Approaches to screening for hyperglycaemia in pregnant women during and after the COVID-19 pandemic.

AIM: To evaluate the diagnostic and prognostic performance of alternative diagnostic strategies to oral glucose tolerance tests, including random plasma glucose, fasting plasma glucose and HbA1c , during the COVID-19 pandemic. METHODS: Retrospective service data (Cambridge, UK; 17 736 consecutive singleton pregnancies, 2004-2008; 826 consecutive gestational diabetes pregnancies, 2014-2019) and 361 women with ≥1 gestational diabetes risk factor (OPHELIA prospective observational study, UK) were included. Pregnancy outcomes included gestational diabetes (National Institute of Health and Clinical Excellence or International Association of Diabetes and Pregnancy Study Groups criteria), diabetes in pregnancy (WHO criteria), Caesarean section, large-for-gestational age infant, neonatal hypoglycaemia and neonatal intensive care unit admission. Receiver-operating characteristic curves and unadjusted logistic regression were used to compare random plasma glucose, fasting plasma glucose and HbA1c performance. RESULTS: Gestational diabetes diagnosis was significantly associated with random plasma glucose at 12 weeks [area under the receiver-operating characteristic curve for both criteria 0.81 (95% CI 0.79-0.83)], fasting plasma glucose [National Institute of Health and Clinical Excellence: area under the receiver-operating characteristic curve 0.75 (95% CI 0.65-0.85); International Association of Diabetes and Pregnancy Study Groups: area under the receiver-operating characteristic curve 0.92 (95% CI 0.85-0.98)] and HbA1c at 28 weeks' gestation [National Institute of Health and Clinical Excellence: 0.83 (95% CI 0.75-0.90); International Association of Diabetes and Pregnancy Study Groups: 0.84 (95% CI 0.77-0.91)]. Each measure predicts some, but not all, pregnancy outcomes studied. At 12 weeks, ~5% of women would be identified using random plasma glucose ≥8.5 mmol/l (sensitivity 42%; specificity 96%) and at 28 weeks using HbA1c ≥39 mmol/mol (sensitivity 26%; specificity 96%) or fasting plasma glucose ≥5.2-5.4 mmol/l (sensitivity 18-41%; specificity 97-98%). CONCLUSIONS: Random plasma glucose at 12 weeks, and fasting plasma glucose or HbA1c at 28 weeks identify women with hyperglycaemia at risk of suboptimal pregnancy outcomes. These opportunistic laboratory tests perform adequately for risk stratification when oral glucose tolerance testing is not available.

Severe neonatal hypoglycaemia and intrapartum glycaemic control in pregnancies complicated by type 1, type 2 and gestational diabetes.

AIMS: To determine if in-target intrapartum glucose control is associated with neonatal hypoglycaemia in women with type 1, type 2 or gestational diabetes. METHODS: This was a retrospective cohort study of pregnant women with diabetes and their neonates. The primary exposure was in-target glucose control, defined as all capillary glucose values within the range 3.5-6.5 mmol/l during the intrapartum period. The primary outcome, neonatal hypoglycaemia, was defined as treatment with intravenous dextrose therapy. Multiple logistic regression was used to examine the association between maternal intrapartum glycaemic control and neonatal hypoglycaemia, adjusting for covariates. RESULTS: Intrapartum glucose testing was available for 157 (86.3%), 267 (76.3%) and 3256 (52.4%) women with type 1, type 2 and gestational diabetes, respectively. In the univariate analysis, in-target glycaemic control was significantly associated with neonatal hypoglycaemia in women with gestational diabetes, but not in women with type 1 or 2 diabetes. However, after adjustment for important neonatal factors (large for gestational age, preterm delivery and infant sex), intrapartum in-target glycaemic control was not significantly associated with neonatal hypoglycaemia in women regardless of diabetes type [adjusted odds ratios 0.4 (95% CI 0.1, 1.4), 0.7 (95% CI 0.3, 1.3) and 0.7 (95% CI 0.5, 1.0) for women with type 1, type 2 and gestational diabetes, respectively]. CONCLUSIONS: There was no significant association between in-target glycaemic control and neonatal hypoglycaemia after adjustment for neonatal factors. Given the high risk of maternal hypoglycaemia and the resources required, future trials should consider whether more relaxed intrapartum glycaemic targets may be safer and yield similar neonatal outcomes.

