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Development and validation of a non-linear IVIVC model for a diltiazem extended release formulation.

To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a diltiazem multi-particulate bead extended release formulation. In vitro dissolution of diltiazem capsules was examined using the following methods: USP Apparatus II (paddle) at 100 rpm and USP Apparatus III at 30 dpm. Seven healthy subjects received three diltiazem formulations (90 mg): slow (S), moderate (M), fast (F) releasing and an oral solution (90 mg). Serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using ultraviolet detection. The f(2) metric (similarity factor) was used to analyze the dissolution data. Linear and non-linear (quadratic, cubic, and sigmoid functions) correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted diltiazem concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for C(max) and AUC to determine the validity of the correlation. Apparatus II using purified water was found to be the most discriminating dissolution method. Significant intersubject (CV%>50) was observed for C(max) and AUC. The quadratic M/F IVIVC model provided a significant relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for C(max) and AUC for all formulations was 12.4% and 9.2%, respectively. The prediction errors observed for C(max) and AUC suggest that the predictability of the quadratic IVIVC model is inconclusive, as such, external validation studies are required.

Calcium Channel Blockers↗

The effect of tobacco ingredients on smoke chemistry. Part I: Flavourings and additives.

The effects of 450 tobacco ingredients added to tobacco on the forty-four "Hoffmann analytes" in mainstream cigarette smoke have been determined. These analytes are believed by regulatory authorities in the USA and Canada to be relevant to smoking-related diseases. They are based on lists published by D. Hoffmann and co-workers of the American Health Foundation in New York. The ingredients comprised 431 flavours, 1 flavour/solvent, 1 solvent, 7 preservatives, 5 binders, 2 humectants, 2 process aids and 1 filler. The cigarettes containing mixtures of the ingredients were smoked using the standard ISO smoking machine conditions. The levels of the "Hoffmann analytes" in the smoke from the test cigarettes containing the ingredient mixture were compared to those from control cigarettes without the ingredients. In practice, flavouring ingredients are typically added to tobacco that also contains casing ingredients and reconstituted tobacco materials. In order to keep the tobacco mixtures as authentic as possible, three comparisons have been made in this study. These are: (a) control cigarette containing a typical US blended, cased tobacco incorporating reconstituted tobacco versus test cigarettes that had flavouring ingredients added to this tobacco; (b) control cigarette containing tobacco only versus test cigarettes with the tobacco cased and incorporating flavourings; (c) control cigarette containing tobacco only versus test cigarette incorporating additives made in an experimental sheet material. The significances of differences between the test and control cigarettes were determined using both the variability of the data on the specific occasion of the measurement, and also taking into account the long-term variability of the analytical measurements over the one-year period in which analyses were determined in the present study. This long-term variability was determined by measuring the levels of the 44 "Hoffmann analytes" in a reference cigarette on many occasions over the one-year period of this study. The ingredients were added to the experimental cigarettes at or above the maximum levels used commercially by British American Tobacco. The effect of the ingredient mixtures on total particulate matter and carbon monoxide levels in smoke was not significantly different to the control in most cases, and was never more than 10% with any ingredient mixture. It was found that, in most cases, the mixtures of flavouring ingredients (generally added in parts per million levels) had no statistically significant effect on the analyte smoke yields relative to the control cigarette. Occasionally with some of the mixtures, both increases and decreases were observed for some smoke analyte levels relative to the control cigarette. These differences were generally up to about 15% with the mixtures containing flavouring ingredients. The significance of many of the differences was not present when the long-term variability of the analytical methodology was taken into account. For the test cigarettes with ingredient mixtures containing casing ingredients, there were again no significant changes in smoke analyte levels in most cases. Those changes that were observed are as follows. Decreases in smoke levels were observed with some ingredient mixtures for most of the tobacco specific nitrosamines (up to 24%), NO(x), most of the phenols (up to 34%), benzo[a]pyrene, and some of the aromatic amines and miscellaneous organic compounds on the "Hoffmann list". Increases were observed for some test cigarettes in smoke ammonia, HCN, formaldehyde and lead levels (up to 24%). The significance of the ammonia and lead increases was not present when the long-term variability of the analytical methodology was taken into account. The yields of some carbonyl compounds in smoke were increased in one comparison with an additives mixture containing cellulosic components; in particular, formaldehyde was increased by 68%. This was the largest single change seen in any smoke analyte level in this study. These carbonyls are produced from the pyrolysis of cellulosnyls are produced from the pyrolysis of cellulosic and other polysaccharide materials, present in the additives mixture. With this test cigarette, all tobacco specific nitrosamines, phenols, semi-volatile bases, NO(x) and some aromatic amines and miscellaneous organic compounds on the "Hoffmann list" were decreased, by up to 22%. The significance of many of these differences remained even when the long-term variability of the analytical methodology was taken into account. The levels of all other "Hoffmann analytes" in the smoke were not significantly different to those of the control cigarette. With the exception of the determinations of "tar", nicotine and carbon monoxide, there are currently no internationally recognised standard methods for measurement of the other "Hoffmann analytes". Each laboratory uses its own methods and there are large laboratory-to-laboratory variations, as well as variations over time in a given laboratory. Therefore, it is important that in any comparison of smoke analytes amongst different cigarettes, all the analytes should be measured in the same laboratory and at the same time. This was the case in the present study and all the methods have been validated internally.

