Darlington Memorial 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.

BACKGROUND: Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (≥65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 10(10) organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204. FINDINGS: Of 17,420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10·8%) participants in the microbial preparation group and 153 (10·4%) participants in the placebo group (relative risk [RR] 1·04; 95% CI 0·84-1·28; p=0·71). CDD was an uncommon cause of AAD and occurred in 12 (0·8%) participants in the microbial preparation group and 17 (1·2%) participants in the placebo group (RR 0·71; 95% CI 0·34-1·47; p=0·35). 578 (19·7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial. INTERPRETATION: We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies. FUNDING: Health Technology Assessment programme; National Institute for Health Research, UK.

Three hundred patients with symptomatic, locally advanced or metastatic NSCLC not requiring immediate radiotherapy were enrolled into this randomized multicentre trial comparing gemcitabine + BSC vs BSC alone. Patients allocated gemcitabine received 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, for a maximum of six cycles. The main aim of this trial was to compare patient assessment of a predefined subset of commonly reported symptoms (SS14) from the EORTC QLQ-C30 and LC13 scales. The primary end-points were defined as (1) the percentage change in mean SS14 score between baseline and 2 months and (2) the proportion of patients with a marked (> or = 25%) improvement in SS14 score between baseline and 2 months sustained for > or =4 weeks. The secondary objectives were to compare treatments with respect to overall survival, and multidimensional QL parameters. The treatment groups were balanced with regard to age, gender, Karnofsky performance status (KPS) and disease stage (40% had metastatic disease). The percentage change in mean SS14 score from baseline to 2 months was a 10% decrease (i.e. improvement) for gemcitabine plus BSC and a 1% increase (i.e. deterioration) for BSC alone (P = 0.113, two-sample t-test). A sustained (> or = 4 weeks) improvement (> or =25%) on SS14 was recorded in a significantly higher proportion of gemcitabine + BSC patients (22%) than in BSC alone patients (9%) (P = 0.0014, Pearson's chi-squared test). The QLQ-C30 and L13 subscales showed greater improvement in the gemcitabine plus BSC arm (in 11 domains) than in the BSC arm (one symptom item). There was greater deterioration in the BSC alone arm (six domains/items) than in the gemcitabine + BSC arm (three QL domains). Tumour response occurred in 19% (95% CI 13-27) of gemcitabine patients. There was no difference in overall survival: median 5.7 months (95% CI 4.6-7.6) for gemcitabine + BSC patients and 5.9 months (95% CI 5.0-7.9) (log-rank, P = 0.84) for BSC patients, and 1 -year survival was 25% for gemcitabine + BSC and 22% for BSC. Overall, 74 (49%) gemcitabine + BSC patients and 119 (79%) BSC patients received palliative radiotherapy. The median time to radiotherapy was 29 weeks for gemcitabine + BSC patients and 3.8 weeks for BSC. Patients treated with gemcitabine + BSC reported better QL and reduced disease-related symptoms compared with those receiving BSC alone. These improvements in patient-assessed QL were significant in magnitude and were sustained.

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.

