempt to identify significant variables predictive of treatment success. Couples received a maximum of three IUI cycles for the treatment of anovulation, cervical factors or unexplained infertility. Male factor problems were largely excluded by pretreatment screening. The overall pregnancy rate was 19.6% per completed cycle, the miscarriage rate 15.6%, the multiple pregnancy rate 23.5% and the cancellation rate 19%. Logistic regression identified four significant IUI variables [follicle number (P < 0.005), endometrial thickness (P < 0.005), duration of infertility (P < 0.01) and progressive motility (P < 0.05)] which were the most predictive of IUI success. The chance of conceiving when only one follicle was produced was only 7.6%, whereas with two follicles this chance increased to 26%. These variables were incorporated into a statistical model to allow the prediction of the chance of success in subsequent cycles. We conclude that careful patient selection criteria coupled with successful ovarian stimulation is the model for IUI success.

AIMS: To describe the clinical and health economic impact of respiratory syncytial virus (RSV) disease in children under 2 years of age. METHODS: Hospitalised children less than 2 years of age with a respiratory illness were studied over three consecutive RSV seasons (1996-99). RESULTS: The rates (per 1000 infants under 1 year of age) of hospitalisations from bronchiolitis and RSV illness were 30.8 and 24.4 respectively. The rates of death, intensive care admission, and need for ventilatory assistance during RSV related hospitalisation were 0.2%, 2.7%, and 1.5% respectively. From a cohort of 841 preterm infants, 6.3% had an RSV related hospitalisation during the study period, with the rate rising to 9.2% among those who were either born before 36 weeks gestation and were under 6 months of age at the onset of the RSV seasons, or were less than 2 years of age with chronic lung disease needing home oxygen therapy. Eight of 25 children on home oxygen therapy had RSV related rehospitalisation. Need for assisted ventilation during the neonatal period and discharge home on oxygen therapy were significantly associated with the risk of subsequent RSV related hospitalisation in preterm infants less than 6 months of age. The direct health authority cost of all RSV hospitalisations was pound 542 203, while the currently recommended immunoprophylaxis for the high risk infants would have cost pound 652 960. CONCLUSIONS: Preterm infants receiving assisted ventilation and those on home oxygen therapy are particularly at risk of RSV related hospitalisation. Serious adverse outcomes are however uncommon even among these high risk infants.

AIM: To investigate the relation between common acid-base parameters and blood lactate concentrations and their prognostic importance in sick, ventilated neonates. METHODS: Two hundred and seventy eight serial simultaneous measurements of arterial acid-base status and blood lactate concentrations were carried out in 75 mechanically ventilated neonates with indwelling arterial catheters (gestational age and birthweight, median (range) -29 (23-40) weeks, and 1340 (550-4080) g, respectively). RESULTS: There were no correlations between arterial blood lactate and pH and base excess within subjects (r = 0.07 and r = -0.06, respectively) and only weakly positive but clinically irrelevant positive correlations between subjects (r = 0.28 and r = 0.27) in this group. Even in those infants who had not received any bicarbonate before their initial measurements (n = 48), there were no correlations between initial blood lactate concentrations and pH (r = 0.27), base excess (r = 0.17), or serum bicarbonate concentrations (r = -0.18). There was no relation between peak lactate concentration (PLC) and base excess (r = 0.16), and only a weak correlation between peak lactate concentration (PLC) and pH (r = 0.28). Negative base excess was an insensitive indicator of raised lactate concentrations. Only two out of 33 (6%) instances of hyperlactataemia (lactate > 2.5 mmol/l) would have been identified with a base excess < -10 mmol/l as a cutoff. Lower cutoff values of base excess or pH performed no better. Raised lactate concentrations were associated with increased mortality at all levels. While six of 53 (11%) infants with a PLC < 2.5 mmol/l died, this proportion increased to four of 15 (27%) with a PLC between 2.5-5.0 mmol/l, and four of seven (57%) with a PLC > 5.0 mmol/l. Infants showing little rise or a substantial fall in blood lactate fared better than those with persistently raised values. A clinically important increase in blood lactate preceded the development of clinical markers of deterioration and complications in six infants. CONCLUSIONS: Contrary to popular belief, pH or base excess cannot be used as proxy measures for blood lactate concentration, and independent measurement of the latter are needed. Blood lactate concentrations may provide an early warning signal and important prognostic information in ill, ventilated neonates. In this regard, serial measurements of blood lactate are more useful than a single value.