Ammonia↗

Recommendations of the ECVAM Workshop on "Alternatives to Animal Testing in the Quality Control of Immunobiologicals; State of the Art and Future Prospects"

With regard to the principles of replacement, reduction and refinement, art. 231 of the Council Directive 86/609/EEC on the Protection of Animals used for Experimental and other Scientific Purposes, is of utmost importance. This article states that "The Commission and Member States. would take steps. to encourage research into the development and validation of alternative techniques.". In order to carry into effect this article, the Commission of the European Communities (EC) has established the European Centre for the Validation of Alternative Methods (ECVAM) on October 29, 1991. The centre is located at the Joint Research Centre (DG XI) at Ispra (Italy), its first director is Michael Balls from the UK. The main goal of ECVAM is to promote the regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine or replace the use of laboratory animals. The activities of the centre are focused on facilitating, co-ordinating, supporting and/or organising international validation studies, preferably in collaboration with other bodies. A working program has been made for 1993 and 1994 by ECVAM"s scientific advisory committee. Animal testing in the quality control of vaccines was selected as one of the area"s of interest. As a first step it was decided to organise a workshop, with the aim to evaluate potential alternatives, to identify obstacles in development, validation and implementation and to discuss possible solutions. The workshop was held in Utrecht, April 16-17 and the 20 invited participants came from national control laboratories, regulatory bodies, vaccine manufacturers and academic world. (article in English) (The main conclusions and recommendations in the field of the quality control of veterinary vaccines have been published in ATLA 22, 420-434, 1994)

Journal Article↗

The performance of methods for correcting measurement error in case-control studies.

BACKGROUND: It is generally agreed that adjustment for measurement error (when feasible) can substantially increase the validity of epidemiologic analyses. Although a broad variety of methods for measurement error correction has been developed, application in practice is rare. One reason may be that little is known about the robustness of these methods against violations of their restrictive assumptions. METHODS: We carried out a simulation study to assess the performance of two error correction methods (a regression calibration method and a semiparametric approach) as compared with standard analyses without measurement error correction in case-control studies with internal validation data. Performance was assessed over a wide range of model parameters including varying degrees of violations of assumptions. RESULTS: In nearly all the settings assessed, the semiparametric estimate performed better than all alternatives under investigation. The regression calibration method is sensitive to violations of the assumptions of nondifferential error and small error variance. CONCLUSIONS: The semiparametric method is a very robust method to correct for measurement error in case-control studies, but lack of functional software hinders widespread use. If the assumptions for the regression calibration method are fulfilled, application of this method, originally developed for cohort studies, in case-control studies may be a useful alternative that is easy to implement.

