"I knew from day one that i'm either gonna fight this thing or be defeated": African American parents' experiences of coping with breast cancer.

Few studies have explored how African American parents navigate breast cancer while parenting their school-age children. This focus-group study examined how African American parents cope with the diagnosis and treatment of breast cancer. Three focus groups were conducted with nine African American parents coping with breast cancer. Interviews were analyzed using content analysis. Participants described a variety of coping strategies. Five primary themes emerged: involvement in community of support, relationship with cancer, being the family emotional regulator, highlighting positives, and spirituality. Findings suggest that providers can improve the care of African American breast cancer patients and their families by facilitating patient advocacy, encouraging patients to reach out to various support systems, discussing with patients their children's functioning, and integrating spirituality into available support programs. Developing more culturally sensitive support groups that promote shared family understanding and open communication among African American parents and their children can facilitate better coping.

African American parents' experiences navigating breast cancer while caring for their children.

African American parents who are navigating breast cancer while parenting their school-age children are an understudied population. We used family systems and sociocultural theories to conduct three focus groups with a total sample of 9 African American parents to understand how they cared for their school-age children (ages 11 to 18) while coping with the diagnosis and treatment of breast cancer. Our content analysis of these focus groups yielded themes that described a variety of ways they protected their children from the emotional consequences of breast cancer. Seven primary themes emerged: (a) increased desire to protect their children, (b) parental concerns for children's coping, (c) openness and transparency with children, (d) reliance on children for support, (e) calibration of their own responses, (f) use of the illness experience as a teachable moment for children, and (g) reliance on others for parenting support. Clinicians and researchers can improve their care by developing culturally sensitive family intervention programs that promote family resilience.

Are We Measuring What Matters? How Student and Clerkship Characteristics Influence Clinical Grading.

PURPOSE: Given the growing emphasis placed on clerkship performance for residency selection, clinical evaluation and its grading implications are critically important; therefore, the authors conducted this study to determine which evaluation components best predict a clinical honors recommendation across 3 core clerkships. METHOD: Student evaluation data were collected during academic years 2015-2017 from the third-year internal medicine (IM), pediatrics, and surgery clerkships at the University of Alabama at Birmingham School of Medicine. The authors used factor analysis to examine 12 evaluation components (12 items), and they applied multilevel logistic regression to correlate evaluation components with a clinical honors recommendation. RESULTS: Of 3,947 completed evaluations, 1,508 (38%) recommended clinical honors. The top item that predicted a clinical honors recommendation was clinical reasoning skills for IM (odds ratio [OR] 2.8; 95% confidence interval [CI], 1.9 to 4.2; P < .001), presentation skills for surgery (OR 2.6; 95% CI, 1.6 to 4.2; P < .001), and knowledge application for pediatrics (OR 4.8; 95% CI, 2.8 to 8.2; P < .001). Students who spent more time with their evaluators were more likely to receive clinical honors (P < .001), and residents were more likely than faculty to recommend clinical honors (P < .001). Of the top 5 evaluation items associated with clinical honors, 4 composed a single factor for all clerkships: clinical reasoning, knowledge application, record keeping, and presentation skills. CONCLUSIONS: The 4 characteristics that best predicted a clinical honors recommendation in all disciplines (clinical reasoning, knowledge application, record keeping, and presentation skills) correspond with traditional definitions of clinical competence. Structural components, such as contact time with evaluators, also correlated with a clinical honors recommendation. These findings provide empiric insight into the determination of clinical honors and the need for heightened attention to structural components of clerkships and increased scrutiny of evaluation rubrics.

Community acquired influenza requiring hospitalization: vaccine status is unrelated to morbidity in children with cancer.

BACKGROUND: Community acquired influenza can be severe and there are few data regarding hospitalization for children with cancer and influenza. Association between prior vaccination and infection severity has not been studied, although vaccination is standard practice. PROCEDURE: Patients with malignancy or prior stem cell transplant (SCT) were identified using a database of children with laboratory confirmed influenza (2000-2005). Other data collected included receipt of vaccine, absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). These were compared with intensive care unit (ICU) stay, respiratory complications and hospital days. RESULTS: There were 39 patients with laboratory-confirmed influenza with a median age of 6.9 years. Twenty-four (62%) were on cancer therapy at time of infection and 18 (46%) had received the influenza vaccination that season. Measures of immune status included ANC at time of infection (median 1,530 cells/microl; inter-quartile range, 315, 4347), presence of graft versus host disease 2 (5%) and steroid therapy 4 (10%) patients. All had a low ALC (median 448 cells/microl; IQR 189, 861). Respiratory complications occurred in 8 (20%), ICU admissions in 4 (10%) and death in 2 (5%) patients. Median hospital stay was 2 days. All ICU admissions occurred in unvaccinated patients (P = 0.1). Vaccine status, ANC (<1,000 cells/microl vs. >1,000) and ALC (<500 cells/microl vs. >500) were not associated with length of stay or respiratory complications. CONCLUSIONS: Influenza infection can be severe in children with cancer and complications occur despite vaccination. Prospective evaluation of vaccine response is worthy of future study.