Abstract Objective: To ascertain the beliefs, current practices, and decision making of general practitioners in the diagnosis and management of suspected heart failure in primary care, with a view to identifying barriers to good care. Design: A qualitative approach using focus groups with 30 general practitioners from four primary care groups. The sampling strategy was stratified and purposive. The contents of interviews were transcribed and analysed according to the principles of “pragmatic variant” grounded theory. Setting: North east England. Results: Three categories of difficulties contribute to variations in medical practice and to the reasons why general practitioners experience difficulties in diagnosing and managing heart failure. The first is uncertainty about clinical practice, including lack of confidence in establishing an accurate diagnosis and worries about using angiotensin converting enzyme inhibitors, β blockers, and spironolactone in patients who are often elderly and frail, with comorbidity and polypharmacy. The second is a lack of awareness of relevant research evidence in what was perceived to be a complex and rapidly changing therapeutic field. Doubts about the applicability of research findings in primary care, and fear of information overload also emerged. The third category consists of influences of individual preference and local organisational factors. Medical training, negative clinical experiences, and outside agencies influenced the behaviour of general practitioners and professional culture. Local factors included the availability of diagnostic services, resources (such as accessible cardiologists), and interactions between professionals in primary or secondary care, and they seemed to shape the practice and decision making processes in primary care. Conclusions: The national service framework for coronary heart disease stresses that the substandard care of patients with heart failure is unacceptable. This study identified barriers to be overcome across primary and secondary care in implementation strategies that are specific to the locality and multifaceted. Single strategies—for example, the provision of guidelines—are unlikely to have an impact on clinical outcomes, and new, conjoint models of care need to be explored. What is already known on this topic Heart failure is a common condition with a high morbidity and mortality and is largely managed in primary care Although modern management with accurate diagnosis and treatment improves prognosis considerably, unacceptable variations exist in the clinical application of current guidelines for heart failure What this study adds General practitioners expressed a lack of confidence in establishing an accurate diagnosis of left ventricular systolic dysfunction, even if open access echocardiography was available Uncertainty about diagnosis led to poor uptake of evidence based treatment strategies for heart failure patients, and, despite awareness, reluctance to initiate modern treatment Local organisational factors around NHS provision of diagnostic services, resources, and interaction between primary and secondary care influence how general practitioners manage heart failure Implementation strategies for heart failure management across primary and secondary care are needed that are specific to their locality and multifaceted

The technique of total three-stage oesophagectomy is described fully. Points of detail in the procedure of the abdominal, thoracic and cervical phases are emphasized. A brief note is made regarding the management of the respiratory situation at the end of the operation.

BACKGROUND: The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, can have an acute systemic (generalized pustular psoriasis [GPP]) or chronic localized (palmoplantar pustulosis [PPP] and acrodermatitis continua of Hallopeau [ACH]) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations. OBJECTIVE: We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort. METHODS: We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases. RESULTS: and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003). CONCLUSIONS: The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.

BACKGROUND: Eosinophilic oesophagitis (EoE) is an increasingly common cause of dysphagia in both children and adults, as well as one of the most prevalent oesophageal diseases with a significant impact on physical health and quality of life. We have provided a single comprehensive guideline for both paediatric and adult gastroenterologists on current best practice for the evaluation and management of EoE. METHODS: The Oesophageal Section of the British Society of Gastroenterology was commissioned by the Clinical Standards Service Committee to develop these guidelines. The Guideline Development Group included adult and paediatric gastroenterologists, surgeons, dietitians, allergists, pathologists and patient representatives. The Population, Intervention, Comparator and Outcomes process was used to generate questions for a systematic review of the evidence. Published evidence was reviewed and updated to June 2021. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used to assess the evidence and make recommendations. Two rounds of voting were held to assess the level of agreement and the strength of recommendations, with 80% consensus required for acceptance. RESULTS: Fifty-seven statements on EoE presentation, diagnosis, investigation, management and complications were produced with further statements created on areas for future research. CONCLUSIONS: These comprehensive adult and paediatric guidelines of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition are based on evidence and expert consensus from a multidisciplinary group of healthcare professionals, including patient advocates and patient support groups, to help clinicians with the management patients with EoE and its complications.

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 ).

In a 12-month prospective study incorporating four neighbouring district general hospitals, 228 patients required a total of 236 admissions with intestinal obstruction. The aetiological factors included adhesions 75 (32 per cent), malignant disease 61 (26 per cent), strangulated hernias 59 (25 per cent), volvulus 10 (4 per cent), acquired megacolon 6 (3 per cent), pseudo-obstruction 4 (2 per cent), faecal impaction 6 (3 per cent) and miscellaneous 15 (6 per cent). The peak incidence for obstruction due to adhesions, malignant disease and strangulated hernias each occurred in the eighth decade. Surgery was performed within 48 h of admission in 29 per cent adhesive obstructions (22), 30 per cent obstructions due to malignant disease (18) and 68 per cent strangulated hernias (40)--bowel resection rates in these three groups were 13.5, 50 and 29 per cent, respectively. The overall mortality was 11.4 per cent (26 deaths) and postoperative mortality was 12.3 per cent (19 deaths). During the 12-month study period, 228 patients required a total of 2993 inpatient hospital days as a result of intestinal obstruction. Postoperative adhesions have become the commonest cause of intestinal obstruction but strangulated hernias and intra-abdominal malignant disease still account for 50 per cent of all cases and mortalities. Obstruction due to strangulated hernias and intra-abdominal malignant disease typically occurs in the elderly age group where a more aggressive policy of elective surgical intervention is likely to be associated with increased postoperative morbidity and mortality.