Bias↗

The surgical management of primary tumorsof the spine: initial results of an ongoing prospective cohort study.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To prospectively validate the application of appendicular surgical oncology principles to the treatment of primary bone tumors of the spine at a quaternary care spine center using local recurrence, survival, and health-related quality of life as outcome measures. SUMMARY OF BACKGROUND DATA: There is clear evidence that violating the margins of a sarcoma or other malignancy during surgical resection will risk local recurrence and diminish overall survival. Previous publications have retrospectively demonstrated this oncologically sound approach to spine tumor management to be internally valid. The external validity or limited generalizability has not been assessed. METHODS: Included were all patients who underwent en bloc surgical resection of a primary tumor of the spine between January 1994 and November 2003, at the authors' institution. Patients were uniformly staged before surgery and baseline demographic and surgical variables were recorded, as well as a cross-sectional evaluation of generic health-related quality of life. RESULTS: Twenty-six patients (12 males and 14 females) were eligible for the study. Average age was 42 (range 16 to 70). There were 19 malignant tumors and 7 benign. There are 20 surviving patients with an average follow-up of 41.5 months (range 6 to 111 months), 15 of whom had malignant tumors. None of these patients have evidence of local recurrence, and one has evidence of systemic disease. The health-related quality of life, using the SF-36, shows acceptable morbidity of these procedures (physical component summary = 37.73 +/- 11.52, MCS = 51.69 +/- 9.54). CONCLUSIONS: Principles of wide surgical resection, commonly applied in appendicular oncology, can and should be used for the treatment of primary bone tumors of the spine with anticipated acceptable morbidity and satisfactory survival.

Adolescent↗

[Clinical evaluation of a new tonometer on the basis of international standard ISO 8612].

BACKGROUND: There is a continuous process of development of new tonometer types following different measurement principles on the tonometer market. A new tonometer working on the dynamic contour measurement principle is currently available for ophthalmologists. This device has special properties, since it determines the intraocular pressure as well as the ocular pulse amplitude. So far, clinical comparison measurements exist between the new tonometer Pascal and the applanation tonometer by Goldmann albeit without any reference to a standard. Besides, these measurements cover only a small pressure range between 7 mmHg and 23 mmHg which is not sufficient for medical diagnosis. PATIENTS AND METHODS: This new tonometer was investigated by clinical comparison measurements according to the currently valid international standard for human eye tonometers (ISO 8612). The tested tonometer determines the intraocular pressure without fluorescein. In an ophthalmogical hospital in Berlin the clinical comparison measurements were carried out by ophthalmologists on 127 patients according to the methods and criteria of the above-mentioned standard. A calibrated AT 870 from the Haag-Streit company served as reference tonometer. RESULTS: The different cornea surface geometries of individual eyes, the variation of tear liquid volume, and also the different elastic properties of the human eye due to a large variation in rigidity led to measurements of intraocular pressure by this tonometer with an excessively high number of outliers p (i) (i = 1, ..., 3) per group (p (1) = 16.28 %, p (2) = 8.85 %, p (3) = 15.69 %, 5.0 % outliers per group only are permitted for the differences method), which do not correspond to the requirements of the international standard for tonometers ISO 8612. This is also shown by application of total method of least squares of regression line (slope a = 0.964, interception b = 2.868 mmHg, standard deviation s (y) = 2.628 mmHg). CONCLUSIONS: The test of conformity of results of clinical comparison measurements to the international standard for tonometers ISO 8612 is the target of this work. The measurement results of the investigated tonometer are analysed and discussed according to this standard. Statements about the medical application of this medical measurement device for ophthalmologists are presented. According to the presented investigations the requirements of this international standard are not fulfilled by the tonometer Pascal.

Equipment Design↗

[The adaptation and validation of the food security scale in a community of Caracas, Venezuela].

This paper describes the process of modifying and validating a hunger index developed in the United States by Wehler et al (1992). It is part of a research whose main objective is to develop and validate a simple method that measures both quantitative (food sufficiency) and qualitative (female self-perception) dimensions of household food insecurity. In a pilot study, the original instrument was modified from a 2 point 8 item to a 4 point 12 item scale. Precision measured with Alpha Chronbach's coefficient was high (0.871) suggesting consistency in the scale's items. The instrument was applied to a sample of 238 poor and very poor households in a peri-urban barrio of Caracas. To determine overall internal validity of the scale the relationship between possible economic, social and behavioral determinants and food security level measured with the scale, was analyzed. Construct validity of the scale was established with factor and principal components analysis. Finally, with multiple regression analysis evidence is presented for overall validity of the scale. Four determinants: predictors of food sufficiency score, monthly income per capita, social class, and number of children in the household predict in the expected direction self-perceived food security level (R2 = 0.343). Results suggest that this instrument, together with an abbreviated measure of food sufficiency, based on strategic foods may be a valid, precise, and simple method for identifying and monitoring households that suffer from some degree of food insecurity in poor urban communities.

Adult↗

Cognitive subtypes in developmentally disabled children: a pilot study.

