Theophylline as a quorum sensing and biofilm inhibitor in Pseudomonas aeruginosa and Chromobacterium violaceum.

Quorum sensing (QS) is pivotal in coordinating virulence factors and biofilm formation in various pathogenic bacteria, making it a prime target for disrupting bacterial communication. Pseudomonas aeruginosa is a member of the "ESKAPE" group of bacterial pathogens known for their association with antimicrobial resistance and biofilm formation. The current antibiotic arsenal falls short of addressing biofilm-related infections effectively, highlighting the urgent need for novel therapeutic agents. In this study, we explored the anti-QS and anti-biofilm properties of theophylline against two significant pathogens, Chromobacterium violaceum and P. aeruginosa. The production of violacein, pyocyanin, rhamnolipid, and protease was carried out, along with the evaluation of biofilm formation through methods including crystal violet staining, triphenyl tetrazolium chloride assay, and fluorescence microscopy. Furthermore, computational analyses were conducted to predict the targets of theophylline in the QS pathways of P. aeruginosa and C. violaceum. Our study demonstrated that theophylline effectively inhibits QS activity and biofilm formation in C. violaceum and P. aeruginosa. In P. aeruginosa, theophylline inhibited the production of key virulence factors, including pyocyanin, rhamnolipid, protease, and biofilm formation. The computational analyses suggest that theophylline exhibits robust binding affinity to CviR in C. violaceum and RhlR in P. aeruginosa, key participants in the QS-mediated biofilm pathways. Furthermore, theophylline also displays promising interactions with LasR and QscR in P. aeruginosa. Our study highlights theophylline as a versatile anti-QS agent and offers a promising avenue for future research to develop novel therapeutic strategies against biofilm-associated infections.

Antibiofilm potential of gallic acid against Klebsiella pneumoniae and Enterobacter hormaechei: in-vitro and in-silico analysis.

Biofilm refers to a community of microorganisms that adhere to a substrate and play a crucial role in microbial pathogenesis and developing infections associated with medical devices. Enterobacter hormaechei and Klebsiella pneumoniae are classified as significant nosocomial pathogens within the ESKAPE category and cause diverse infections. In addition to their reputation as prolific biofilm formers, these pathogens are increasingly becoming drug-resistant and pose a substantial threat to the healthcare setting. Due to the inherent resistance of biofilms to conventional therapies, novel strategies are imperative for effectively controlling E. hormaechei and K. pneumoniae biofilms. This study aimed to assess the anti-biofilm activity of gallic acid (GA) against E. hormaechei and K. pneumoniae. The results of biofilm quantification assays demonstrated that GA exhibited significant antibiofilm activity against E. hormaechei and K. pneumoniae at concentrations of 4 mg mL-1, 2 mg mL-1, 1 mg mL-1, and 0.5 mg mL-1. Similarly, GA exhibited a dose-dependent reduction in violacein production, a QS-regulated purple pigment, indicating its ability to suppress violacein production and disrupt QS mechanisms in Chromobacterium violaceum. Additionally, computational tools were utilized to identify the potential target involved in the biofilm formation pathway. The computational analysis further indicated the strong binding affinity of GA to essential biofilm regulators, MrkH and LuxS, suggesting its potential in targeting the c-di-GMP and quorum sensing (QS) pathways to hinder biofilm formation in K. pneumoniae. These compelling findings strongly advocate GA as a promising drug candidate against biofilm-associated infections caused by E. hormaechei and K. pneumoniae.

Synergistic Effect of Thymol-Ciprofloxacin Combination on Planktonic Cells and Biofilm of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic bacteria causing severe and life-threatening infections in individuals with weakened immune systems. P. aeruginosa forms antibiotic-resistant biofilms, rendering it challenging to treat; hence, alternate therapies are required to eliminate it. Treatment of infections using a combination of drugs is gaining momentum to combat drug-resistant pathogens, including P. aeruginosa. This study explores the synergistic effects of Thymol in combination with Ciprofloxacin, Amikacin and Colistin against planktonic cells and biofilm of P. aeruginosa. Thymol in combination with Ciprofloxacin yields the fractional inhibitory concentration index values 0.156 and 0.375 in P. aeruginosa strains, GC14 and ATCC 9027, respectively, highlighting a robust synergistic effect on both the planktonic and biofilm of P. aeruginosa. The results showed that Thymol (512 µg/mL) and Ciprofloxacin (0.125 µg/mL) were the most effective combination with 95 and 93.5% total biofilm inhibition in GC14 and PA27, respectively, compared to the Thymol (512 µg/mL) and Ciprofloxacin (0.125 µg/mL) alone. Our findings suggest that the combinations of Thymol and Ciprofloxacin may be a potential therapeutic strategy to address the issue of infections caused by P. aeruginosa biofilms.