OBJECTIVES: To investigate epidemiological, social, diagnostic and economic aspects of chlamydia screening in non-genitourinary medicine settings. METHODS: Linked studies around a cross-sectional population-based survey of adult men and women invited to collect urine and (for women) vulvovaginal swab specimens at home and mail these to a laboratory for testing for Chlamydia trachomatis. Specimens were used in laboratory evaluations of an amplified enzyme immunoassay (PCE EIA) and two nucleic acid amplification tests [Cobas polymerase chain reaction (PCR), Becton Dickinson strand displacement amplification (SDA)]. Chlamydia-positive cases and two negative controls completed a risk factor questionnaire. Chlamydia-positive cases were invited into a randomised controlled trial of partner notification strategies. Samples of individuals testing negative completed psychological questionnaires before and after screening. In-depth interviews were conducted at all stages of screening. Chlamydia transmission and cost-effectiveness of screening were investigated in a transmission dynamic model. SETTING AND PARTICIPANTS: General population in the Bristol and Birmingham areas of England. In total, 19,773 women and men aged 16-39 years were randomly selected from 27 general practice lists. RESULTS: Screening invitations reached 73% (14,382/19,773). Uptake (4731 participants), weighted for sampling, was 39.5% (95% CI 37.7, 40.8%) in women and 29.5% (95% CI 28.0, 31.0%) in men aged 16-39 years. Chlamydia prevalence (219 positive results) in 16-24 year olds was 6.2% (95% CI 4.9, 7.8%) in women and 5.3% (95% CI 4.4, 6.3%) in men. The case-control study did not identify any additional factors that would help target screening. Screening did not adversely affect anxiety, depression or self-esteem. Participants welcomed the convenience and privacy of home-sampling. The relative sensitivity of PCR on male urine specimens was 100% (95% CI 89.1, 100%). The combined relative sensitivities of PCR and SDA using female urine and vulvovaginal swabs were 91.8% (86.1, 95.7, 134/146) and 97.3% (93.1, 99.2%, 142/146). A total of 140 people (74% of eligible) participated in the randomised trial. Compared with referral to a genitourinary medicine clinic, partner notification by practice nurses resulted in 12.4% (95% CI -3.7, 28.6%) more patients with at least one partner treated and 22.0% (95% CI 6.1, 37.8%) more patients with all partners treated. The health service and patients costs (2005 prices) of home-based postal chlamydia screening were 21.47 pounds (95% CI 19.91 pounds, 25.99) per screening invitation and 28.56 pounds (95% CI 22.10 pounds, 30.43) per accepted offer. Preliminary modelling found an incremental cost-effectiveness ratio (2003 prices) comparing screening men and women annually to no screening in the base case of 27,000 pounds/major outcome averted at 8 years. If estimated screening uptake and pelvic inflammatory disease incidence were increased, the cost-effectiveness ratio fell to 3700 pounds/major outcome averted. CONCLUSIONS: Proactive screening for chlamydia in women and men using home-collected specimens was feasible and acceptable. Chlamydia prevalence rates in men and women in the general population are similar. Nucleic acid amplification tests can be used on first-catch urine specimens and vulvovaginal swabs. The administrative costs of proactive screening were similar to those for opportunistic screening. Using empirical estimates of screening uptake and incidence of complications, screening was not cost-effective.

Those involved in the practice of laboratory medicine are convinced of its value to effective and safe patient care, and usually have much anecdotal evidence of instances in which appropriate testing or the provision of interpretative comments 1 have improved care. However, systematic evidence of the contribution of laboratory medicine to the overall process of diagnosis and management of patients is much harder to obtain – understandably so, in view of the multitude of factors that are involved in reaching a diagnosis and planning treatment for an individual. Many articles seeking to promote the value of laboratory medicine make use of what has become known as the ‘70% claim’. This presents itself in various forms, most commonly that ‘Laboratory medicine data influences 70% of clinical decisions’, 2 or minor variations around this figure (60 – 80%). The percentage of the electronic medical record that consists of laboratory medicine data is also often adduced in support of the importance of the contribution made by pathologists and clinical scientists to patient care. The earliest published reference to the claim, and the one most frequently cited, is from 1996, by Forsman at the Mayo Clinic in the USA. 3 The author states: ‘We know that, although the laboratory represents a small percentage of medical center costs, it leverages 60 – 70% of all critical decisions, e.g. admission, discharge and therapy’. The evidence for this is not provided in the paper, but in an interview with Clinical Laboratory News in 2004, Forsman is quoted as saying: ‘ ... the statements that have been made take two forms. The first is that the laboratory represents 5% of a health system’s costs, yet it affects 95% of the remaining costs. The second statement is that the laboratory contributes 80% of the objective data in the clinical record and influences 60% – 70% of critical decision making. Unpublished sources for these statements include conversations with Dr Peter Dysert at Baylor University in Houston,