Differential diagnoses within the pervasive developmental disorders have insufficient reliability, validity, and descriptive homogeneity within groups to be used as distinct categories for research purposes. This study reports the results of cognitive subtyping of 54 developmentally disabled children. Fifty-one were successfully categorized in a small number of groups, characterized by different strengths and weaknesses on verbal, performance, memory, and quantitative tests. About half of the children had the relatively good visuospatial performance expected on the basis of previous literature on autistic children; these children were not behaviorally more autistic than the others. Measures of internal validity are reported, as well as validation by cognitive and behavioral variables. These results tentatively suggest that such psychiatric manifestations as autistic aloofness and maintenance of sameness may be relatively independent of cognitive skill patterns.

Adolescent↗

Validation of the caregiving at life's end questionnaire.

The researchers in this study developed and validated a questionnaire to measure the needs of end-of-life (EOL) caregivers. The model is used to facilitate meaningful and supportive experiences for both the patient and caregiver The questionnaire was developed using existing scales of meaning, self-acceptance, burden, and gain as well as new scales of caregiver comfort, importance of caregiving tasks, and caregiver closure. The sample included 34 current and 17 bereaved caregivers affiliated with The Hospice Institute of the Florida Suncoast. The scales performed well in terms of concurrent validity, internal consistency, and reliability.

Aged↗

Retrovirus translation initiation: Issues and hypotheses derived from study of HIV-1.

Human immunodeficiency virus type 1 (HIV-1) has a small, multifunctional genome that encodes a relatively large and complex proteome. The virus has adopted specialized post-transcriptional control mechanisms to maximize its coding capacity while economically maintaining the information stored in cis-acting replication sequences. The conserved features of the 5' untranslated region of all viral transcripts suggest they are poor substrates for cap-dependent ribosome scanning and provide a compelling rationale for internal initiation of translation. This article summarizes key experimental results of studies that have evaluated HIV-1 translation initiation. A model is discussed in which cap-dependent and cap-independent initiation mechanisms of HIV-1 co-exist to ensure viral protein production in the context of 1) structured replication motifs that inhibit ribosome scanning, and 2) alterations in host translation machinery in response to HIV-1 infection or other cellular stresses. We discuss key issues that remain to be understood and suggest parameters to validate internal initiation activity in HIV-1 and other retroviruses.

HIV-1↗

The impact of worksite-based safety belt programs: a review of the literature.

PURPOSE: The purpose of this paper is to provide a literature review of the research that examines the effectiveness of worksite intervention programs designed to increase the use of safety belts by employees. SEARCH METHODS: The literature search, which identified 14 research studies on worksite safety belt programs conducted between 1968 and 1994, originated as part of a larger review on the health impact of worksite health promotion programs that was conducted by the Centers for Disease Control and Prevention (CDC). In addition, the authors conducted an additional search in an effort to validate the CDC search, but found no additional research articles. SUMMARY OF IMPORTANT FINDINGS: The literature specific to the effectiveness of safety belt programs is limited to only 14 studies. The safety belt intervention most commonly evaluated used behavioral modification principles involving incentives. These and other interventions demonstrated effective increases in seat belt utilization that, upon withdrawal of the intervention, achieved a recidivism rate above baseline levels. However, the vast majority of studies failed to incorporate control groups into their research design, which caused significant threats to internal validity. Thus, a summary of findings is only suggestive at best. MAJOR CONCLUSIONS: Based on the literature, there appears to be an insufficient number of quality research studies from which to derive a clear view of the impact of worksite safety belt programs. While the evidence is suggestive of a positive impact on safety belt use, there is a clear need for new, well-designed research initiatives on the effectiveness of theory-based safety belt intervention programs.

Accidents, Traffic↗

[Quality of life in chronic inflammatory bowel diseases. Validation of a questionnaire and first French data].