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

The aim was to describe trends in prevalence, maternal age-specific prevalence, associated anomalies, clinical outcomes and the sensitivity of antenatal diagnosis of congenital anterior abdominal wall defects (in particular gastroschisis and exomphalos). Data were identified from a population-based register of major congenital abnormalities in the Northern health region of England, the Northern Congenital Abnormality Survey (NorCAS), between 1986 and 1996. 296 cases were notified; there were 133 cases of gastroschisis, 98 exomphalos, 30 limb-body wall defects and 23 other anterior abdominal wall defects. 12 cases could not be classified. In 19 (6 per cent) the initial diagnosis was changed following case review. 30 (30.6 per cent) cases of exomphalos were associated with a chromosomal anomaly compared with 1 (0.8 per cent) case of gastroschisis. The total prevalence for the 11 years was 6.33 (95 per cent CI=5.57-7.08) per 10 000 live births, still births and terminations of pregnancy, and the overall birth prevalence was 4.30 (95 per cent CI=3.68-4.93) per 10 000 live births and still births. For gastroschisis, there was a significant increase over the study period in both the total prevalence (1.48 in 1986 to 5.29 per 10 000 in 1996; chi(2)=8.41, p=0.00433) and the birth prevalence (1.48 in 1986 to 4.72 per 10 000 in 1996; chi(2)=7.42, p=0.00644), but there was no such significant increase for exomphalos (total prevalence chi(2)=2.29, p=0.13055; birth prevalence chi(2)=0.16, p=0.69348). The maternal age-specific prevalence was highest in the 11-19 year age group for gastroschisis but in the 35-39 year age group for exomphalos. Fewer pregnancies with gastroschisis resulted in a termination and a greater proportion of cases were alive at one year compared with exomphalos. The sensitivity of abnormality detection by ultrasonography was 75 per cent and 77.3 per cent for gastroschisis and exomphalos, respectively. Antenatal diagnosis improved from 47.4 per cent during 1986-91 to 80 per cent between 1992-96 for gastroschisis (chi(2)=5.7, p=0.00169), and from 55.6 per cent to 68.8 per cent for isolated exomphalos, although this increase was not significant. Total and birth prevalence of gastroschisis increased in the Northern region between 1986 and 1996. For exomphalos, there was a trend towards an increase in total prevalence and towards a decrease in birth prevalence. This decreasing trend has been accompanied by improvements in antenatal detection and subsequent termination of cases of exomphalos associated with other anomalies.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

OBJECTIVE: To investigate the effects of interventions promoting placental transfusion at delivery (delayed cord clamping or umbilical cord milking) compared with early cord clamping on outcomes among premature neonates of less than 32 weeks of gestation. DATA SOURCES: A systematic search was conducted of PubMed, Embase, and ClinicalTrials.gov databases (January 1965 to December 2013) for articles relating to placental transfusion strategies in very preterm neonates. METHODS OF STUDY SELECTION: Literature searches returned 369 articles with 82 considered in full. We only included data from studies with an average gestational age of less than 32 weeks of gestation enrolled in randomized trials of enhanced placental-fetal transfusion interventions (delayed cord clamping or umbilical cord milking) compared with early cord clamping. TABULATION, INTEGRATION, AND RESULTS: We identified 12 eligible studies describing a total of 531 neonates with an average gestation of 28 weeks. Benefits of greater placental transfusion were decreased mortality (eight studies, risk ratio 0.42, 95% confidence interval [CI] 0.19-0.95, 3.4% compared with 9.3%, P=.04), lower incidence of blood transfusions (six studies, risk ratio 0.75, 95% CI 0.63-0.92, 49.3% compared with 66%, P<.01), and lower incidence of intraventricular hemorrhage (nine studies, risk ratio 0.62, 95% CI 0.43-0.91, 16.7% compared with 27.3%, P=.01). There was a weighted mean difference of -1.14 blood transfusions (six studies, 95% CI -2.01-0.27, P<.01) and a 3.24-mmHg increase in blood pressure at 4 hours of life (four studies, 95% CI 1.76-4.72, P<.01). No differences were observed between the groups across all available safety measures (5-minute Apgar scores, admission temperature, incidence of delivery room intubation, peak serum bilirubin levels). CONCLUSIONS: Results of this meta-analysis suggest that enhanced placental transfusion (delayed umbilical cord clamping or umbilical cord milking) at birth provides better neonatal outcomes than does early cord clamping, most notably reductions in overall mortality, lower risk of intraventricular hemorrhage, and decreased blood transfusion incidence. The optimal umbilical cord clamping practice among neonates requiring immediate resuscitation remains uncertain.