Effective Dose of Prophylactic Oxytocin Infusion During Cesarean Delivery in 90% Population of Nonlaboring Patients With Preeclampsia Receiving Magnesium Sulfate Therapy and Normotensives: An Up-Down Sequential Allocation Dose-Response Study.

BACKGROUND: Oxytocin administration during cesarean delivery is the first-line therapy for the prevention of uterine atony. Patients with preeclampsia may receive magnesium sulfate, a drug with known tocolytic effects, for seizure prophylaxis. However, no study has evaluated the minimum effective dose of oxytocin during cesarean delivery in women with preeclampsia. METHODS: This study compared the effective dose in 90% population (ED90) of oxytocin infusion for achieving satisfactory uterine tone during cesarean delivery in nonlaboring patients with preeclampsia who were receiving magnesium sulfate treatment with a control group of normotensives who were not receiving magnesium sulfate. This prospective dual-arm dose-finding study was based on a 9:1 biased sequential allocation design. Oxytocin infusion was initiated at 13 IU/h, on clamping of the umbilical cord, in the first patient of each group. Uterine tone was graded as satisfactory or unsatisfactory by the obstetrician at 4 minutes after initiation of oxytocin infusion. The dose of oxytocin infusion for subsequent patients was decided according to the response exhibited by the previous patient in the group; it was increased by 2 IU/h after unsatisfactory response or decreased by 2 IU/h or maintained at the same level after satisfactory response, in a ratio of 1:9. Oxytocin-associated side effects were also evaluated. Dose-response data for the groups were evaluated using a log-logistic function and ED90 estimates were derived from fitted equations using the delta method. RESULTS: The ED90 of oxytocin was significantly greater for the preeclampsia group (n = 27) than for the normotensive group (n = 40) (24.9 IU/h [95% confidence interval {CI}, 22.4-27.5] and 13.9 IU/h [95% CI, 12.4-15.5], respectively); the difference in dose requirement was 10.9 IU/h (95% CI, 7.9-14.0; P < .001). The number of patients with oxytocin-related hypotension, defined as a decrease in systolic blood pressure >20% from baseline or to <90 mm Hg, was significantly greater in the preeclampsia group (92.6% vs 62.5%; P = .030), while other side effects such as ST-T depression, nausea/vomiting, headache, and flushing, were not significantly different. There was no significant difference in the need for additional uterotonic or uterine massage, estimated blood loss, and need for re-exploration for uncontrolled bleeding. CONCLUSIONS: Patients with preeclampsia receiving preoperative magnesium therapy need a greater intraoperative dose of oxytocin to achieve satisfactory contraction of the uterus after fetal delivery, as compared to normotensives.

A bootstrapping method to optimize go/no-go decisions from single-arm, signal-finding studies in oncology.

Phase Ib trials are common in oncology development but often are not powered for statistical significance. Go/no-go decisions are largely driven by observed trends in response data. We applied a bootstrapping method to systematically compare tumor dynamic end points to historical control data to identify drugs with clinically meaningful efficacy. A proprietary mathematical model calibrated to phase Ib anti-PD-1 therapy trial data (KEYNOTE-001) was used to simulate thousands of phase Ib trials (n = 30) with a combination of anti-PD-1 therapy and four novel agents with varying efficacy. A redacted bootstrapping method compared these results to a simulated phase III control arm (N = 511) while adjusting for differences in trial duration and cohort size to determine the probability that the novel agent provides clinically meaningful efficacy. Receiver operating characteristic (ROC) analysis showed strong ability to separate drugs with modest (area under ROC [AUROC] = 83%), moderate (AUROC = 96%), and considerable efficacy (AUROC = 99%) from placebo in early-phase trials (n = 30). The method was shown to effectively move drugs with a range of efficacy through an in silico pipeline with an overall success rate of 93% and false-positive rate of 7.5% from phase I to phase III. This model allows for effective comparisons of tumor dynamics from early clinical trials with more mature historical control data and provides a framework to predict drug efficacy in early-phase trials. We suggest this method should be employed to improve decision making in early oncology trials.