UNLABELLED: Inflammatory bowel diseases have an important impact on the daily life of patients. This impact can be measured by the evaluation of the health related quality of life. The aim of this study was to develop and to validate a questionnaire of quality of life in a French population. METHODS: The questionnaire comprised 70 items and was completed in 15 min. It was made up of a) a general questionnaire of 36 items (SF-36) exploring daily physical and social functioning, mental and general health, body pain and vitality. A sleep module of 6 items was added. b) a specific questionnaire of 28 items (RFIPC), exploring the concerns of the patients. The questionnaire was self-administered to 101 patients with Crohn's disease (57 F. 44 M. mean age: 35 years, acute disease: 28%, inpatients: 27%), 96 patients with ulcerative colitis (38 F. 58 M. mean age: 39 years, acute disease: 53%, inpatients: 21%). Each patient was sex and age matched with a healthy control. RESULTS: The psychometric analysis confirmed the validation of the questionnaire for the item's convergent validity, internal consistency (Cronbach's coefficient being > 0.70), analyses of discrimination. Scores of each scale of SF-36 were worse in patients than in controls. Scores of patients with active disease were worse than those of patients with quiescent disease. Scores were comparable in patients with Crohn's disease and with ulcerative colitis except for score of pain which was worse in acute Crohn's disease. The most important concerns of patients were the uncertain nature of the disease, energy level and having surgery. CONCLUSION: This study allowed the validation of a questionnaire for the evaluation of the quality of life in French patients with inflammatory bowel disease and provides first indications which need to be confirmed by future epidemiological studies.

Adult↗

Admission of patients with severe and moderate traumatic brain injury to specialized ICU facilities: a search for triage criteria.

OBJECTIVE: To investigate whether triage for direct admission of patients with traumatic brain injury to a trauma center is facilitated by predicting the risk of potentially removable lesions or raised intracranial pressure (ICP). DESIGN AND SETTING: Cohort study in a level I university trauma center. PATIENTS AND PARTICIPANTS: A prospective cohort of primarily (n=200) and secondarily (n=75) referred patients with moderate or severe traumatic brain injury. MEASUREMENTS AND RESULTS: Predictive characteristics for the risk of surgically removable lesions and the risk of raised ICP (repeatedly > or = 20 mmHg) were identified and included in prognostic models. These models were validated internally with bootstrapping techniques and externally on a historic sample (n=205) regarding discriminative ability (AUC). Among the cohort patients, 67% had raised ICP and 54% had surgically removable lesions. Both outcomes occurred more frequently in patients secondarily referred, but the incidence in patients primarily referred was also high (62% and 33% respectively). No strong predictors of raised ICP were identified. Age and pupillary reactivity were significant predictors of surgically removable lesions. The models discriminated reasonably for surgically removable lesions (AUC=0.78 at development and AUC=0.67 at external validation) but not for raised ICP (AUC=0.59 at development and AUC=0.50 at external validation). CONCLUSIONS: It is difficult accurately to identify patients in need of specialized intensive care using baseline characteristics. The high incidence of both outcomes in patients primarily referred support direct admission of more and particularly older patients with severe or moderate brain trauma to level I trauma centers.

Adult↗

A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of highly active antiretroviral therapy.

BACKGROUND: The established International Prognostic Index for lymphomas has not included patients with systemic AIDS-related non-Hodgkin lymphoma. OBJECTIVE: To establish the most appropriate prognostic index for use in patients with systemic AIDS-related non-Hodgkin lymphoma. DESIGN: A prospective study involving univariate and multivariable analyses of patients with AIDS-related non-Hodgkin lymphoma whose data were used to examine standard and new criteria for survival after diagnosis. SETTING: The Chelsea and Westminster cohort of HIV-1-infected persons. PATIENTS: 9621 HIV-positive patients, 111 in whom AIDS-related non-Hodgkin lymphoma was treated after 1996, in the era of highly active antiretroviral therapy (HAART). INTERVENTION: Cox proportional hazards regression analysis to determine the prognostic significance of multiple clinicopathologic variables. RESULTS: Survival of patients with AIDS-related non-Hodgkin lymphoma has increased in the HAART era (log-rank chi-square, 9.23; P = 0.002). Univariate analyses using the established International Prognostic Index factors of age, tumor stage, lactate dehydrogenase level, Eastern Cooperative Oncology Group performance status, and number of extranodal sites were confirmed to be significant variables. Regression modeling for patients in whom disease was diagnosed after 1996 revealed only 2 independent predictors of death: International Prognostic Index risk group and CD4 cell count. These predictors yielded 4 internally validated risk strata with predicted 1-year survival rates of 82%, 47%, 20%, and 15% (P < 0.001). Prognostic risk scores in the highest quartile yielded a likelihood ratio for death of 7.90 (hazard ratio, 1.0), whereas a prognostic score less than 1.0 yielded a likelihood ratio of 0.23 (hazard ratio, 0.15 [95% CI, 0.06 to 0.33]). LIMITATIONS: The sample was small, and different HAART regimens were used. CONCLUSIONS: For patients with AIDS-related non-Hodgkin lymphoma that was diagnosed in the era of HAART, application of the International Prognostic Index remains useful. The addition of CD4 cell count provides further independent prognostic information. Patients who present with AIDS-related non-Hodgkin lymphoma and a low CD4 cell count have a poor prognosis; this information can be used to guide therapeutic options.

