Evaluating the performance of temporal pattern discovery: new application using statins and rhabdomyolysis in OMOP databases.

BACKGROUND: Temporal pattern discovery (TPD) is a method of signal detection using electronic healthcare databases, serving as an alternative to spontaneous reporting of adverse drug events. Here, we aimed to replicate and optimise a TPD approach previously used to assess temporal signals of statins with rhabdomyolysis (in The Health Improvement Network (THIN) database) by using the OHDSI tools designed for OMOP data sources. METHODS: We used data from the Truven MarketScan US Commercial Claims and the Commercial Claims and Encounters (CCAE). Using an extension of the OHDSI ICTemporalPatternDiscovery package, we ran positive and negative controls through four analytical settings and calculated sensitivity, specificity, bias and AUC to assess performance. RESULTS: Similar to previous findings, we noted an increase in the Information Component (IC) for simvastatin and rhabdomyolysis following initial exposure and throughout the surveillance window. For example, the change in IC was 0.266 for the surveillance period of 1-30 days as compared to the control period of - 180 to - 1 days. Our modification of the existing OHDSI software allowed for faster queries and more efficient generation of chronographs. CONCLUSION: Our OMOP replication matched the we can account forwe can account for of the original THIN study, only simvastatin had a signal. The TPD method is a useful signal detection tool that provides a single statistic on temporal association and a graphical depiction of the temporal pattern of the drug outcome combination. It remains unclear if the method works well for rare adverse events, but it has been shown to be a useful risk identification tool for longitudinal observational databases. Future work should compare the performance of TPD with other pharmacoepidemiology methods and mining techniques of signal detection. In addition, it would be worth investigating the relative TPD performance characteristics using a variety of observational data sources.

The impact of bisphenol S on bovine granulosa and theca cells.

Bisphenol S (BPS) is an endocrine-disrupting chemical with multiple potential mechanisms of action, including as an oestrogen receptor agonist. BPS is increasingly used in plastics and thermal receipts as a substitute for bisphenol A, which has been phased out due to concerns about human health implications. The ability of BPS to alter female reproductive function in mammals has not been widely studied, despite the importance of normal hormone signalling for female reproduction. The aim of this study was to investigate how BPS (in a wide range of doses, including very low doses) affects granulosa cell and theca cell steroid hormone production and cell viability in the bovine. Granulosa cell oestradiol production was stimulated when cells were exposed to 100 µM BPS under basal conditions, but there was no effect of BPS when cells were stimulated with follicle-stimulating hormone (FSH). Additionally, there was no effect of BPS on granulosa cell progesterone production or cell viability under basal or FSH-stimulated conditions. BPS did not affect theca cell androstenedione or progesterone production, or theca cell viability under basal or luteinizing hormone-stimulated conditions. This study suggests for the first time that BPS may alter oestradiol production by bovine granulosa cells, albeit at a concentration that is unlikely to be physiologically relevant. Further studies are needed to determine the effects of BPS on the bovine oocyte and on other functions of follicular cells.

Comparison of four-year toxicities and local control of ultra-hypofractionated vs moderate-hypofractionated image guided prostate radiation with HDR brachytherapy boost: A phase I-II single institution trial.

Purpose/Objectives: To analyze the long term efficacy and safety of an ultra-hypofractionated (UHF) radiation therapy prostate treatment regimen with HDR brachytherapy boost (BB) and compare it to moderate-hypofractionated regimens (MHF). Materials/Methods: In this single arm, prospective monocentric study, 28 patients with intermediate risk prostate cancer were recruited in an experimental treatment arm of 25 Gy in 5 fractions plus a 15 Gy HDR BB. They were then compared to two historical control groups, treated with either 36 Gy in 12 fractions or 37.5 Gy in 15 fractions with a similar HDR BB. The control groups included 151 and 311 patients respectively. Patient outcomes were reported using the International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC-26) questionnaires at baseline and at each follow-up visit. Results: Median follow-up for the experimental arm was 48.5 months compared to 47 months and 60 months compared to the 36/12 and 37,5/15 groups respectively. The IPSS and EPIC scores did not demonstrate any significant differences in the gastrointestinal or genitourinary domains between the three groups over time. No biochemical recurrence occurred in the UHF arm as defined by the Phoenix criterion. Conclusion: The UHF treatment scheme with HDR BB seems equivalent to standard treatment arms in terms of toxicities and local control. Randomized control trials with larger cohorts are ongoing and needed to further confirm our findings.

