Associations of the correlates of protection and implication on the statistical power for demonstrating non-inferiority: application of a re-sampling method on a large phase III influenza vaccine clinical trial.

BACKGROUND: In the later stage of the clinical development of new vaccines it is required to demonstrate their efficacy with the immunogenicity measures established as correlates for disease protection. Evaluation of interpandemic trivalent influenza vaccines is commonly assessed by three immunogenicity measures for each strain in different age groups: Seroprotection, Seroconversion and Geometric Mean Titers. US and European guidelines with respect to this topic have been issued for the licensure of new influenza vaccines. The statistical power of comparative trials, which consider these endpoint variables, could be affected to the extent that these measures are correlated. Results from a large non-inferiority trial in the clinical development of a novel cell-derived influenza vaccine have been analyzed with the aim of evaluating how statistical dependency between the above-mentioned three immunogenicity measures might affect the power to demonstrate non-inferiority. METHODS: The statistical non-inferiority criteria, which were met in the trial, were applied to different subsets (n=250, n=370 and n=500) using a re-sampling method from the original dataset (re-samples=10,000). RESULTS: The measures of immunogenicity were highly correlated, and the fulfillment or failure of any of the non-inferiority criteria for a specific measure partially predicted the same outcome for the other measures. Due to this dependency within each strain, the levels of power obtained by re-sampling methods were always higher than those obtained by theoretical calculations, which were based on the assumptions of independency between the three measures of immunogenicity. Seroconversion and Geometric Mean Ratio (GMR) showed a higher correlation. A failure in the fulfillment of the non-inferiority criteria for GMR predicted the failure for Seroconversion in >76% of cases. CONCLUSIONS: The correlation between different measures of immunogenicity should be taken into account when evaluating statistical power for non-inferiority in influenza vaccine trials and in establishing sample sizes. Statistical approaches that include either all three measures of immunogenicity or both Seroconversion and the ratio of GMTs as co-primary non-inferiority endpoints might create redundancy and could increase the probability of not meeting at least one non-inferiority criterion by chance, due to multiplicity.

Impact of prior or concomitant seasonal influenza vaccination on MF59-adjuvanted H1N1v vaccine (Focetria) in adult and elderly subjects.

BACKGROUND: When H1N1v vaccines become widely available, most elderly subjects will have already received their seasonal influenza vaccination. Adults seeking H1N1v vaccination may be offered seasonal vaccine as well. We investigated prior seasonal vaccination in adult and elderly subjects, and concomitant vaccination with seasonal vaccine in adults, on the tolerability and immunogenicity of the Novartis MF59-adjuvanted H1N1v vaccine, Focetria. METHODS: A total of 264 adult (four groups) and 154 elderly (three groups) subjects were enrolled. The licensure study cohorts for plain (Agrippal) and MF59-adjuvanted (Fluad) 2009-2010 seasonal vaccines were invited to receive Focetria 3 months later, with seasonal vaccine-naïve controls, and adults who received Focteria and seasonal vaccine concomitantly. Immunogenicity of all vaccines was assessed by haemagglutination inhibition on Days 1 and 22, safety and reactogenicity were monitored using patient diaries. RESULTS: All adult and elderly groups met all the European CHMP licensing criteria for H1N1v, as did adults receiving concomitant seasonal vaccine for the three seasonal strains. Vaccines were generally well tolerated, causing no SAEs, and profiles typical of MF59-adjuvanted vaccines. Reactions were mainly mild or moderate and transient, and unaffected by prior or concomitant seasonal vaccination except for elderly subjects previously given MF59-adjuvanted seasonal vaccine, whose reaction rates to Focetria were about half those seen in groups receiving their first MF59 vaccine. CONCLUSION: One dose of MF59-adjuvanted H1N1v vaccine met the licensure criteria for adult and elderly subjects 3 months after seasonal vaccination, or concomitantly with seasonal vaccine in adults, without impacting the tolerability or immunogenicity of either vaccine, thus facilitating mass influenza immunisation campaigns.