Association between aldosterone production and variation in the 11beta-hydroxylase (CYP11B1) gene.

CONTEXT: Variation in the region of chromosome 8 including the genes steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown. OBJECTIVE: Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism. DESIGN: We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus. PARTICIPANTS: Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband. MAIN OUTCOME MEASURES: We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype. RESULTS: The heritability of THAldo excretion was 52% (P < 10(-6)). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P < 0.001). CONCLUSIONS: Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.

In situ on-line toxicity biomonitoring in water: recent developments.

In situ on-line biomonitoring is an emerging branch of aquatic biomonitoring. On-line biomonitoring systems use behavioral and/or physiological stress responses of caged test organisms exposed in situ either in a bypass system or directly in-stream. Sudden pollution waves are detected by several existing single-species on-line biomonitors, which until now have been placed mostly in streamside laboratories. However, recent achievements have been multispecies biomonitors, mobile biomonitors for direct in-stream use, development of new instruments, new methods for data analysis and alarm generation, biomonitors for use in soil and sediment, and scientific research supporting responses as seen in on-line biomonitors by linking them to other biological and ecological effects. Mobile on-line monitoring platforms containing an array of biomonitors, biosensors, and chemical monitoring equipment might be the future trend, especially in monitoring transboundary rivers at country borders as well as in coastal zones.

Genetic variation at the locus encompassing 11-beta hydroxylase and aldosterone synthase accounts for heritability in cortisol precursor (11-deoxycortisol) urinary metabolite excretion.

Genetic variation in the gene encoding aldosterone synthase (CYP11B2) has previously been shown to be associated with hypertension and left ventricular hypertrophy. The intermediate phenotype most consistently associated with variation at this locus is that of elevated plasma 11-deoxycortisol (S). However, in normal subjects, aldosterone synthase does not metabolize S, which is converted to cortisol (F) by the enzyme 11 beta hydroxylase, encoded by the gene CYP11B1, which lies adjacent to CYP11B2 on chromosome 8. It is possible that the quantitative trait locus for the phenotype is within CYP11B1 and that linkage disequilibrium across the extended locus could account for these observations. However, variation across the whole CYP11B1/B2 locus had not been extensively characterized with respect to these phenotypes. We genotyped six polymorphisms in the CYP11B2 gene and three polymorphisms in the CYP11B1 gene in 248 Caucasian nuclear families comprising 1428 individuals. We measured plasma levels of S and F in 460 individuals from 86 families and urinary excretion rates of tetrahydrodeoxycortisol (THS) and tetrahydrodeoxycorticosterone in 573 individuals from 105 families. We examined heritability of the phenotypes and their association with genotypes and haplotypes at this locus. All steroid phenotypes except urinary tetrahydrodeoxycorticosterone were highly heritable (P < 0.00001). There was strong linkage disequilibrium across the CYP11B1/B2 locus. There was modest evidence for association between polymorphisms of CYP11B2 and plasma levels of S (P = 0.02 for T4986C polymorphism) and the plasma S to F ratio, reflecting the activity of 11-beta hydroxylase (P = 0.01 for T4986C polymorphism). There was strong evidence for association between polymorphisms of both CYP11B1 and CYP11B2 and urinary THS, which was strongest for the CYP11B1 exon 1 polymorphism (P = 0.00002). Addition of other marker data to CYP11B1 exon 1 did not improve the fit of a log-linear model. Genotype at CYP11B1 explained approximately 5% of the variance in urinary THS excretion in the population. Thus, it is likely that linkage disequilibrium between causative CYP11B1 variants and CYP11B2 polymorphisms account for the previous observations. Further fine-mapping studies across the CYP11B1 locus are required to localize the causative variant(s) for the biochemical phenotype; this may also identify susceptibility alleles for hypertension and left ventricular hypertrophy.

The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation.