The effect of hypoglycaemia during hospital admission on health-related outcomes for people with diabetes: a systematic review and meta-analysis.

AIM: To assess the health-related outcomes of hypoglycaemia for people with diabetes admitted to hospital; specifically, hospital length of stay and mortality. METHODS: We conducted a systematic review and meta-analysis of studies relating to hypoglycaemia (< 4 mmol/l) for hospitalized adults (≥ 16 years) with diabetes reporting the primary outcomes of interest, hospital length of stay or mortality. Final papers for inclusion were reviewed in duplicate and the adjusted results of each were pooled, using a random effects model then undergoing further prespecified subgroup analysis. RESULTS: In total, 15 studies were included in the meta-analysis. The pooled mean difference in length of stay for ward-based inpatients exposed to hypoglycaemia was 4.1 days longer [95% confidence interval (CI) 2.36 to 5.79; I² = 99%] compared with those without hypoglycaemia. This association remained robust across the pre-specified subgroup analyses. The pooled relative risk (RR) of in-hospital mortality was greater for those exposed to hypoglycaemia (RR 2.09, 95% CI 1.64 to 2.67; I² = 94%, n = 7 studies) but not in intensive care unit mortality (RR 0.75, 95% CI 0.49 to 1.16; I² =0%, n = 2 studies). CONCLUSION: There is an association between inpatient hypoglycaemia and longer length of stay and greater in-hospital mortality. Studies examining this association were heterogenous in terms of both clinical populations and effect size, but the overall direction of the association was consistent. Therefore, glucose concentration should be considered a potential tool to aid the identification of inpatients at risk of poor health-related outcomes.

Maternal glycaemic control and risk of neonatal hypoglycaemia in Type 1 diabetes pregnancy: a secondary analysis of the CONCEPTT trial.

AIMS: To examine the relationship between maternal glycaemic control and risk of neonatal hypoglycaemia using conventional and continuous glucose monitoring metrics in the Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Trial (CONCEPTT) participants. METHODS: A secondary analysis of CONCEPTT involving 225 pregnant women and their liveborn infants. Antenatal glycaemia was assessed at 12, 24 and 34 weeks gestation. Intrapartum glycaemia was assessed by continuous glucose monitoring measures 24 hours prior to delivery. The primary outcome was neonatal hypoglycaemia defined as glucose concentration < 2.6 mmol/l and requiring intravenous dextrose. RESULTS: Neonatal hypoglycaemia occurred in 57/225 (25.3%) infants, 21 (15%) term and 36 (40%) preterm neonates. During the second and third trimesters, mothers of infants with neonatal hypoglycaemia had higher HbA1c [48 ± 7 (6.6 ± 0.6) vs. 45 ± 7 (6.2 ± 0.6); P = 0.0009 and 50 ± 7 (6.7 ± 0.6) vs. 46 ± 7 (6.3 ± 0.6); P = 0.0001] and lower continuous glucose monitoring time-in-range (46% vs. 53%; P = 0.004 and 60% vs. 66%; P = 0.03). Neonates with hypoglycaemia had higher cord blood C-peptide concentrations [1416 (834, 2757) vs. 662 (417, 1086) pmol/l; P < 0.00001], birthweight > 97.7th centile (63% vs. 34%; P < 0.0001) and skinfold thickness (P ≤ 0.02). Intrapartum continuous glucose monitoring was available for 33 participants, with no differences between mothers of neonates with and without hypoglycaemia. CONCLUSIONS: Modest increments in continuous glucose monitoring time-in-target (5-7% increase) during the second and third trimesters are associated with reduced risk for neonatal hypoglycaemia. While more intrapartum continuous glucose monitoring data are needed, the higher birthweight and skinfold measures associated with neonatal hypoglycaemia suggest that risk is related to fetal hyperinsulinemia preceding the immediate intrapartum period.

Intrapartum glycaemic control and neonatal hypoglycaemia in pregnancies complicated by diabetes: a systematic review.