Decaying warm dark matter and neutrino masses.

Neutrino masses may arise from spontaneous breaking of ungauged lepton number. Because of quantum gravity effects the associated Goldstone boson - the majoron - will pick up a mass. We determine the lifetime and mass required by cosmic microwave background observations so that the massive majoron provides the observed dark matter of the Universe. The majoron decaying dark matter scenario fits nicely in models where neutrino masses arise via the seesaw mechanism, and may lead to other possible cosmological implications.

Use of RAPD and killer toxin sensitivity in Saccharomyces cerevisiae strain typing.

AIMS: Two different strain characterization techniques, random amplified polymorphic DNA (RAPD) and killer toxin sensitivity (KTS), were compared to assess their typing performance using a set of 30 certified Saccharomyces cerevisiae strains. METHODS AND RESULTS: A sequential random resampling procedure was employed to subdivide the 32 descriptors in eight sets, in order to compare the differential performances of the two techniques with diverse number of characters. Results showed that RAPD performs better than killer, although the complete differentiation of the strains under study could be obtained only by combining profiles from the two techniques. CONCLUSIONS: The combination of different typing techniques was useful when discriminating similar organisms. In such cases, the introduction of a second typing technique can be more advantageous than increasing the number of characters obtained with a single method. SIGNIFICANCE AND IMPACT OF THE STUDY: The distribution of among-strains pairwise distances and the relative performance of the two techniques has implications for the study of biodiversity, taxonomy and microbial ecology.

Expression of 3 beta-hydroxysteroid dehydrogenase in early bovine embryo development.

We analyzed the presence of 3 beta-Hydroxysteroid Dehydrogenase/Delta(5-->4)-isomerase enzyme (3 beta-HSD) activity, a key enzyme of the steroid metabolic pathway, the mRNA of this enzyme, and the steroid metabolism in in vitro produced bovine embryos. 3 beta-HSD activity was detected in in vitro matured oocytes (74.4 +/- 1.4%), 1-cell (72.9 +/- 6.1%), 2-cell (61.8 +/- 7.4%), 8-cell (50 +/- 5%), morulae (50.8 +/- 2.6%), blastocysts (94.4 +/- 3%), and hatched blastocysts (100 +/- 0%) meanwhile the 4-cell stage showed a significant reduction (16.7 +/- 4.7%). When total embryonic RNA of different stages was subjected to RT-PCR assays, the mRNA of 3 beta-HSD was found to be present in all developmental stages of in vitro produced bovine embryos, from the oocyte to the blastocyst, with a marked decrease at the 4-cell stage. To determine whether the temporal pattern of enzyme activity was dependent on the maternal to zygotic transition, embryos were incubated in the presence of a transcription inhibitor, alpha-amanitin. The reappearance of the enzyme activity after the 4-cell stage was blocked in alpha-amanitin treated embryos, indicating the requirement of embryonic transcription. On the other hand, the embryonic steroid metabolism was tested by incubating blastocyst with tritiated pregnenolone. Analysis of the metabolites by TLC indicated the production of a compound with a mobility identical to progesterone. These results described the expression of the 3 beta-HSD and the activity of this metabolic enzyme in bovine oocytes and preimplantation embryos, suggesting that steroids may act as autocrine effectors on preimplantation embryo development.

Patterns of macrolide resistance determinants among community-acquired Streptococcus pneumoniae isolates over a 5-year period of decreased macrolide susceptibility rates.

Erythromycin resistance rates were found to be increased, from 7.1 in 1993 to 32.8% in 1997, among community-acquired Streptococcus pneumoniae isolates from the Siena area of central Italy. Most of the erythromycin-resistant isolates carried ermAM determinants and were also resistant to josamycin and clindamycin, whereas a minority (5.8%) carried mefA determinants and remained susceptible to the latter drugs.

[Upper digestive hemorrhage in liver cirrhosis: clinical and endoscopic findings]. / Hemorragia digestiva alta en la cirrosis hepática: hallazgos clínicos y endoscópicos.