Cognitive Digital Biomarkers from Automated Transcription of Spoken Language.

BACKGROUND: Although patients with Alzheimer's disease and other cognitive-related neurodegenerative disorders may benefit from early detection, development of a reliable diagnostic test has remained elusive. The penetration of digital voice-recording technologies and multiple cognitive processes deployed when constructing spoken responses might offer an opportunity to predict cognitive status. OBJECTIVE: To determine whether cognitive status might be predicted from voice recordings of neuropsychological testing. DESIGN: Comparison of acoustic and (para)linguistic variables from low-quality automated transcriptions of neuropsychological testing (n = 200) versus variables from high-quality manual transcriptions (n = 127). We trained a logistic regression classifier to predict cognitive status, which was tested against actual diagnoses. SETTING: Observational cohort study. PARTICIPANTS: 146 participants in the Framingham Heart Study. MEASUREMENTS: Acoustic and either paralinguistic variables (e.g., speaking time) from automated transcriptions or linguistic variables (e.g., phrase complexity) from manual transcriptions. RESULTS: Models based on demographic features alone were not robust (area under the receiver-operator characteristic curve [AUROC] 0.60). Addition of clinical and standard acoustic features boosted the AUROC to 0.81. Additional inclusion of transcription-related features yielded an AUROC of 0.90. CONCLUSIONS: The use of voice-based digital biomarkers derived from automated processing methods, combined with standard patient screening, might constitute a scalable way to enable early detection of dementia.

Can access to spirometry in asthma education centres influence the referral rate by primary physicians for education?

BACKGROUND AND OBJECTIVES: Asthma remains uncontrolled in a large number of asthmatic patients. Recent surveys have shown that a minority of asthmatic patients are referred to asthma educators. The objective of the present study was to assess the influence of increased access to spirometry in asthma education centres (AECs) on the rate of patient referrals to these centres by general practitioners. METHODS: A one-year, prospective, randomized, multicentric, parallel group study was conducted over two consecutive periods of six months each, with added spirometry being offered in the second six-month period to the experimental group. Ten AECs were enrolled in the project. An advertisement describing the AECs' services was sent by mail to a total of 303 general practitioners at the start of each period, inviting them to refer their patients. Measures of the frequency of medical referrals to the AECs were assessed for each period. RESULTS: The group of AECs randomly selected for spirometry in the second six-month period received 48 medical referrals during the first period and 32 during the second one, following proposed spirometry. AECs that had not offered spirometry received five referrals during the first period and seven during the second period. One AEC withdrew a few weeks after the study began and others encountered administrative problems, reducing their ability to provide interventions. CONCLUSIONS: Referral to AECs is not yet integrated into the primary care of asthma and offering more rapid access to spirometry in the AECs does not seem to be a significant incentive for such referrals.

A study on the electrical resistance of the frog sartorius muscle.

Four different methods of measuring the resistance of a muscle fiber have been applied to the frog sartorius muscle. The methods, in which the resistance of the microelectrode entered the calculation of the effective resistance of the fiber, resulted in values which were 8 times higher than the resistance values obtained with methods independent of the electrode resistance. A simple cable model of a muscle fiber could not account for the discrepancy in the effective resistance found in these measurements; therefore, an enlarged cable model for a muscle fiber has been proposed, and its biological implications have been discussed. The effective resistance (measured with the two different groups of methods) decreased when the potassium concentration in the bath increased. Using the proposed enlarged cable model for the interpretation of these results, it is shown that not only the membrane resistance but also the myoplasmic resistance decreases with an increasing potassium concentration in the Ringer solution.