AIMS: To examine whether, in neonates of mothers with Type 1, Type 2 and gestational diabetes, in-target intrapartum glycaemic control was associated with a lower risk of neonatal hypoglycaemia compared with out-of-target glycaemic control. METHODS: We searched PubMed and EMBASE for all available publications, regardless of year, based on a published protocol (PROSPERO CRD42016052439). Studies were excluded if they did not report original data or were animal studies. Data were extracted from published reports in duplicate using a prespecified data extraction form. The main outcome of interest was the association between in-target intrapartum glycaemic control and neonatal hypoglycaemia. RESULTS: We screened 2846 records for potential study inclusion; 23 studies, including approximately 2835 women with diabetes, were included in the systematic review. Only two of those studies specifically examined in-target vs out-of-target intrapartum glycaemic control. Of the studies included, six showed a relationship between intrapartum glucose and neonatal hypoglycaemia, five others showed a relationship in at least one of the analyses performed and 12 did not find a significant relationship. Only one study was identified as having a low risk of bias. CONCLUSIONS: There is a paucity of high-quality data supporting the association of glucose during labour and delivery with neonatal hypoglycaemia in pregnancies complicated by diabetes. Further studies are required to examine the impact of tight glycaemic targets in labour.

Polylactic acid nanosheets in prevention of postoperative intestinal adhesion and their effects on bacterial propagation in an experimental model.

BACKGROUND: Ultrathin films (nanosheets) adhere tightly to organ surfaces but prevent adhesion to other organs. The antiadhesive effect of nanosheets and their effect on bacterial propagation were investigated in a murine intestinal adhesion model. METHODS: Polylactic acid nanosheets (approximately 80 nm thick) were produced. Serosal defects were created by peeling off the intestinal serosa; these were left open or covered with nanosheets or Seprafilm® and the formation of intestinal adhesions was analysed. To examine bacterial propagation, a nanosheet or Seprafilm® was placed on intact murine jejunum followed by Escherichia coli inoculation at the site. RESULTS: Treatment both with nanosheets and with Seprafilm® reduced postoperative intestinal adhesion (mean adhesion score 0·67 for nanosheets, 0·43 for Seprafilm® and 2·87 for no antiadhesive treatment; P < 0·001 for nanosheets or Seprafilm® versus no adhesive treatment). Nanosheet treatment did not affect bacterial propagation in the peritoneal cavity, whereas Seprafilm®-treated mice showed bacterial propagation, leading to increased mortality. CONCLUSION: Nanosheets may be effective novel antiadhesive agents even in the presence of bacterial contamination. Surgical relevance Intra-abdominal adhesions following surgical contamination can trigger postoperative complications and lead to deterioration in long-term quality of life. However, currently there are no effective antiadhesion materials to prevent the formation of adhesions. Treatment with ultrathin nanosheets effectively reduced postoperative intestinal adhesion in an experimental mouse model, and did not affect bacterial propagation in the peritoneal cavity. These nanosheets are potent novel antiadhesive materials that potentially can be applied even in contaminated conditions.

Preoperative chemoradiation therapy for esophageal cancer is a risk factor for the elevation of high mobility group box-1, leading to an increase in postoperative severe pulmonary complications.

We herein clarified the time course of changes in the serum high mobility group box chromosomal protein-1 (HMGB-1) concentrations in esophageal cancer patients after esophagectomy, and investigated whether the perioperative serum HMGB-1 levels correlate with the administration of neoadjuvant chemoradiation therapy (NACRT) and the postoperative clinical course, especially the occurrence of pulmonary complications, in such patients. Sixty patients who underwent right transthoracic esophagectomy for esophageal cancer were enrolled in this study. The relationship between the perioperative serum HMGB-1 levels and NACRT, and the postoperative severe pulmonary complications were evaluated. Patients with severe pulmonary complications (n = 44) tended to have undergone NACRT more often than those without severe pulmonary complications (n = 16). The preoperative and postoperative day 7 serum HMGB-1 concentrations were significantly higher in patients with severe pulmonary complications than those in patients without severe pulmonary complications. In the univariate and multivariate analyses, the use of NACRT and the preoperative elevations in the serum HMGB-1 levels (>4.2 ng/mL) were found to be significantly associated with pulmonary dysfunction. Furthermore, the response to NACRT was found to be significantly associated with the preoperative serum HMGB-1 levels. The use of NACRT contributes to preoperative serum HMGB-1 elevation, and these were risk factors for the occurrence of severe postoperative pulmonary complications in patients with esophageal cancer after thoracic esophagectomy.