There are different opinions in respect to the main sources in upper gastrointestinal bleeding in hepatic cirrhosis. Some authors claim that ruptured esophageal varices are the cause of most of the hemorrhages. Recently, characteristic lesions have been showed in the gastric mucosa in portal hypertension (congestive gastropathy), and many believe that they are frequently the origin of the bleeding. We reviewed the records of 195 episodes of upper gastrointestinal bleeding in cirrhosis, with endoscopy performed within 12 hours of entry, and report here the endoscopic findings and the bleeding sites. We also investigated the relation between the etiology and functional class of the hepatic disease and the bleeding source. We observed variceal hemorrhage in 52.2% of cases; by gastroduodenal mucosal lesions in 13.8%; by gastric and duodenal ulcers in 13.8%; undetermined origin in 14.8% (due to coexistence of two or more lesions, without active bleeding). We found no differences between alcoholic and nonalcoholic cirrhotics in the bleeding sources. Furthermore, the bleeding sites were not different either in child A, B and C patients. In contrast, in major hemorrhages, esophageal varices were more frequently the origin (73.5%) than in minor ones (40.4%) (p < 0.002). The mortality was significantly higher in CHild C group (25%), than in groups B (14.3%) and A (2.3%) (p < 0.05 and p < 0.002, respectively). We recommend to carry out early endoscopy in every cirrhotic patient suffering from gastrointestinal bleeding, by skilled performers who are able to recognize the gastric red signs, before making a decision about potentially dangerous therapeutic measures, such as surgery, balloon tamponade, etc.

Hemorragia digestiva alta en la cirrosis hepática: hallazgos clínicos y endoscópicos. / [Upper digestive hemorrhage in liver cirrhosis: clinical and endoscopic findings]

There are different opinions in respect to the main sources in upper gastrointestinal bleeding in hepatic cirrhosis. Some authors claim that ruptured esophageal varices are the cause of most of the hemorrhages. Recently, characteristic lesions have been showed in the gastric mucosa in portal hypertension (congestive gastropathy), and many believe that they are frequently the origin of the bleeding. We reviewed the records of 195 episodes of upper gastrointestinal bleeding in cirrhosis, with endoscopy performed within 12 hours of entry, and report here the endoscopic findings and the bleeding sites. We also investigated the relation between the etiology and functional class of the hepatic disease and the bleeding source. We observed variceal hemorrhage in 52.2

of cases; by gastroduodenal mucosal lesions in 13.8

; by gastric and duodenal ulcers in 13.8

; undetermined origin in 14.8

(due to coexistence of two or more lesions, without active bleeding). We found no differences between alcoholic and nonalcoholic cirrhotics in the bleeding sources. Furthermore, the bleeding sites were not different either in child A, B and C patients. In contrast, in major hemorrhages, esophageal varices were more frequently the origin (73.5

) than in minor ones (40.4

) (p < 0.002). The mortality was significantly higher in CHild C group (25

), than in groups B (14.3

) and A (2.3

) (p < 0.05 and p < 0.002, respectively). We recommend to carry out early endoscopy in every cirrhotic patient suffering from gastrointestinal bleeding, by skilled performers who are able to recognize the gastric red signs, before making a decision about potentially dangerous therapeutic measures, such as surgery, balloon tamponade, etc.

Hemorragia digestiva alta en la cirrosis hepática: hallazgos clínicos y endoscópicos. / [Upper digestive hemorrhage in liver cirrhosis: clinical and endoscopic findings]