Endothelin-dependent effects limit flow-induced dilation of conductance coronary vessels after blockade of nitric oxide formation in conscious dogs.

OBJECTIVE: To determine whether endothelin (ET)-dependent effects limit shear stress-induced dilation of large epicardial coronary arteries after blockade of nitric oxide (NO) formation. METHODS: In conscious dogs instrumented for measuring coronary blood flow (CBF) and external diameter (CD) of the circumflex coronary artery, flow-dependent CD dilation was elicited by intracoronary (i.c.) adenosine (500 ng kg-1 min-1). RESULTS: I.c. adenosine increased CBF by 28 +/- 4 from 38 +/- 5 ml min-1 and CD by 0.25 +/- 0.03 from 3.53 +/- 0.07 mm without other hemodynamic effects. After N omega-nitro-L-arginine methyl ester (L-NAME), baseline CD fell (P < 0.01) to 3.35 +/- 0.08 mm but CBF was not significantly altered (36 +/- 5 ml min-1). CBF increases caused by adenosine were smaller (17 +/- 2 ml min-1, P < 0.05) and CD responses were nearly abolished (0.02 +/- 0.01 mm, P < 0.01). I.c. Ro 61-1790, an ETA receptor blocker, given after L-NAME did not significantly influence baseline CBF (36 +/- 5 ml min-1) but increased (P < 0.01) CD to 3.45 +/- 0.09 mm. CBF responses to adenosine were not significantly altered by Ro 61-1790 but CD responses (0.10 +/- 0.01 mm) were partially restored (P < 0.01). In contrast, blockade of ETB receptors with Ro 46-8443 after L-NAME had no further effects on CD and CBF responses to adenosine. CONCLUSION: ETA receptor-mediated effects limit flow-dependent dilation of large epicardial coronary arteries in conscious dogs. Suppression of the L-arginine/NO-dependent pathway with L-NAME reveals significant ET-dependent effects.

Contrasting effects of blockade of nitric oxide formation on resistance and conductance coronary vessels in conscious dogs.

OBJECTIVES: To determine the differential effects of blockade of nitric oxide (NO) formation by an arginine analogue on basal and stimulated NO release in conductance and resistance coronary vessels. METHODS: In conscious dogs, instrumented for measuring coronary blood flow (CBF) and external epicardial coronary artery diameter (CD), intracoronary (ic) acetylcholine (ACH, 3.0 ng/kg), adenosine (ADENO 100.0 ng/kg) and nitroglycerin (NTG, 10.0 ng/kg) were injected before and after ic N omega-nitro-L-arginine methyl ester (L-NAME, 50.0 micrograms.kg-1 min-1 for 12 min) to block NO synthesis. RESULTS: Before L-NAME, ACH increased CBF by 65.3 +/- 9.0 from 42.4 +/- 2.9 ml/min and CD by 0.199 +/- 0.035 from 3.374 +/- 0.193 mm. L-NAME failed to alter baseline CBF but reduced (P < 0.01) CD to 3.220 +/- 0.199 mm. CBF responses to ACH were smaller (P < 0.01) (32.8 +/- 5.3 ml/min) after L-NAME. In contrast, ACH-induced increases in CD (0.184 +/- 0.053 mm) were not altered. L-NAME did not change CBF responses to NTG but increased CD responses (0.345 +/- 0.062 vs 0.217 +/- 0.043 mm, P < 0.01). ADENO-induced increases in CBF were smaller after L-NAME (46.5 +/- 5.6 vs 79.8 +/- 10.9 ml/min, P < 0.01). Increases in CD created by ADENO, a flow-dependent phenomenon, were nearly abolished after L-NAME (0.043 +/- 0.018 vs 0.195 +/- 0.026 mm, P < 0.01) and partially restored by ic L-arginine. The effects of L-NAME on CBF and CD responses to ACH and ADENO continuously delivered into the coronary artery were similar to those of boluses. CONCLUSIONS: L-NAME selectively reduced ACH-induced dilation in resistance coronary vessels but failed to prevent responses of conductance coronary vessels in spite of reducing baseline CD and blocking flow-dependent effects of ADENO. Therefore, blockade of NO formation resulted in disparate effects on receptor-operated dilation of resistance and conductance coronary vessels.