Factors related to advanced colorectal neoplasm at the Policlínico Peruano Japonés.

BACKGROUND: Identifying persons at high risk for advanced colorectal neoplasia can aid in the prevention of colon cancer. Previous studies have shown that some patients can present with proximal advanced neoplasia with no distal findings. AIMS: To determine the factors related to advanced neoplasia and advanced proximal colorectal neoplasia in a Latin American population. MATERIAL AND METHODS: A prospective, cross-sectional, observational, analytic study was conducted. It included patients that underwent colonoscopy at the Policlínico Peruano Japonés within the time frame of January and July 2012. Advanced neoplasia was defined as the presence of lesions ≥ 10mm with a villous component, high-grade dysplasia, or carcinoma. The splenic flexure was the limit between the proximal and distal colon. RESULTS: A total of 846 patients were included in the study. Advanced neoplasia was detected in 108 patients (12.8%) and advanced proximal neoplasia in 55 patients (6.7%), 42 (76.4%) of whom had no neoplasia in the distal colon. Factors related to advanced neoplasia found in the multivariate analysis were age, at the intervals of 50-59 (p=0.019), 60-69 (p=0.016), and ≥ 70 years (0.002) and male sex (p=0.003). In the evaluation of advanced proximal neoplasia, the multivariate analysis identified the 60-69 year age interval (p=0.039) and advanced distal neoplasia (p=0.028) as factors related to advanced proximal disease. The ROC curve established the age cut-off point at 60 years for initially performing colonoscopy, rather than sigmoidoscopy. CONCLUSIONS: Age and sex are related to advanced neoplasia, whereas age and advanced distal neoplasia are related to advanced proximal neoplasia.

Prognostic impact of histological categorisation of epithelial-mesenchymal transition in colorectal cancer.

BACKGROUND: The crosstalk between cancer cells and stroma is involved in the acquired capability for metastasis through the induction of epithelial-mesenchymal transition (EMT). We aimed to clarify the prognostic value of the histological category of EMT in colorectal cancer (CRC). METHODS: Tumour EMT was graded into one of three histological categories on the basis of integrated assessment of poorly differentiated clusters and pro-EMT desmoplasia at the leading edge of the primary tumour (Histology(EMT)). Stage II and III CRC patients (cohort 1, N=500) and stage IV patients (cohort 2, N=196) were retrospectively analysed. RESULTS: In cohort 1, patients were stratified into three groups with widely different disease-free survival rates (95%, 83% and 39%) on the basis of Histology(EMT) (P<0.0001). In cohort 2, Histology(EMT) significantly stratified overall survival of patients irrespective of metasectomy. Multivariate analyses indicated that Histology(EMT) had a strong prognostic impact independent of staging factors. Statistically, Histology(EMT) had a better prognostic stratification power than T and N stages; however, in cohort 2, the power of M substage was superior. CONCLUSIONS: A histological model to categorise EMT by integrated assessment of dedifferentiation and desmoplastic environment is a potent prognostic index independent of staging factors.

Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. METHODS: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. RESULTS: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. CONCLUSIONS: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Envelope surface ultrastructure and specific gravity of artificially fertilized Pacific cod Gadus macrocephalus eggs.