The terminal stages in the synthesis of aldosterone and cortisol are catalysed by the enzymes aldosterone synthase and 11beta-hydroxylase respectively. We have previously reported that polymorphic variation in the 5' promoter region (-344C/T) of the gene encoding aldosterone synthase (CYP11B2) is associated with increased aldosterone metabolite excretion and with hypertension associated with a raised aldosterone to renin ratio (ARR). Additionally, basal and ACTH-stimulated plasma levels of 11-deoxycortisol, the precursor of cortisol, are higher in subjects carrying the T-allelic variant. We have now identified in a family study (573 individuals from 105 extended families ascertained through a hypertensive proband) that excretion of the main metabolite of this steroid (tetrahydro-11-deoxycortisol, THS) is heritable (19.4%) and that the T-allele of CYP11B2 is more strongly associated with higher THS levels than the C-allele. Raised plasma and urinary levels of 11-deoxycortisol suggest that there is relative inefficiency of 11beta-hydroxylation in the zona fasciculata; the P450 enzyme responsible for this step is encoded by the gene CYP11B1, which is highly homologous with and adjacent to CYP11B2. The association of genetic variation in the promoter of CYP11B2 which, in the adrenal cortex, is only expressed in zona glomerulosa, and zona fasciculata 11beta-hydroxylation function is paradoxical. There may be linkage dys-equilibrium between this polymorphism and a quantitative trait locus (QTL) in CYP11B1. Chronic alteration of 11beta-hydroxylase activity may increase ACTH drive to the adrenal cortex, altering the regulation of aldosterone synthesis. This may explain, at least partly, the association between CYP11B2 polymorphisms and hypertension.

"To be a phenomenal doctor you have to be the whole package": physicians' interpersonal behaviors during difficult conversations in pediatrics.

BACKGROUND: Delivery of bad news is a challenging task for physicians and other health care professionals. Several studies have assessed parental perceptions of the delivery of bad news, but none have focused on the role of physicians' interpersonal behaviors in the communication process. OBJECTIVE: The study's objective was to assess parental perceptions of physicians' interpersonal behaviors and their role in communication of bad news. DESIGN: The design was a cross-sectional qualitative interview study of 13 parents of patients hospitalized or previously hospitalized in the pediatric intensive care unit or oncology/bone marrow transplant unit at an academic children's hospital. RESULTS: Eleven interpersonal behaviors were identified as important by parents. The majority of parents identified empathy in physicians as critical. Availability, treating the child as an individual, and respecting the parent's knowledge of the child were mentioned by almost half of parents. Themes also considered important but by a smaller number of parents were allowing room for hope, the importance of body language, thoroughness, going beyond the call of duty, accountability, willingness to accept being questioned, and attention to the suffering of the child. CONCLUSIONS: To increase parental satisfaction and enhance the parent-physician therapeutic partnership, we recommend that physicians consider attending to the 11 interpersonal behaviors described in this manuscript, and that educational programs pay particular attention to these behaviors when training health care providers in the communication of bad news.

Extracellular protease imaging for cell mass tracking of xenografted human malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is locally aggressive and challenging to quantitate non-invasively in vivo, particularly in orthotopic models of disease. We describe imaging of extracellular protease activity, typically elevated in locally aggressive tumors, as a novel method for tracking MPM in vivo. Mice bearing human MPM subcutaneous flank xenografted tumors were imaged with ProSense 680, an optical imaging agent of extracellular cysteine protease activity. The relative contribution of extracellular cysteine proteases to the ProSense tumor signal was estimated using RT-PCR quantitation of cysteine protease RNA expression of the MPM cell lines and compared to ArrayExpress microarray RNA expression data from human MPM tumors. Feasibility of orthotopic intraperitoneal MPM cell mass tracking with fluorescence signal was evaluated using CellVue Maroon-coated MSTO-211H and compared to bioluminescent signal using luciferase-transfected MSTO-211H cells. ProSense 680 yielded a robust tumor signal in MPM subcutaneous grafts, primarily resulting from MPM secretion of cathepsin L demonstrated not only by RT-PCR data on MPM cell lines but also by microarray expression data from resected human patient tumors. CellVue Maroon intraperitoneal tumor signal was robust and durable indicating feasibility of intraperitoneal cell mass tracking of orthotopically-xenografted MPM. Optical imaging of extracellular cysteine protease activity is useful for tracking MPM tumor cell mass in vivo. Intraperitoneal MPM cell mass tracking of fluorescently labeled tumor is feasible.

Plasma corticosteroid profiling: brief opinion of its current status in clinical diagnosis and research.

Adrenal steroid biosynthesis comprises a series of dynamically interrelated, enzyme-catalyzed reactions in two separate compartments, the zona glomerulosa and the zona fasciculata/reticularis. End products (cortisol, aldosterone and androgens), together with a proportion of the intermediate compounds, appear in the circulation as a characteristic profile. Rare deficiencies of individual enzymes modify this profile in a recognizable way. Previous exhaustive profiling suggests that their diagnosis can now often be made on the basis of single-compound analyses with concomitant genetic tests. However, high-capacity liquid chromatography coupled with tandem mass spectrometry-based methods are facilitating profiling of large population samples, revealing that smaller differences in enzyme efficiency, indicated by potentially more complex corticosteroid patterns, may be related to clinical wellbeing in a much larger proportion of the population.

The validity and responsiveness of generic utility measures in rheumatoid arthritis: a review.