Antiretroviral Therapy, Highly Active↗

Internal consistency and validity of an observational method for assessing disability in mobility in patients with osteoarthritis.

OBJECTIVE: To establish the internal consistency and validity of an observational method for assessing disability in mobility in patients with osteoarthritis (OA). METHODS: Data were obtained from 198 patients with OA of the hip or knee. Results of the observational method were compared with results of self-report methods (questionnaires) on disability in mobility. RESULTS: Both Cronbach's alpha and Mokken Scale Analysis indicate that the method is internally consistent. Using factor analysis, observed and self-reported disability in mobility were found to be closely associated and could not be differentiated. CONCLUSIONS: The observational method is internally consistent and indeed measures disability in mobility (high convergent validity), but observations and self-report seem to yield largely equivalent information (low divergent validity). This raises questions regarding the simultaneous use of both observational and self-report methods in the assessment of disability in mobility in OA patients.

Activities of Daily Living↗

Sensitive bioassay for determination of fluconazole concentrations in plasma using a Candida albicans mutant hypersusceptible to azoles.

The antifungal agent fluconazole (FLC) is widely used in clinical practice. Monitoring FLC levels is useful in complicated clinical settings and in experimental infection models. A bioassay using Candida pseudotropicalis, a simple and cost-effective method, is validated only for FLC levels ranging from 5 to 40 mg/liter. An extension of the analytical range is needed to cover most yeast MICs. A new bioassay in RPMI agar containing methylene blue was developed using C. albicans DSY1024, a mutant rendered hypersusceptible to FLC constructed by the deletion of the multidrug efflux transporter genes CDR1, CDR2, CaMDR1, and FLU1. Reproducible standard curves were obtained with FLC concentrations in plasma ranging from 1 to 100 mg/liter (quadratic regression coefficient > 0.997). The absolute sensitivity was 0.026 microg of FLC. The method was internally validated according to current guidelines for analytical method validation. Both accuracy and precision lied in the required +/-15% range. FLC levels measured by bioassay and by high-performance liquid chromatography (HPLC) performed with 62 plasma samples from humans and rats showed a strong correlation (coefficients, 0.979 and 0.995, respectively; percent deviations of bioassay from HPLC values, 0.44% +/- 15.31% and 2.66% +/- 7.54%, respectively). In summary, this newly developed bioassay is sensitive, simple, rapid, and inexpensive. It allows nonspecialized laboratories to determine FLC levels in plasma to within the clinically relevant concentration range and represents a useful tool for experimental treatment models.

Animals↗

The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument.

BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.

Aged↗

Mitochondria related gene signature serves as prognosis prediction and risk stratification of cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CHOL) is a highly aggressive biliary malignancy with poor clinical outcomes and limited effective prognostic biomarkers. Mitochondrial dysfunction participates in multiple oncological processes of CHOL, yet the prognostic roles of mitochondria&#x2011;related genes (MRGs) remain poorly understood. This study aimed to characterize MRGs expression in CHOL and develop a molecular prognostic model for predicting patient survival and guiding clinical management. METHODS: RNA sequencing (RNA-seq) and clinical data of CHOL were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) (GSE89748) databases. Differentially expressed MRGs were identified, and 10 machine learning algorithms were used to construct prognostic models. The optimal model (highest average C-index) was selected to establish a mitochondria-related risk score (MRRS), which was validated internally and externally. A nomogram integrating clinical factors and MRRS was developed, and biological mechanisms were explored via functional and immune analyses. RESULTS: A 3-MRG (MAP3K1, MRPL18, PYGB) prognostic signature was constructed, stratifying patients into high- and low-risk groups with significantly different overall survival. The model showed high predictive accuracy, with an area under the curve (AUC) up to 0.845, and MRRS was an independent prognostic factor. The signature was associated with mitochondrial pathways, and the high-risk group had distinct immune infiltration and mutation profiles. CONCLUSIONS: A validated MRG prognostic model effectively stratifies CHOL patients and has potential clinical value for prognosis prediction. Further validation in larger cohorts is needed to confirm its applicability.

Cholangiocarcinoma (CHOL)↗