There are different opinions in respect to the main sources in upper gastrointestinal bleeding in hepatic cirrhosis. Some authors claim that ruptured esophageal varices are the cause of most of the hemorrhages. Recently, characteristic lesions have been showed in the gastric mucosa in portal hypertension (congestive gastropathy), and many believe that they are frequently the origin of the bleeding. We reviewed the records of 195 episodes of upper gastrointestinal bleeding in cirrhosis, with endoscopy performed within 12 hours of entry, and report here the endoscopic findings and the bleeding sites. We also investigated the relation between the etiology and functional class of the hepatic disease and the bleeding source. We observed variceal hemorrhage in 52.2

of cases; by gastroduodenal mucosal lesions in 13.8

; by gastric and duodenal ulcers in 13.8

; undetermined origin in 14.8

(due to coexistence of two or more lesions, without active bleeding). We found no differences between alcoholic and nonalcoholic cirrhotics in the bleeding sources. Furthermore, the bleeding sites were not different either in child A, B and C patients. In contrast, in major hemorrhages, esophageal varices were more frequently the origin (73.5

) than in minor ones (40.4

) (p < 0.002). The mortality was significantly higher in CHild C group (25

), than in groups B (14.3

) and A (2.3

) (p < 0.05 and p < 0.002, respectively). We recommend to carry out early endoscopy in every cirrhotic patient suffering from gastrointestinal bleeding, by skilled performers who are able to recognize the gastric red signs, before making a decision about potentially dangerous therapeutic measures, such as surgery, balloon tamponade, etc.

The Ryle Marital Patterns Test as a predictor of symptoms of anxiety and depression in couples in the community.

The associations between marital relationships, as measured by the Ryle Marital Patterns Test, and symptoms of anxiety and depression as measured by the Interval General Health Questionnaire (I-GHQ), were assessed in 98 married couples in the community. Logistic regression analyses showed that symptoms of anxiety and depression in wives were best predicted by low ratings of affection exchange. Occupational class interacted with husbands' affection ratings, suggesting that in the nonmanual class only lower affection ratings were significantly associated with more symptoms. Anxiety in men was best predicted by low affection ratings while depression was best predicted by unemployment, by an affection discrepancy score indicating that more affection is given than received, and by a marriage which was rated as relatively more wife-dominated by wives and as relatively more husband-dominated by husbands.

Life events, social problems and physical health status as predictors of emotional distress in men and women in a community setting.

The main aim of this study was to construct logistic models of emotional distress (defined as a GHQ-30 score of 6 or greater) in a community sample of 226 men and 225 women. The independent variables included were: sociodemographic characteristics, physical health status, social problems and undesirable life events. Univariate comparisons showed that in both sexes undesirable life events and social problems were associated with emotional distress; in men the presence of physical symptoms and widowed, separated or divorced status also showed such an association. Separate logistic regression models for men and women confirmed the importance of undesirable life events and social problems as predictors for emotional distress. In women there was also a significant interaction effect between the two variables on emotional distress. Sociodemographic characteristics and physical health status did not exert a statistically significant effect in these models.

Methodology of the H2 breath test. II. Importance of the test duration in the diagnosis of carbohydrate malabsorption.

We analyzed the results of 352 consecutive four-hour lactose hydrogen breath tests with the aim of verifying whether the results after two hours have the same accuracy as those after four hours in the diagnosis of malabsorption of 20g of lactose. Our results show that in 208 subjects who proved to be lactose malabsorbers the mean changes in breath H2 concentration were higher at three and a half hours than at any other time. Moreover, although the majority of the subjects (63%) reached the cut-off value (more than 20 parts per million with respect to the baseline value) in the first two hours of the test, in 76 of our 208 lactose malabsorbers (37%) a hydrogen increase higher than the cut-off value is only detectable after the second hour of the test. Therefore, unlike those who believe that two samples of expired air at 0 time and after two hours are sufficient, we think that for greater diagnostic accuracy the lactose H2 breath test must be prolonged for at least 4 hours.

