Impact of severity of illness bias and control group misclassification bias in case-control studies of antimicrobial-resistant organisms.

BACKGROUND: Case-control studies often analyze risk factors for antibiotic resistance. Recently published articles have illustrated that randomly selected control-patients may be preferable to those with the susceptible phenotype of the organism. A possible methodologic problem with randomly selected control-patients is potential bias due to control group misclassification. This occurs if some control-patients did not have clinical cultures performed and thus might have been unidentified case-patients. If this bias exists, these studies might be expected to report lower odds ratios (ORs) because control-patients would be more like case-patients. OBJECTIVE: To analyze potential biases that might arise due to control group misclassification and potentially larger selection biases that may be introduced if control-patients are required to have at least one clinical culture. PATIENTS: One hundred twenty case-patients, 770 control-patients in group 1, and 510 control-patients in group 2. METHODS: Two case-control studies. Case-patients had clinical cultures positive for imipenem-resistant Pseudomonas aeruginosa. The first group of control-patients were random. The second group of control-patients were identical to those in group 1 except being required to have at least one clinical culture. RESULTS: Univariate analyses showed higher ORs for case-patients versus control-patients in group 1 (imipenem [OR, 12.5], piperacillin-tazobactam [OR, 3.7], and vancomycin [OR, 4.7]) as compared with case-patients versus control-patients in group 2 (imipenem [OR, 8.0], piperacillin-tazobactam [OR, 2.5], and vancomycin [OR, 3.0]). CONCLUSION: Requiring control-patients to have at least one clinical culture introduces a selection bias likely because it eliminates patients with less severe illness.     

The case-case-control study design: addressing the limitations of risk factor studies for antimicrobial resistance.

OBJECTIVE: There are significant limitations of the standard case-control study design for identifying risk factors for resistant organisms. The objective of this study was to develop a study design to overcome these limitations. DESIGN: Theoretical analysis of different types of study designs that can be used in risk factor studies for resistant organisms. RESULTS: We developed the case-case-control study design, which uses two separate case-control analyses within a single study. The first analysis compares patients infected with resistant bacteria (resistant cases) with control-patients without infection caused by the target organism, who are therefore representative of the source population; and the second analysis compares patients infected with the susceptible phenotype of the target organism (susceptible cases) with the same control-patients without infection caused by the target organism. These two analyses provide risk models for (1) isolation of the resistant phenotype of the target organism as compared with the source population and (2) isolation of the susceptible phenotype of the organism as compared with the source population. When these two risk models are compared and contrasted, risk factors specifically associated with isolation of the resistant phenotype can be identified. CONCLUSIONS: The case-case-control study design is an effective method for identifying risk factors for antimicrobial-resistant pathogens. Although the case-case-control study design has limitations, it is, in our opinion, more informative and less flawed than the standard case-control study design.     

Anxiogenic effects of Sumatriptan in panic disorder: a double-blind, placebo-controlled study.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with panic disorder (PD). Our goal was to further examine central serotonergic function in panic patients using autonomic and subjective responses to the postsynaptic serotonin 5-HT1D receptor agonist Sumatriptan. METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed autonomic and subjective responses to oral Sumatriptan (100 mg) and placebo in 15 patients with PD, free of medication. Subjective responses were measured using the Hamilton Anxiety Rating Scale (HAM-A), National Institute of Mental Health Anxiety Scale (NIMHA), a modified version of the Panic Symptom Inventory (PI), Hamilton Depression Rating Scale (HAM-D), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: PD patients exhibited significantly enhanced autonomic and subjective responses following challenge with Sumatriptan. We observed an increased pulse rate and augmentation of various parameters measured on different anxiety scales. A constant inclination of aggravation of the measured parameters was detected during the hour post challenge. CONCLUSION: Oral administration of Sumatriptan, a 5-HT1D agonist, has been associated with an anxiogenic effect in PD patients.     

Polymorphism in endostatin,an angiogenesis inhibitor,and prostate cancer risk and survival: A prospective study

Endostatin inhibits endothelial cell proliferation and migration, prerequisites of angiogenesis. A functional missense mutation (D104N) in endostatin was associated with an increased prostate cancer risk in a small study. We undertook a larger, prospective study within the Physicians' Health Study to examine D104N and prostate cancer risk and progression among 544 incident prostate cancer cases (1982–1995) and 678 matched controls. The association between endostatin genotype and cancer risk was estimated using logistic regression models. Among cases, Cox models were used to assess D104N and lethal prostate cancer. Given the role of endostatin in neovascularization of adipose tissue, we cross classified individuals on D104N genotype and body mass index (BMI). The genotype frequency was 1.3% homozygous (NN), 14.5% heterozygous (DN) and 84.2% wildtype homozygous (DD). There was no overall association between carriage of the N allele and prostate cancer risk (RR = 1.2, 95% CI: 0.9–1.6) or cancer‐specific mortality (HR = 1.2, 0.7–1.8). Cases with the polymorphic allele were less likely to be overweight (BMI 25 kg/m² or greater, 26%) compared to men wildtype homozygous (48%), p < 0.0001. Being overweight was associated with a 60% greater prostate cancer risk among those who were wildtype homozygous. In contrast, being overweight was associated with a 50% lower risk of cancer among those with the N allele. We did not confirm an earlier observation between the D104N polymorphism and prostate cancer. However, our data indicate that prostate cancer cases who carry the variant N allele are more likely to be overweight, and may be more susceptible to the angiogenic influences of obesity in prostate cancer pathogenesis. © 2009 UICC     