The envelope surface ultrastructure and specific gravity of artificially fertilized eggs of the Pacific cod Gadus macrocephalus were examined. The unfertilized, demersal and slightly adhesive eggs of G. macrocephalus were almost spherical and had no oil globules. Wrinkled envelope surface with elaborated hexagonal reticulated patterns and type I micropyle were observed under a scanning electron microscope. The adhesiveness of the eggs was lost at the blastodermal-cap stage after fertilization. The micropylar canal was sealed by secretion of the perivitelline fluid, and the entire surface became rough. Numerous bacilli were deposited at the micropyle and the outer envelope surface at the late germ-ring stage and at the embryo five-eighths around the yolk stage. The micropyle was completely deformed at the embryo seven-eighths around the yolk stage. The specific gravity of the fertilized G. macrocephalus eggs ranged from c. 1·0316 to 1·0454. These values, however, sharply decreased towards the end stages of egg development to produce pelagic larvae. The ultrastructural changes in the micropyle and envelope surface of the G. macrocephalus eggs protected the embryo from microorganism infections and mechanical stress during the long incubation period. The adhesiveness and specific gravity of the eggs influenced their dispersion potential.

Temperature-mediated survival, development and hatching variation of Pacific cod Gadus macrocephalus eggs.

Laboratory-validated data on the survival, development and hatching responses of fertilized Pacific cod Gadus macrocephalus eggs from the northern Japan stock were determined through an incubation experiment. The optimum temperature for survival until hatching ranged from 4 to 8°C. No significant difference in development rates was found between the populations from Mutsu Bay, Japan, and western Canadian coastal waters even though the samples may belong to different G. macrocephalus stocks. Gadus macrocephalus larvae hatched asynchronously from egg batches despite incubation under the same environment during their development. Both incubation temperature and temperature-mediated hatch rank affect size and yolk reserve. These data suggest that variations in water temperatures within an ecological range markedly influence the development rates, survival and hatching of the eggs, as well as the stage at hatch larvae of G. macrocephalus. Asynchronous hatching and the production of offspring with variable sizes and yolk reserves are considered evolutionary bet-hedging strategies that enable the species to maximize their likelihood of survival in an environment with variable temperatures.

Paediatric presentation and outcome of congenital protein C deficiency in Japan.

Severe heritable protein C (PC) deficiency is quite rare, although heterozygous PROC mutation is the second leading cause of genetic predisposition to thrombosis in Japanese adults. The aim of the study was to search the optimal management, the paediatric onset and outcomes of PC deficiency were characterized in Japan. The genetic study, postmarketing survey of activated PC(aPC) concentrate (Anact(®)C) and intensive review in Japan for 20 years enabled the analysis of the disease onset, genotype, treatment and prognosis. Symptomatic PC deficiency was determined in 27 Japanese children. All but two patients presented within 16 days after birth (three prenatal and six neonatal onsets). Postnatal-onset cases had normal growth at full-term delivery. Of the 27 patients, 19 suffered intracranial thrombosis or haemorrhage (ICTH) (three foetal hydrocephalies), 16 developed purpura fulminans (PF) and 10 had both at the first presentation. ICTH preceded PF in both affected cases. Low PC activities of 18 mothers and/or 12 fathers indicated 20 inherited PC deficiencies (2 homozygotes, 11 compound heterozygotes and 7 heterozygotes) and seven unidentified causes of PC deficiency. Nine of 11 patients studied had PROC mutations. Four unrelated patients (50%) carried PC nagoya (1362delG). No PC-deficient parents had experienced thromboembolism. Of the 18 patients with aPC therapy, two died and eight evaluable survivors had neurological sequelae. This first comprehensive study of paediatric PC deficiency suggested that perinatal ICTH was the major presentation, occurring earlier than neonatal PF. PC nagoya was prevalent in paediatric, but not adult, patients in Japan. Early maternal screening and optimal PC therapy are required for newborns at risk of PC deficiency.

Evaluation of the seventh edition of the tumour, node, metastasis (TNM) classification for colon cancer in two nationwide registries of the United States and Japan.