Prevalence of Tuberculosis Infection among Adults of Thiruvananthapuram District of Kerala as Measured by Interferon Gamma Release Assay - A Cross-Sectional Study.

Background: To achieve the goals of the end tuberculosis (TB) strategy, strategies for management of TB infection (TBI) have to be expanded. The first step to devise policies is to understand the distribution and determinants of TBI in the community. The objectives of the study were to estimate the prevalence of TBI using Interferon Gamma Release Assay (IGRA) and its determinants among the adult population of Thiruvananthapuram district, Kerala. Materials and Methods: A community-based, cross-sectional study using the stratified cluster sampling was carried out among the adults. TBI was detected using IGRA conducted on whole blood sample. Data on determinants were collected using a structured questionnaire by the face-to-face interview. The prevalence of TBI was estimated. Univariate and multivariate analysis was conducted to identify the determinants. Results: Age standardized prevalence of TBI among 396 adults was 20.5% (95% confidence interval [CI] 16.52-24.48). On adjusting for the possible confounders, increasing age (adjusted odds ratio [OR] 1.028; 95% CI 1.008-1.048; P = 0.005), history of contact with active TB disease (adjusted OR 7.61; 95% CI 4.43-13.05; P < 0.001), childhood contact (adjusted OR 8.20; 95% CI 3.14-21.41; P < 0.001), and household contact (adjusted OR 10.12; 95% CI 5.39-18.98; P < 0.001) were found to be the determinants of TBI in this population. Conclusion: The present study observed that nearly one-fifth of the adult population in the Thiruvananthapuram district has TBI. For the programmatic management, factors such as increasing age and contact history may be considered for the elimination of TBI in the state.

Hallmarks of neurodegenerative disease: A systems pharmacology perspective.

Age-related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease-modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.

Overview of statistical methods usage in Indian anaesthesia publications.

Background and Aims: Despite the importance of statistics being well established for medical research, it remains a neglected area of understanding and learning. The present survey aimed to examine the use of various statistical methods in a two-year sample (2019-2020) of representative Indian anaesthesia journals and compare it with an international top-ranked journal. Methods: The literature survey included analysis of 748 original articles from 'Indian Journal of Anaesthesia' (179), 'Journal of Anaesthesiology Clinical Pharmacology' (125) and 'Anesthesia & Analgesia' (444) published over the period. Original research articles were identified from the table of contents of each issue. Articles were assessed for statistical methods, categorised as being descriptive, elementary, multivariable, advanced multivariate or diagnostic/classification. Results: Compared to Anesthesia & Analgesia, the Indian journals (considered together) had a significantly greater use of mean (standard deviation) (91.2% versus 70%) and percentages (79.5% versus 67.6%) (P = 0.000 each); and lesser for Wilcoxon (5.4% versus 14.6%) and Pearson/Spearman (5.1% versus 13.5%) correlation tests (P = 0.000 each), multivariable tests including various regression methods (P < 0.001), classification/diagnostic tests [Receiver operating characteristic (ROC) curve analysis, P = 0.022; sensitivity/specificity, P = 0.000; precision, P = 0.006; and relative risk/risk ratio, P = 0.010] and a virtual absence of complex multivariate tests. Conclusion: The findings show limited use of advanced complex statistical methods in Indian anaesthesia journals, usually being restricted to descriptive or elementary. There was a strong bias towards using randomised controlled designs. The findings suggest an urgent and focussed need on training in research methodology, including statistical methods, during postgraduation and continued medical training.

Early Warning Scores at Time of ICU Admission to Predict Mortality in Critically Ill COVID-19 Patients.