OBJECTIVE: Cost-utility analysis is increasingly important as healthcare providers aim to invest scarce resources in interventions offering the greatest health benefit. The ability to attach utility values to health states is essential, and is increasingly performed using generic scales. However, the evidence regarding the validity of generic utility scales in rheumatoid arthritis (RA) is unclear. We summarize and review evidence on the validity and comparative performance of generic utility scales in RA. METHODS: We searched the English-language medical literature for studies using utilities in RA between 1980 and mid-2006. Reports describing primary evidence of the validity or performance of a generic utility scale in RA were selected, summarized, and reviewed using the OMERACT filter. RESULTS: In total 923 articles were identified, of which 228 reported the use of utility scales in RA; 26 studies related to the validation or evidence of generic utility scales in RA, the EQ-5D, Health Utility Index-2 (HUI2) and HUI3, SF-6D, and Quality of Well-Being Scale. The EQ-5D, HUI2 and HUI3, and SF-6D all have consistent evidence of construct validity and responsiveness in RA, but each has limitations. CONCLUSION: The EQ-5D and HUI3 have been the most extensively studied instruments and show validity and responsiveness for use in RA, but both instruments have limitations. The SF-6D is relatively new and appears to have potential for use in milder RA, but needs further evaluation. More longitudinal head-to-head evaluation of measures is needed across the spectrum of RA disease severity to further investigate their comparative properties, and to seek consensus on the best utility measure for use in economic evaluation.

Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency.

The -344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11beta-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11beta-hydroxylase gene (CYP11B1) and arises through linkage disequilibrium between CYP11B1 and CYP11B2. The pattern of variation across the entire CYP11B locus was determined by sequencing 26 normotensive subjects stratified by and homozygous for the -344 and intron conversion variants. Eighty-three variants associated with -344 and intron conversion were identified. Haplotype analysis revealed 4 common haplotypes, accounting for 68% of chromosomes, confirming strong linkage disequilibrium across the region. Two novel CYP11B1 polymorphisms upstream of the coding region (-1889 G/T and -1859 A/G) were identified as contributing to the common haplotypes. Given the potential for such mutations to affect transcriptional regulation of CYP11B1, these were analyzed further. A total of 512 hypertensive subjects from the British Genetics of Hypertension Study population were genotyped for these polymorphisms. A significant association was identified between the -1889 polymorphism and urinary tetrahydrodeoxycortisol/total cortisol metabolite ratio, indicating reduced 11beta-hydroxylase efficiency. A similar pattern was observed for the -1859 polymorphism, but this did not achieve statistical significance. Functional studies in vitro using luciferase reporter gene constructs show that these polymorphisms significantly alter the transcriptional response of CYP11B1 to stimulation by adrenocorticotropic hormone or forskolin. This study strongly suggests that the impaired 11beta-hydroxylase efficiency associated previously with the CYP11B2 -344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1.

Aldosterone synthase gene variation and adrenocortical response to sodium status, angiotensin II and ACTH in normal male subjects.

OBJECTIVE: Aldosterone synthase, a key enzyme in the terminal steps of aldosterone synthesis, is encoded by the CYP11B2 gene. A polymorphism in the 5' coding region of this gene (-344 C/T) is associated with hypertension, particularly with elevation of the aldosterone to renin ratio. A second polymorphism (a conversion in intron 2 to resemble that of the neighbouring 11beta-hydroxylase (CYP11B1) gene) is found in close linkage dysequilibrium with the variant at -344 C/T. The mechanism by which these variants predispose to cardiovascular disease and the precise intermediate phenotype associated with them remains speculative. DESIGN: We performed a focused physiological study in normal volunteers stratified by CYP11B2 genotype. PATIENTS: Twenty-three subjects homozygous for the T allele and 21 homozygous for the C allele of the -344 C/T polymorphism of CYP11B2 were studied. MEASUREMENTS: Basal and angiotensin II stimulated plasma and 24-h urinary steroid excretion during low (60 mmol/day) and high (160 mmol/day) sodium intake and plasma steroids after ACTH stimulation were measured. RESULTS: No influence of polymorphic variation on basal or stimulated plasma cortisol or aldosterone or other plasma steroid concentrations during either dietary phase was seen. However, excretion of tetrahydro-11-deoxycortisol (the urinary metabolite of 11-deoxycortisol), which is the precursor of cortisol) was increased in TT subjects during sodium restriction, consistent with impairment of zona fasciculata 11beta-hydroxylation. CONCLUSIONS: We conclude that this polymorphism has no major influence on normal zona glomerulosa function but is associated with a change in 11beta-hydroxylation in the zona fasciculata. The mechanism remains uncertain, but alteration of 11-deoxycortisol levels without change in cortisol suggests altered efficiency of 11beta-hydroxylation. In the long term, this may lead to a minor but chronic increase in ACTH drive to the gland, which may have consequences for steroid synthesis and predispose to the risk of cardiovascular disease.