Endothelin-dependent tone limits acetylcholine-induced dilation of resistance coronary vessels after blockade of NO formation in conscious dogs.

Nitric oxide (NO) impairs endothelin (ET) formation and/or action in isolated vessels. We hypothesized that ET may magnify the consequences of NO formation blockade on receptor-operated dilation of resistance coronary vessels in conscious dogs. In conscious instrumented dogs, graded intracoronary (IC) doses of acetylcholine (ACh) were delivered before IC administration of Nomega-nitro-L-arginine methyl ester (L-NAME), after L-NAME, and after L-NAME plus IC bosentan, an ETA/ETB receptor blocker. Before L-NAME, ACh (100 ng. kg-1. min-1) increased coronary blood flow (CBF) by 43+/-4% from 47+/-6 mL. min-1. After L-NAME, ACh failed to increase CBF (-3+/-2% from 50+/-7 mL. min-1). CBF responses to ACh were partially restored (+10+/-2% from 50+/-7 mL. min-1, P<0.01) after the addition of bosentan. Bosentan alone (without L-NAME) did not alter CBF responses to ACh. Blockade of ETA (Ro 61-1790) but not ETB (Ro 46-8443) receptors partially restored CBF responses to ACh after L-NAME. Myocardial immunoreactive ET levels in the perfusion territories of the circumflex and left anterior descending coronary arteries did not differ. ETA-dependent tone magnified the inhibitory effects of blockade of NO formation on receptor-operated dilation to ACh in resistance coronary vessels. Presumably, stimulated NO release has an inhibitory action on endogenous ET production and/or action at the level of resistance coronary vessels.

Hemodynamic and renal responses to physiological levels of atrial natriuretic factor in conscious dogs.

The effects of increases in plasma atrial natriuretic factor (ANF) similar to those encountered after rapid volume expansion were examined in conscious dogs. Hemodynamics and renal function were continuously monitored during 30 minutes of human ANF infusion (10 ng/kg.min) and throughout a 30-minute recovery period. Ten minutes into the infusion period, plasma levels of ANF were elevated (p less than 0.01) by 34 +/- 9 from 36 +/- 5 pg/ml and sodium excretion increased (p less than 0.05) by 34 +/- 7 from 67 +/- 9 mueq/min. At that time, urine flow did not differ from baseline (0.25 +/- 0.03 ml/min). Renal blood flow velocity fell (p less than 0.01) by 5.0 +/- 0.5 from 42.3 +/- 3.7 cm/sec. Thirty minutes into the infusion period, plasma ANF levels were increased (p less than 0.01) by 61 +/- 9 pg/ml, similar to levels found after rapid volume expansion in conscious dogs. Urine flow and sodium excretion were elevated (p less than 0.01) by 0.35 +/- 0.06 ml/min and by 65 +/- 12 mueq/min, respectively. Renal blood flow velocity was reduced (p less than 0.05) by 4.4 +/- 1.5 cm/sec. Neither right atrial pressure, left ventricular end-diastolic pressure, mean arterial pressure, the first derivative of left ventricular pressure over time (dP/dt), nor heart rate were influenced by the elevated ANF plasma levels. Circulating levels of vasopressin and aldosterone were unaltered by these increases in plasma ANF. Thirty minutes into the recovery period, all variables were similar to the preinfusion baseline. Thus, in conscious dogs, physiologically relevant increases in plasma levels of ANF reached diuretic and natriuretic thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of common acute lymphoblastic leukemia-associated antigen on germ cell tumor.