Valor de las pruebas de laboratorio y ecografia en el diagnostico de la patologia biliar en el periodo inicial de la pancreatitis aguda / Value of laboratory tests and echography in the diagnosis of biliary pathology in the initial phase of acute pancreatitis

El objetivo de este trabajo fue determinar la utilidad de la bilirrubina, TGO, TGP, fosfatasa alcalina (FA) y ecografía en el diagnóstico de la etiología biliar y del estado funcional de la vía biliar principal, en el período inicial de la pancreatitis aguda (PA) y comparar sus resultados (aU)

Valor de las pruebas de laboratorio y ecografia en el diagnostico de la patologia biliar en el periodo inicial de la pancreatitis aguda / Value of laboratory tests and echography in the diagnosis of biliary pathology in the initial phase of acute pancreatitis

El objetivo de este trabajo fue determinar la utilidad de la bilirrubina, TGO, TGP, fosfatasa alcalina (FA) y ecografía en el diagnóstico de la etiología biliar y del estado funcional de la vía biliar principal, en el período inicial de la pancreatitis aguda (PA) y comparar sus resultados (aU)

Methodology of the H2 breath test. I. Collection and storage for gas measurement.

The measurement of hydrogen and methane in expired air is widely used in the field of gastrointestinal diagnosis. Techniques as simple and as reliable as possible are therefore requested for the collection and storage of breath samples. As far as collection is concerned, we compared three systems of end-expiratory sampling: a modified Haldane-Priestley tube, a Y-piece device fitted to a plastic syringe and a commercially available two-bag system. There was a significant correlation between the results obtained with all three systems, suggesting that all are sufficiently reliable. However, the two-bag system does not require particular training on behalf of the operator or particular cooperation from the patients and also makes it possible to take samples from more than one patient at the same time. For the storage of breath samples plastic syringes are the most commonly used device. Nonetheless, at room temperature there is a leakage of hydrogen equal to 9% after 24 hours, increasing to 29% after 5 days of storage. Refrigeration of the syringes at -20 degrees C prevents any loss in the first 48 hours and limits it to 5% after 5 days. The stability of the methane was higher than that of the hydrogen: after 5 days the loss is 4% at room temperature and 2% at -20 degrees C. For both gases the losses increase significantly at a temperature of 37 degrees C and are not affected by the initial concentration of the stored gas.(ABSTRACT TRUNCATED AT 250 WORDS)

[Value of laboratory tests and echography in the diagnosis of biliary disease in the initial phase of acute pancreatitis]. / Valor de las pruebas de laboratorio y ecografía en el diagnóstico de la patología biliar en el período inicial de la pancreatitis aguda.

The aim of this study was to investigate the usefulness of serum bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (APh) and real time ultrasonography (US) in distinguishing between gallstone and non gallstone related acute pancreatitis (A.P.). The second aim was to evaluate whether or nor there was biliary tract hypertension. Both aims were designed in order to evaluate them in the early stage of A.P. Two Groups of patients were studied. Group 1--gallstone related A.P., 63 pts. Group 2--Non gallstone related A.P. 21 pts. Fifty nine (93.6%) of Group 1 and 11 (52.3%) of Group 2 had surgical confirmation. In the other, the diagnosis was based on US and C.T. Blood samples were taken during the three days after admission for biochemical test and US was performed within the same period. Statistical evaluation and Student's t test were used. Biochemical test: when the cut off level was expressed by the upper limit of normal (ULN), the highest diagnostic sensibility was (table 1): ALT 85.7%, APH 80.9%. AST 71%, bilirubin 65%. When the cut off level was chosen at twice the ULN (Table 1), the sensibility was: ALT 61.9%, bilirubin and AST 47%, APh 30%, Group 2 (Table 2) values higher than the ULN were: AST 42.8%, bilirubin 33%, ALT 19%, APh 14.2%. The differences between the two Groups were statistically significant: APh and bilirubin P less than 0.001, ALT less than 0.05 m AST, NS. Ultrasonography: Group 1: gallstones were detected in 96.6% (58/60). Biliary tree was not visualized in 10 (15.8%), diagnosed as normal in 38 (60.3%) and pathologic (dilatation and/or lithiasis) in 15 (23.8%).(ABSTRACT TRUNCATED AT 250 WORDS)

Valor de las pruebas de laboratorio y ecografía en el diagnóstico de la patología biliar en el período inicial de la pancreatitis aguda. / [Value of laboratory tests and echography in the diagnosis of biliary disease in the initial phase of acute pancreatitis]