Relation of Anthropometric Measurements to Ovarian Cancer Risk in a Population-based Case–control Study (United States)

Objective To examine the relationship between anthropometric measures and ovarian cancer by menopausal status. Methods We analyzed data from a population-based case–control study comprised of 700 incident cases of epithelial ovarian cancer and 5,943 population controls from Massachusetts and Wisconsin enrolled between 1993 and 2001. In a telephone interview, information was gathered on established ovarian cancer risk factors, as well as adult height and age-specific body weight. Logistic regression was used to estimate multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for body mass index (BMI) throughout life. Results Recent BMI had no significant association with ovarian cancer risk (P-trend 0.14 for continuous BMI), after adjustment for age and other ovarian cancer risk factors. However, a non-significant positive association (overall P-trend 0.08) was observed for BMI at age 20; the risk estimate comparing a body mass of >25 kg/m2 to the lowest quintile (≤18.88 kg/m2) was moderately but non-significantly elevated (OR 1.46; 95% CI 0.92, 2.31). Conclusion Results of this study suggest that maintenance of a lean body mass, particularly in early adult life, may decrease ovarian cancer risk.     

Effects of dietary fat on pain threshold, thermoregulation and motor activity in rats

Groups of young male Sprague-Dawley (albino) or Long-Evans (hooded) rats were fed the same semi-purified diets containing 20% (w/w) fat in the form of soybean oil vs. lard, or a reference diet of standard Purina Chow (4.5% mixed fats) for 21 days. Behavioral testing after this time revealed that albino rats fed the diet containing soybean oil had increased paw-lick latencies on a 58 degrees C hot plate compared to chow-fed rats. In addition, both strains fed the diet containing soybean oil were protected from hypothermia induced by placing animals in a 4 degrees C cold room for 60 min following systemic injection of 10-15 mg/kg d-amphetamine. Rats of both strains fed the lard diet displayed paw-lick latencies similar to those shown by rats fed chow and hypothermic changes intermediary to those shown by rats fed soybean oil vs. chow diets. Horizontal crossings as well as rearings in a 15 min test of open field activity were the same for all diet groups within strains. No substantial differences were observed in the number of calories consumed, amount of body weight gained or basal colonic temperatures across diet conditions. The results suggest that a soybean oil-based diet can alter physiological mechanisms which mediate these indices of pain perception and thermoregulation. More generally, they indicate that qualitative changes in dietary fat content may be capable of altering certain behavioral states.     

Interests and specialty choice in medicine

The study deals with the origin of occupational satisfaction in the medical profession. It examines the relationship between the specialty choice within the medical profession on the one hand, and satisfaction with the occupational choice on the other. Following an intensive analysis of the medical profession and interviews with senior physicians, three dimensions along which the medical specialties differ were defined: contact with people (contact), usage of instruments and equipment (instruments), and occurrence of dramatic events in the physician's daily work (sensation). Eighty-one medical practitioners answered the IIP (interest inventory for physicians) which was constructed to measure their vocational interests. Results show: reliability coefficients of 0.85, 0.92 and 0.83 for the contact, instruments and sensation components of the IIP, respectively; and correlations of 0.31, 0.27 and 0.53 between interest-specialty congruence in contact, instruments and sensation, respectively, on the one hand, and satisfaction with the medical specialty choice on the other. Several implications and applications are discussed.     

Optimizing T-cell receptor avidity with somatic hypermutation

Adoptive transfer of T cells that have been genetically modified to express an antitumor T-cell receptor (TCR) is a potent immunotherapy, but only if TCR avidity is sufficiently high. Endogenous TCRs specific to shared (self) tumor-associated antigens (TAAs) have low affinity due to central tolerance. Therefore, for effective therapy, anti-TAA TCRs with higher and optimal avidity must be generated. Here, we describe a new in vitro system for directed evolution of TCR avidity using somatic hypermutation (SHM), a mechanism used in nature by B cells for antibody optimization. We identified 44 point mutations to the Pmel-1 TCR, specific for the H-2D^b-gp100_25-33 melanoma antigen. Primary T cells transduced with TCRs containing two or three of these mutations had enhanced activity in vitro. Furthermore, the triple-mutant TCR improved in vivo therapy of tumor-bearing mice, which exhibited improved survival, smaller tumors and delayed or no relapse. TCR avidity maturation by SHM may be an effective strategy to improve cancer immunotherapy.     

Intravenous immunoglobulin therapy for autoimmune diseases

Therapeutic approaches for autoimmune diseases are primarily based on suppressive measures that down regulate an over productive immune system. The increasing availability of modern biological therapies has advanced the ability to target and to neutralize essential components of the immune response without experiencing the hazardous adverse effects caused by the traditional immunosuppressants. One of the noticeable examples of this approach is the increasing use of high-dose intravenous immunoglobulin (IVIg). IVIg mechanisms include modulating function of Fc receptors, interference with complement activation and cytokine network, provision of anti-idiotypic antibodies, regulation of cell growth, and effects on of T and B cells. In this review we gather existing information regarding IVIg mechanisms of action, clinical applications and its effects on various conditions.