A mediastinal germ cell tumor is described that reacts with the anti-common acute lymphoblastic leukemia-associated antigen antibody J5 using both immunofluorescence and immunoperoxidase techniques. This antigen has been reported recently on various cell lines including melanoma, colon, and breast. It has also been seen on normal fibroblasts and peripheral granulocytes. This is believed to be the first description of a solid nonlymphoid neoplasm possessing this antigen, and the implications regarding prognosis and therapy are discussed.

Ultrastructural localization of a breast tumor-associated antigen.

We used a monoclonal antibody to a high molecular weight glycoprotein of the milk fat globule membrane to study at the ultrastructural level the sites of accumulation of immunoreactive material in breast tumors. By light microscopy, the antigen was found only on the luminal membrane of normal resting or lactating breast cells. In tumors, antigen could be found in the cytoplasm. We used the avidin-biotin-peroxidase complex immunoperoxidase technique to localize the site of cytoplasmic accumulation of immunoreactive material in breast tumors. This technique showed that antigen is found on the membrane of cytoplasmic vesicles. Some of these vesicles were collapsed and gave rise to what appeared to be clumps of free cytoplasmic immunoreactive material. We have also documented that in some tumors the entire cytoplasmic membrane bears antigen, whereas in other tumors only areas of cytoplasmic membrane that form microscopic lumina express antigen.

Monoclonal antibodies to antigens abnormally expressed in breast cancer.

We report the production, screening, and characterization of ten murine monoclonal antibodies directed at antigens that are expressed abnormally in human breast tumors. Immunoperoxidase staining of frozen and fixed tissues shows the antigens to be present at low levels on the luminal membrane of normal breast cells and at high levels in the cytoplasm and surface membrane of breast tumor cells. The ten antibodies appear to recognize six different epitopes on the basis of their quantitative differences in reactivity against four antigen preparations, as measured by ELISA. Immunoblots show that eight of the ten antibodies recognize a 300,000 MW molecule from breast tumor preparations; six of these antibodies also react with a second molecule from the same tumor preparations of 280,000 MW. Seven antibodies react with an antigen from milk fat globule membrane of 330,000 MW. It therefore appears that the two molecules from tumor tissue and the one molecule from normal tissue share common epitopes. Selected antibodies were tested for reactivity against 25 primary breast tumors and 14 pairs of primary and metastatic breast tumors. Three antibodies have broad reactivity and stain more than 80% of primary tumors; the three other antibodies identify subsets of those tumors. Results of staining pairs of primary and metastatic lesions show that metastases continue to express antigens of the primary lesion in a high percentage of cells.

Influence of dual ET(A)/ET(B)-receptor blockade on coronary responses to treadmill exercise in dogs.

We hypothesized that endothelin (ET) release during exercise may be triggered by alpha-adrenergic-receptor activation and thereby influence coronary hemodynamics and O(2) metabolism in dogs. Exercise resulted in coronary blood flow increases (to 1.88+/-0.26 from 1.10+/- 0.12 ml x min(-1) x g(-1)) and in a fall (P<0.01) in coronary sinus O(2) saturation (17.4+/-1.5 to 9.6+/-0.7 vol%), whereas myocardial O(2) consumption (MVO(2)) increased (109+/-13% from 145+/-16 microl O(2) min(-1) x g(-1)). Tezosentan, a dual ET(A)/ET(B)-receptor blocker, slightly reduced mean arterial pressure (MAP) and increased heart rate throughout exercise. The relationship between coronary sinus O(2) saturation and MVO(2) was shifted upward (P<0.05) after tezosentan administration; i.e., as MVO(2) increased during exercise, coronary sinus O(2) saturation was disproportionately higher after ET-receptor blockade. After propranolol, tezosentan resulted in significant decreases (P<0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise. As MVO(2) increased during exercise, coronary sinus O(2) saturation levels after tezosentan became superimposable over those observed before ET-receptor blockade. Thus dual blockade of ET(A)/ET(B) receptors alters coronary hemodynamics and O(2) metabolism during exercise, but ET activity failed to increase beyond baseline levels.