The aim of this study was to investigate the usefulness of serum bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (APh) and real time ultrasonography (US) in distinguishing between gallstone and non gallstone related acute pancreatitis (A.P.). The second aim was to evaluate whether or nor there was biliary tract hypertension. Both aims were designed in order to evaluate them in the early stage of A.P. Two Groups of patients were studied. Group 1--gallstone related A.P., 63 pts. Group 2--Non gallstone related A.P. 21 pts. Fifty nine (93.6

) of Group 1 and 11 (52.3

) of Group 2 had surgical confirmation. In the other, the diagnosis was based on US and C.T. Blood samples were taken during the three days after admission for biochemical test and US was performed within the same period. Statistical evaluation and Students t test were used. Biochemical test: when the cut off level was expressed by the upper limit of normal (ULN), the highest diagnostic sensibility was (table 1): ALT 85.7

, APH 80.9

. AST 71

, bilirubin 65

. When the cut off level was chosen at twice the ULN (Table 1), the sensibility was: ALT 61.9

, bilirubin and AST 47

, APh 30

, Group 2 (Table 2) values higher than the ULN were: AST 42.8

, bilirubin 33

, ALT 19

, APh 14.2

. The differences between the two Groups were statistically significant: APh and bilirubin P less than 0.001, ALT less than 0.05 m AST, NS. Ultrasonography: Group 1: gallstones were detected in 96.6

(58/60). Biliary tree was not visualized in 10 (15.8

), diagnosed as normal in 38 (60.3

) and pathologic (dilatation and/or lithiasis) in 15 (23.8

).(ABSTRACT TRUNCATED AT 250 WORDS)

The pancreatic enzymes value in the diagnosis of acute pancreatitis and acute biliary tract diseases.

UNLABELLED: The aim of this study was to investigate the usefulness of lipase and isoamylases in the diagnosis of acute pancreatitis and to determine if its use permits differential diagnosis between acute pancreatitis and acute biliary tract disease. Three groups of patients were studied. a) CONTROL: 60 patients without abdominal diseases. b) Acute pancreatitis: 60 patients, the diagnosis was made according to clinical symptoms, biochemical tests, U.S. and C.T. in 24 (40%), in the remainder 36 (60%) surgical confirmation was obtained. c) Acute biliary tract disease without macroscopic pancreatic damage, 30 patients, the diagnosis was made according to biochemical tests and U.S. in 4 (13.3%) whereas in the remainder 26 (86.6%) surgical confirmation was accomplished no later than a week of the beginning of the symptoms. Biochemical tests: serum and urine amylase, lipase, and total pancreatic and salivary isoamylases were evaluated. In the group of acute pancreatitis the highest diagnostic sensibility was: pancreatic isoamylase 95.5%, lipase 95%, total serum amylase 93.3% urine amylase 90%, serum amylase 78.3%. In acute biliary tract diseases a high number of elevated enzyme values were also found: pancreatic isoamylase 83.3%, total isoamylase 73.3%, urine amylase 66.6%, lipase 63.3%, serum amylase 53.3%. The mean enzyme values of both groups were compared statistically and showed no significant difference. We conclude that lipase and isoamylases are the best markers for the diagnosis of acute pancreatitis and the differential diagnosis with acute biliary diseases is difficult because an elevation of these enzymes is a characteristic shared by both pathologies. The diagnosis of acute pancreatitis based only in clinical symptoms and hyperamylasemia can be erroneous.

Psychosocial factors in women who undergo cholecystectomy. A case-control study.

Thirty women admitted to hospital for cholecystectomy were compared with a healthy community control group. Univariate comparisons showed that patients had significantly more social problems, manifested greater psychological distress and reported poorer social support. Logistic multiple regression analysis indicated that patient status was best predicted by manual occupational class and the interaction between employment and presence/absence of young children. The findings are discussed within the framework of illness behaviour.