OBJECTIVE: To assess ability of National Early Warning Score 2 (NEWS2), systemic inflammatory response syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA), and CRB-65 calculated at the time of intensive care unit (ICU) admission for predicting ICU mortality in patients of laboratory confirmed coronavirus disease 2019 (COVID-19) infection. METHODS: This prospective data analysis was based on chart reviews for laboratory confirmed COVID-19 patients admitted to ICUs over a 1-mo period. The NEWS2, CRB-65, qSOFA, and SIRS were calculated from the first recorded vital signs upon admission to ICU and assessed for predicting mortality. RESULTS: Total of 140 patients aged between 18 and 95 y were included in the analysis of whom majority were >60 y (47.8%), with evidence of pre-existing comorbidities (67.1%). The most common symptom at presentation was dyspnea (86.4%). Based upon the receiver operating characteristics area under the curve (AUC), the best discriminatory power to predict ICU mortality was for the CRB-65 (AUC: 0.720 [95% confidence interval [CI]: 0.630-0.811]) followed closely by NEWS2 (AUC: 0.712 [95% CI: 0.622-0.803]). Additionally, a multivariate Cox regression model showed Glasgow Coma Scale score at time of admission (P < 0.001; adjusted hazard ratio = 0.808 [95% CI: 0.715-0.911]) to be the only significant predictor of ICU mortality. CONCLUSIONS: CRB-65 and NEWS2 scores assessed at the time of ICU admission offer only a fair discriminatory value for predicting mortality. Further evaluation after adding laboratory markers such as C-reactive protein and D-dimer may yield a more useful prediction model. Much of the earlier data is from developed countries and uses scoring at time of hospital admission. This study was from a developing country, with the scores assessed at time of ICU admission, rather than the emergency department as with existing data from developed countries, for patients with moderate/severe COVID-19 disease. Because the scores showed some utility for predicting ICU mortality even when measured at time of ICU admission, their use in allocation of limited ICU resources in a developing country merits further research.

Bacterium isolated from coffee waste pulp biosorps lead: Investigation of EPS mediated mechanism.

Kleibsiella pneumoniae Kpn555, isolated from coffee waste pulp showed high level of tolerance to lead with a minimum inhibitory concentration of 900 mg/L. On its growth in nutrient broth supplemented with lead, brown clumps were visualised at the bottom of the flask. On scanning and transmission electron microscopic studies the brown clumps were corroborated to be bacterial cells with lead biosorbed on the cell surface and accumulated inside the cytoplasm. Biochemical and FT-IR analysis of the extracellular polymeric substance produced on exposure to lead revealed its chemical nature as glycolipid with protein moieties. Purified EPS (100 mg/L) could remove 50% of lead from aqueous solution (200 mg/L). Isolation of plasmid from Klebsiella pneumoniae Kpn555 revealed the presence of a plasmid of size 30-40 kb. This capability of the bacteria was proven to be plasmid mediated as the Escherichia coli DH5α cells transformed with the plasmid of Klebsiella pneumoniae Kpn555 also could tolerate 900 mg/L of lead and form brown clumps. This study shows that these bacteria, aided by EPS could serve as an effective agent for the removal of lead from contaminated water environmental samples.

Successful management of a case of true radicular dens invaginatus using platelet-rich fibrin and guided tissue regeneration.

A radicular variant of dens invaginatus (DI) is a rare form of dens invaginatus which develops in the root of the tooth after the crown development is completed. This report involves successful management of a case with guided tissue regeneration and describes the cone beam computed tomography (CBCT) characteristics of true radicular DI. A 20-year-old woman reported with recurrent swelling and pus discharge associated with her maxillary left central incisor (#21). Cone beam computed tomography (CBCT) of the region revealed #21 had an invagination in the mesial aspect of the coronal third of the root with a para radicular low-density region perforating both the cortices. A diagnosis of true radicular variant of DI was made by exclusion. The case was managed with Biodentine® , platelet-rich fibrin and freeze-dried demineralised bone graft. A 2-year review showed that the tooth was functional with normal periodontal parameters and normal response to electric pulp sensibility test.

Estimating historical radiation doses to a cohort of U.S. radiologic technologists.

Data have been collected and physical and statistical models have been constructed to estimate unknown occupational radiation doses among 90,000 members of the U.S. Radiologic Technologists cohort who responded to a baseline questionnaire during the mid-1980s. Since the availability of radiation dose data differed by calendar period, different models were developed and applied for years worked before 1960, 1960- 1976 and 1977-1984. The dose estimation used available film-badge measurements (approximately 350,000) for individual cohort members, information provided by the technologists on their work history and protection practices, and measurement and other data derived from the literature. The dosimetry model estimates annual and cumulative occupational badge doses (personal dose equivalent) for each technologist for each year worked from 1916 through 1984 as well as absorbed doses to organs and tissues including bone marrow, female breast, thyroid, ovary, testes, lung and skin. Assumptions have been made about critical variables including average energy of X rays, use of protective aprons, position of film badges, and minimum detectable doses. Uncertainty of badge and organ doses was characterized for each year of each technologist's working career. Monte Carlo methods were used to generate estimates of cumulative organ doses for preliminary cancer risk analyses. The models and predictions presented here, while continuing to be modified and improved, represent one of the most comprehensive dose reconstructions undertaken to date for a large cohort of medical radiation workers.

Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration.

BACKGROUND: Carticel is an autologous cultured chondrocyte product that has been approved by the United States Food and Drug Administration for the repair of symptomatic cartilaginous defects of the femoral condyle that are caused by acute or repetitive trauma in patients who have been previously managed with arthroscopy or other surgical procedures. The present report describes the adverse events following Carticel implantation as reported to the Food and Drug Administration from 1996 to 2003. METHODS: We reviewed adverse event reports that had been submitted to the Food and Drug Administration's MedWatch system for information on demographic characteristics, adverse events, and surgical revisions. Adverse events were categorized into sixteen non-mutually exclusive groups. Five categories were used to classify reoperations. Food and Drug Administration regulations require manufacturers to report adverse events; however, reporting by clinicians and others is voluntary. Therefore, adverse event reporting is likely to underestimate the number of event occurrences. Adverse events may be either causally or coincidentally related to the product. RESULTS: A total of 497 adverse events among 294 patients receiving Carticel were reported. The median interval from Carticel implantation to the diagnosis of an adverse event was 240 days (range, one to 2105 days). The median age of the patients was thirty-eight years, and 63% of the patients were male. Of the 270 events for which the anatomic site was noted, 258 (96%) involved the femoral condyles. More than one adverse event was reported for 135 patients (46%). The most commonly reported events were graft failure (seventy-three patients; 25%), delamination (sixty-five patients; 22%), and tissue hypertrophy (fifty-two patients; 18%). In addition, eighteen surgical site infections were reported, including eleven joint and seven soft-tissue infections. Surgical revision subsequent to Carticel implantation was mentioned in the records for 273 patients (93%). The reasons for the 389 revision procedures included graft-related problems (187 procedures; 48.1%), periarticular soft-tissue problems (ninety-seven procedures; 24.9%), and intra-articular problems (sixty-three procedures; 16.2%). Eight patients had a total knee replacement. Based on the manufacturer's reported distribution of 7500 Carticel lots between 1995 and 2002, 285 patients (3.8%) had an adverse event that was reported to the Food and Drug Administration. CONCLUSIONS: The most common adverse events reported in association with the Carticel technique involved graft failure, delamination, and tissue hypertrophy.

Breast cancer mortality among female radiologic technologists in the United States.

We evaluated breast cancer mortality through 1997 among 69 525 female radiologic technologists who were certified in the United States from 1926 through 1982 and who responded to our questionnaire. Risk of breast cancer mortality was examined according to work history and practices and was adjusted for known risk factors. Breast cancer mortality risk was highest among women who were first employed as radiologic technologists prior to 1940 (relative risk [RR] = 2.92, 95% confidence interval [CI] = 1.22 to 7.00) compared with risk of those first employed in 1960 or later and declined with more recent calendar year of first employment (P for trend =.002). Breast cancer mortality risk increased with increasing number of years of employment as a technologist prior to 1950 (P for trend =.018). However, risk was not associated with the total number of years a woman worked as a technologist. Technologists who first performed fluoroscopy (RR = 1.69, 95% CI = 1.02 to 3.11) and multifilm procedures (RR = 1.87, 95% CI = 1.04 to 3.34) before 1950 had statistically significantly elevated risks compared with technologists who first performed these procedures in 1960 or later. The high risks of breast cancer mortality for women exposed to occupational radiation prior to 1950 and the subsequent decline in risk are consistent with the dramatic reduction in recommended radiation exposure limits over time.

Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases.