Experience of aboriginal health interpreters in mediation of conflicting values in end-of-life decision making.

This paper examines the experience of Aboriginal medical interpreters working with terminally ill patients, family members, and care providers, and serving as mediators when cultural values and decision frameworks are in conflict. The discussion is based on a qualitative analysis of interaction in 12 patient encounters which were observed and for which transcripts were made of the discourse and interaction. Each case involved intervention by a professional interpreter. Interaction involved the signing of advance directives or other consent agreements in situations in which Aboriginal patients were terminally ill. Analysis will focus on the cultural dimension of value conflict situations, particularly in relation to issues of individual autonomy and biomedical emphasis on truth-telling in the communication of terminal prognosis.

[Validation of a questionnaire of physical sensations in a French-Canadian population]. / Validation du questionnaire des sensations physiques auprès de la population canadienne-française.

The objectives of this study are three-fold. The first objective is to present the aspects of reliability and validity of a self-reported questionnaire that evaluates a specific facet of Panic Disorder with Agoraphobia (PDA) for the francophone population of Quebec, mainly the fear of fear. The Body Sensations Questionnaire (17), translated as the Questionnaire des Sensations Physiques (QSP) evaluates the degree to which individuals fear somatic symptoms commonly associated with panic. A second objective is to determine the factorial validity of the QSP and to investigate the dimensionality of the construct as assessed by the questionnaire. The third objective is to establish a reference database for the agoraphobic (N = 141 and N = 70) and the non-clinical population (N = 223). Results suggest that both questionnaires have similar internal consistency, temporal stability, construct validity, and discriminative validity. While the factorial solution of the present study uncovered a three-factor model (somatic, cardiac, and psychosensorial), which points to the multidimensional nature of the construct evaluated by the QSP, it greatly differs from the one obtained by Arrindel's study (5). Nevertheless, the extraction of the three principal components is supported by the results of the screen test and by two different implementations of parallel analysis, i.e., the computation of random eigen values and the use of an interpolation table of eigen values. Finally, it can be concluded that the psychometric properties of the French-Canadian translation of the BSQ are indications that it is an appropriate instrument to use in clinical research and in clinical practice to assess the fear of bodily sensations associated with the fear of fear.

Left ear (right temporal lobe) suppressions during dichotic listening, ego-alien intrusion experiences and spiritualistic beliefs in normal women.

Beliefs in spiritualism, a history of a sensed presence, and mental diplopia may share a common source of psychometric variance. We hypothesized that this variance should be specifically associated with right temporal-lobe function. Inferences of temporal lobe signs, hemisphericity (Vingiano's quotient) and self-esteem as well as dichotic listening measures were obtained for 26 university women. As predicted, the numbers of left-ear suppressions (right temporal-lobe function) but not of right-ear suppressions were specifically and moderately (rho = 0.64) correlated with the intensity of Tobacyk's spiritualistic beliefs and a history of sensed presences and ego-alien intrusions. However, the negative association (rhos about -0.45) between indices of left-right hemisphericity and self-esteem was related to a separate factor.

The empirical testing of Harter's self-concept matrix on female adult students.

This research aimed at testing an hypothetical matrix to be used for the study of self-concept development within a life-span perspective. Following data categorization collected from 111 female university students, a significant relationship was found between structural levels and content dimensions, demonstrating a linear form of development. Also several content dimensions were often used in subjects' self-definitions, illustrating the multidimensional aspect of such development in adults.