Plasma zinc levels were measured in 14 patients with primary affective disorder on admission to hospital; they were compared with plasma zinc levels in group of 14 age- and sex-matched controls. A significant difference in zinc levels was found between the 2 groups. Plasma zinc levels of 9 of the depressed patients on admission to hospital and at the point of discharge were compared; a significant increase in zinc levels was detected.

BACKGROUND: Ménière's disease is a disorder characterised by hearing loss, tinnitus and disabling vertigo. Diuretics are used to try and reduce the severity and frequency of episodes but there is little evidence behind this treatment. OBJECTIVES: To assess the effect of diuretic treatment in patients with Ménière's disease. SEARCH STRATEGY: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1 2005), MEDLINE (1966 to 2005), EMBASE (1974 to 2005), CINAHL and the metaRegister of Controlled Trials (mRCT) (up to 2005). SELECTION CRITERIA: Randomised controlled trials of diuretic versus placebo in Ménière's patients. DATA COLLECTION AND ANALYSIS: One author identified studies which loosely met the inclusion criteria and full texts were retrieved. Two authors independently applied the inclusion criteria. Seven studies were excluded from the review due to inappropriate study design or absence of randomisation. MAIN RESULTS: There were no trials of high enough quality to meet the standard set for this review. AUTHORS' CONCLUSIONS: There is insufficient good evidence of the effect of diuretics on vertigo, hearing loss, tinnitus or aural fullness in clearly defined Ménière's disease.

OBJECTIVE: To determine whether parenteral penicillin given before admission to hospital reduces the case fatality rate in patients with meningococcal disease. DESIGN: Retrospective analysis of 46 consecutive patients admitted to hospital with meningococcal disease from January 1986 to March 1991. SETTING: District general hospital. MAIN OUTCOME MEASURE: Hospital case fatality rate. RESULTS: None of the 13 patients given parenteral penicillin by the referring doctor before admission died, compared with eight deaths (24%) in 33 patients admitted without such treatment. CONCLUSION: Parenteral penicillin given before admission probably contributed to a reduction in the case fatality rate from meningococcal disease, and primary care physicians should be encouraged to give such treatment immediately on suspicion of the diagnosis before transferring the patient to hospital. Public health physicians are well placed to inform and alert general practitioners of the potential benefit of this action.

BACKGROUND: The prevalence of tuberculosis, especially extrapulmonary tuberculosis, is increasing worldwide. Because information on the outcome of pregnancy among women with extrapulmonary tuberculosis is limited, we studied the course of pregnancy and labor and the perinatal outcome in these women and their infants. METHODS: From 1983 to 1993, we followed 33 pregnant women who had extrapulmonary tuberculosis (12 with tuberculous lymphadenitis and 9 with intestinal, 7 with skeletal, 2 with renal, 2 with meningeal, and 1 with endometrial tuberculosis) through their deliveries. Of the 33, 29 received antituberculosis treatment during pregnancy. The antenatal complications, intrapartum events, and perinatal outcomes were compared with those among 132 healthy pregnant women without tuberculosis who were matched for age, parity, and socioeconomic status. RESULTS: Tuberculous lymphadenitis did not affect the course of pregnancy or labor or the perinatal outcome. However, as compared with the control women, the 21 women with tubercular involvement of other extrapulmonary sites had higher rates of antenatal hospitalization (24 percent vs. 2 percent, P< 0.001), infants with low Apgar scores (< or =6) soon after birth (19 percent vs. 3 percent, P=0.01), and low-birth-weight (<2500 g) infants (33 percent vs. 11 percent, P=0.01). CONCLUSIONS: Extrapulmonary tuberculosis that is confined to the lymph nodes has no effect on obstetrical outcomes, but tuberculosis at other extrapulmonary sites does adversely affect the outcome of pregnancy.