BACKGROUND: Botulinum toxin type A (BTA) (Botox) received Food and Drug Administration (FDA) approval for therapeutic treatment of strabismus and blepharospasm in 1989, cervical dystonia in 2000, and cosmetic treatment of glabellar wrinkles (Botox Cosmetic) in 2002. In 2002 alone there were approximately 1.1 to 1.6 million patients using cosmetic BTA. Our objective was to review adverse event (AE) reporting to the FDA after BTA administration. METHODS: We reviewed all (therapeutic and cosmetic use) serious (per FDA regulations) AEs reported to the FDA for the 13.5 years since licensure of the product (December 1989-May 2003) and nonserious AEs reported from December 2001 to November 2002. AEs are reported to the FDA through the MedWatch system. RESULTS: We reviewed 1437 AE reports; 406 followed therapeutic use of BTA (217 serious and 189 nonserious) and 1031 followed cosmetic use (36 serious and 995 nonserious). Reported AEs occurred predominantly in female patients, with a median age of 50 years. In the year December 2001 to November 2002, when both serious and nonserious reports were evaluated, the proportion of reports classified as serious was 33-fold higher for therapeutic than for cosmetic cases. The 217 serious AEs reported in therapeutic cases involved a wide spectrum of events and included all 28 reported deaths. Among cosmetic users, no deaths were reported and, of the 36 serious AEs, 30 were included as possible complications in the FDA-approved label. The remaining 6 serious AEs did not display a pattern suggesting a common causal relationship to BTA. Among the 995 cosmetic cases reported to have nonserious AEs, most commonly noted were lack of effect (623, 63%), injection site reaction (190, 19%), and ptosis (111, 11%). CONCLUSIONS: Serious AEs were more likely to be reported for therapeutic than for cosmetic use, which may be related to higher doses, complicated underlying diseases, or both. Among cosmetic cases, few serious AEs were reported, and these were predominantly events that were previously recognized in clinical trials of BTA for the labeled use. This study is limited primarily by the incomplete nature of AE reporting by clinicians. Numerous departures from FDA-approved recommendations for drug dose, dilution, handling, site of injection, and storage were noted in these AE reports.

Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor.

Infliximab, a tumor necrosis factor (TNF) antagonist, is associated with tuberculosis (TB), but it is unknown whether this phenomenon is true of all TNF antagonists. We reviewed 25 cases of TB due to another TNF antagonist, etanercept, that were reported to the US Food and Drug Administration (FDA) between November 1998 and March 2002. Such cases are sometimes incomplete and are subject to underreporting. Fifteen patients received other immunosuppressive medications. The median interval between the receipt of the first dose of etanercept and the diagnosis of TB was 11.5 months. Thirteen patients had extrapulmonary TB at the time of diagnosis. Diagnosis was made on the basis of culture results for 12 patients, biopsy findings for 9, and sputum staining for 4. There were 2 deaths, 1 of which was directly attributed to TB. The estimated number of TB cases reported to the FDA for each person-year of treatment with etanercept (i.e., the "reporting rate") among patients with rheumatoid arthritis (RA) was ~10 cases/100,000 patient-years of exposure. Clinicians considering etanercept for patients with RA should be alert to the possibility of the occurrence of TB, sometimes with an unusual extrapulmonary presentation. It is unclear whether etanercept therapy increases the risk of TB beyond the elevated TB rates already documented for patients with RA.

Trends in reproductive, smoking, and other chronic disease risk factors by birth cohort and race in a large occupational study population.

PURPOSE: To illustrate the value of cohort studies to assess trends in chronic disease risk factors. METHODS: In collaboration with the American Registry of Radiologic Technologists and the University of Minnesota, the National Cancer Institute initiated a cohort study of cancer among radiologic technologists. More than 90,000 technologists who responded to a mailed questionnaire were grouped into ten birth cohorts from before 1920 through 1960 and later, and stratified by self-reported racial/ethnic groups. Trends in height, smoking, and reproductive factors were analyzed. RESULTS: Among the trends observed were that the proportion of young men (< 18 years) smoking generally fell in each birth cohort after 1925, whereas the proportion of young women smoking rose for those born after 1950. Among women born since 1940, the mean age at menarche for white women has remained at 12.5 years, but has declined among black and Asian/Pacific Islander women. Recent birth cohorts (since 1955) show among the highest mean ages at birth of first child (> 26 years), highest rates of nulliparity at age 25 (>/= 63 %), and lowest mean parity levels (< or = 1.7) compared with earlier cohorts. CONCLUSION: Analyses of large cohorts can clarify birth cohort trends in chronic disease risk factors.