AIM: The new TNM classification is currently being implemented. We evaluated the TNM-7 staging system based on the two nationwide colon cancer registries in the United States and Japan to clarify whether this system better stratifies patients' prognoses than the TNM-6 did and to determine whether stratification can be effectively simplified. METHODS: The Surveillance, Epidemiology, and End Results population-based data from 1988 to 2001 for 50139 colon cancer patients and the multi-institutional registry data from the Japanese Society for Cancer of the Colon and Rectum from 1984 to 1994 for 10754 patients were analysed. We devised a modified version of the TNM-7 staging system to allow simpler classification of the TN categories and compared the TNM-6, TNM-7, modified TNM-7, and the Dukes staging system based on survival curves and objective statistical tests such as likelihood ratio χ(2) tests, Akaike's information criterion, and Harrell's c-index. RESULTS: The TNM-7 was superior to the TNM-6 in all objective statistical tests in the United States (c-index; 0.700 vs 0.696, P<0.001) as well as in the Japan data sets (0.732 vs 0.729, P=0.035). The modified TNM-7 is much simpler, but it nevertheless showed similar values to those of the original TNM-7 (c-index; the United States 0.702, Japan 0.733). CONCLUSIONS: The new TNM-7 is complicated but better at stratifying patients than the TNM-6 in the United States and Japan, and could be effectively simplified.

Optimal margins and lymphadenectomy in colonic cancer surgery.

BACKGROUND: A standard management policy has not yet been established with respect to the extent of lymphadenectomy for colonic cancer. METHODS: A total of 914 consecutive patients who underwent potentially curative surgery for T2-T4 colonic cancer were reviewed retrospectively. The number of lymph nodes (LNs) examined and the potential contributions to the staging accuracy of the distinct area were analysed. The survival benefit of dissection was compared for pericolic (local), mesocolic (intermediate) and main arterial trunk (main) LN. RESULTS: Removal of the pericolic LNs within 5 cm of the tumour and intermediate LNs resulted in a mean LN number of 15.9, a sensitivity for overall node positivity of 97.5 per cent, and a survival benefit calculated as a therapeutic value index of 31.4 points. The additional removal of LNs more than 5 cm from the tumour and main LNs did not improve the staging accuracy, while adding only 3.4 points to the survival benefit. CONCLUSION: Current guidelines may encourage needlessly extensive surgery. Clinical trials to establish the optimal extent of lymphadenectomy are warranted.

Correlation between proximal serrated polyp detection and clinically significant serrated polyps: inter-endoscopist variability.

INTRODUCTION AND AIMS: The adenoma detection rate (ADR) is the most important quality indicator for the prevention of colorectal cancer but serrated polyps are also precursor lesions of the disease. The aim of our study was to compare the detection rate of proximal serrated polyps (PSPs) and that of clinically significant serrated polyps (CSSPs) between endoscopists and analyze the relation of those parameters to the ADR. METHODS: An observational, prospective, cross-sectional study was conducted on all patients that underwent colonoscopy at the Policlínico Peruano Japonés within the time frame of July 2015 and August 2016. The ADR and PSP and CSSP detection rates between endoscopists were compared through multivariate logistic regression and the association between those parameters was calculated through the Pearson correlation coefficient. RESULTS: The study included 15 endoscopists and 1,378 colonoscopies. The PSP detection rate ranged from 1.8-17% between endoscopists and had an almost perfect correlation with the CSSP detection rate (p = 0.922), as well as strongly correlating with the ADR (p = 0.769). CONCLUSIONS: There was great variability in the PSP detection rate between endoscopists. It also had an almost perfect correlation with the CSSP detection rate and strongly correlated with the ADR. Those results suggest a high CSSP miss rate at endoscopy and a low PSP detection rate.

Xenogeneic human anti-mouse T cell responses are due to the activity of the same functional T cell subsets responsible for allospecific and major histocompatibility complex-restricted responses.

Human T cells respond strongly to mouse major histocompatibility complex (MHC) antigens. The response is directed predominantly to the polymorphic determinants of the MHC antigens and there is little or no response to the nonpolymorphic determinants or to non-MHC antigens. Human cytotoxic T lymphocytes (CTL) are generated specific for the mouse class I MHC antigens and the CTL effectors are blocked by anti-Leu-2a antisera. Human interleukin 2-producing T cells are generated specific for mouse class II antigens and their induction is blocked by anti-Leu-3a antisera. These and other considerations lead us to propose a model for the T cell receptor that provides an explanation for several of the features of T cell recognition. In this model, the recognition of the "class" (I or II) of MHC antigen is separate from the recognition of the polymorphic determinants. We suggest that the initial recognition of the conserved "class" determinants positions another domain of the receptor so that it can only engage with the part of the MHC molecule carrying the polymorphic determinants.

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.