AIMS: The study evaluated the use of age-related decision limits for N-terminal pro-B-type natriuretic peptide (NT-proBNP), for ruling out suspected systolic dysfunction in symptomatic patients in primary care, compared with the present standards. METHODS AND RESULTS: Data were obtained from 5508 patients from 10 studies in the UK, New Zealand, Europe, and USA. All have had NT-proBNP analysis and echocardiography. The median age was 62 years (range 18-100 years) with a prevalence of reduced left ventricular systolic function (left ventricular ejection fraction < or =40%) of 18%. In a receiver operating characteristic curve analysis, overall area under the curve (AUC) was 0.89. When looking at different age groups, AUC was highest (0.95) for <50 years, intermediate (0.90) for 50-75 years, and lowest (0.82) for >75 years. Using optimized decision limits, sensitivity, specificity, and negative predictive values (NPVs) were: <50 years (50 ng/L): 99.2, 57.2, and 99.7%; 50-75 years (75 ng/L): 95.9, 51.0, and 96.8%; and >75 years (250 ng/L): 87.9, 53.7, and 92.4%, respectively. Using only a single decision value (125 ng/L for all ages) gave sensitivities of 89.1, 91.9, and 94.3%; specificities of 84.0, 69.1, and 29.3% and NPVs of 97.7, 97.6, and 93.4%. A decision value of 400 ng/L for all ages gave much lower sensitivities. CONCLUSION: In a large population of patients in primary care, the use of age-stratified NT-proBNP decision limits considerably improves performance over current standards, with an excellent NPV for exclusion of reduced left ventricular systolic function.

BACKGROUND: National guidelines suggest the use of natriuretic peptides in suspected heart failure but there have been no studies comparing assays in primary care. AIM: To test and compare the diagnostic accuracy and utility of B-type natriuretic peptide (BNP) and N-terminal B-type natriuretic peptide (NT proBNP) in diagnosing heart failure due to left ventricular systolic dysfunction in patients with suspected heart failure referred by GPs to one-stop diagnostic clinics. DESIGN OF STUDY: Community cohort, prospective, diagnostic accuracy study. SETTING: One-stop diagnostic clinics in Darlington Memorial and Bishop Auckland General Hospitals and general practices in South Durham. SUBJECTS: Two hundred and ninety-seven consecutive patients with symptoms and signs suggestive of heart failure referred from general practice. METHOD: The study measured sensitivity, specificity, positive and negative predictive values (PPV, NPV), and area under receiver operating characteristic curve for BNP (near patient assay) and NT proBNP (laboratory assay) in diagnosis of heart failure due to left ventricular systolic dysfunction. The NPV of both assays was determined as a potential method of reducing the number of referrals for echocardiography. RESULTS: One hundred and fourteen of the 297 patients had left ventricular systolic dysfunction (38%). At the manufacturer's recommended cut-off of 100 pg/ml BNP gave a NPV of 82%. BNP performed better at a cut-off of 40 pg/ml with a NPV of 88%. At a cut-off of 150 pg/ml, NT proBNP gave a NPV of 92%. Using cut-offs of 40 pg/ml and 150 pg/ml for BNP and NT pro-BNP, respectively, could have prevented 24% and 25% of referrals to the clinic, respectively. CONCLUSIONS: In this setting, NT pro-BNP performed marginally better than BNP, and would be easier to use practically in primary care. A satisfactory cut-off has been identified, which needs validating in general practice. NT pro-BNP could be used to select referrals to a heart failure clinic or for echocardiography. This process needs testing in real-life general practice.