Specific extra chromosomes occur in a modal number dependent pattern in pediatric acute lymphoblastic leukemia

Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (>50 chromosomes) are considered to have a relatively good prognosis. The specific extra chromosomes are not random; extra copies of some chromosomes occur more frequently than those of others. We examined the extra chromosomes present in high hyperdiploid ALL to determine if there were a relation of the specific extra chromosomes and modal number (MN) and if the extra chromosomes present could differentiate high hyperdiploid from near-triploid and near-tetraploid cases. Karyotypes of 2,339 children with ALL and high hyperdiploidy at diagnosis showed a distinct nonrandom sequential pattern of gain for each chromosome as MN increased, with four groups of gain: chromosomes 21, X, 14, 6, 18, 4, 17, and 10 at MN 51-54; chromosomes 8, 5, 11, and 12 at MN 57-60; chromosomes 2, 3, 9,16, and 22 at MN 63-67; chromosomes 1, 7 13, 15, 19, and 20 at MN 68-79, and Y only at MN >or=80. Chromosomes gained at lower MN were retained as the MN increased. High hyperdiploid pediatric ALL results from a single abnormal mitotic division. Our results suggest that the abnormal mitosis involves specific chromosomes dependent on the number of chromosomes aberrantly distributed, raising provocative questions regarding the mitotic mechanism. The patterns of frequencies of tetrasomy of specific chromosomes differs from that of trisomies with the exception of chromosome 21, which is tetrasomic in a high frequency of cases at all MN. These results are consistent with different origins of high hyperdiploidy, near-trisomy, and near-tetrasomy.     

Description of a method to support public health information management: organizational network analysis

In this case study, we describe a method that has potential to provide systematic support for public health information management. Public health agencies depend on specialized information that travels throughout an organization via communication networks among employees. Interactions that occur within these networks are poorly understood and are generally unmanaged. We applied organizational network analysis, a method for studying communication networks, to assess the method's utility to support decision making for public health managers, and to determine what links existed between information use and agency processes. Data on communication links among a health department's staff was obtained via survey with a 93% response rate, and analyzed using Organizational Risk Analyzer (ORA) software. The findings described the structure of information flow in the department's communication networks. The analysis succeeded in providing insights into organizational processes which informed public health managers' strategies to address problems and to take advantage of network strengths.     

Gender-based wage differentials among registered dietitians

The debate on compensation equity is broad-based, addressing many organizational, personal, and outcome factors. Central to compensation philosophy is the issue of gender equity. Health care, like many other industries, remains fraught with gender inequity in compensation. This inequity is partially explained by choice of practice area. However, much remains unexplained. Health care is a female-dominated industry with most of the women working in the allied health professions (eg, nurses, dietitians, etc). Registered dietitians (RD) may experience wage discrimination, similar to registered nurses, but prior to the present study, the assumption was not tested. Using data from the first comprehensive study of RD compensation, we examined gender equity in total cash compensation to RDs. Data were collected on total cash compensation, and questions focused on career progression and work outcomes. For purposes of our study, we analyzed data on 5,477 full-time RDs. Ninety-six percent were women, the median age was 43, and median total cash compensation for RDs employed in the position for at least 1 year was $45,500.00. Women earned $45,285.00 and men earned $50,250.00. A median wage gap of $4,965.00 between women and men was observed. Variability in total cash compensation to women was best explained by size of budget, years of experience, work setting, and educational level. Variability for men was explained by size of budget, years of experience, educational level, and employer status. Conclusions suggest that given the wage discrimination that female RDs experience, work organizations should evaluate their pay plans to monitor pay equity. Factors that women can manage to receive compensation that is equal to that of the men include size of budgets they manage, years of experience in the field, employer status, work setting, and educational level attained. Findings are useful for career advisers, human resource specialists, compensation specialists, supervisors, RDs, and compensation researchers.     

Development and validation of an instrument to measure nurse educator perceived confidence in clinical teaching

Teaching nursing in clinical environments is considered complex and multi‐faceted. Little is known about the role of the clinical nurse educator, specifically the challenges related to transition from clinician, or in some cases, from newly‐graduated nurse to that of clinical nurse educator, as occurs in developing countries. Confidence in the clinical educator role has been associated with successful transition and the development of role competence. There is currently no valid and reliable instrument to measure clinical nurse educator confidence. This study was conducted to develop and psychometrically test an instrument to measure perceived confidence among clinical nurse educators. A multi‐phase, multi‐setting survey design was used. A total of 468 surveys were distributed, and 363 were returned. Data were analyzed using exploratory and confirmatory factor analyses. The instrument was successfully tested and modified in phase 1, and factorial validity was subsequently confirmed in phase 2. There was strong evidence of internal consistency, reliability, content, and convergent validity of the Clinical Nurse Educator Skill Acquisition Assessment instrument. The resulting instrument is applicable in similar contexts due to its rigorous development and validation process.     

Awareness of Dysphagia by Patients Following Stroke Predicts Swallowing Performance

Patients awareness of their disability after stroke represents an important aspect of functional recovery. Our study aimed to assess whether patient awareness of the clinical indicators of dysphagia, used routinely in clinical assessment, related to an appreciation of a swallowing problem and how this awareness influenced swallowing performance and outcome in dysphagic stroke patients. Seventy patients were studied 72 h post hemispheric stroke. Patients were screened for dysphagia by clinical assessment, followed by a timed water swallow test to examine swallowing performance. Patient awareness of dysphagia and its significance were determined by detailed question-based assessment. Medical records were examined at three months. Dysphagia was identified in 27 patients, 16 of whom had poor awareness of their dysphagic symptoms. Dysphagic patients with poor awareness drank water more quickly (5 ml/s vs. <1 ml/s, p = 0.03) and took larger volumes per swallow (10 ml vs. 6 ml, p = 0.04) than patients with good awareness. By comparison, neither patients with good awareness or poor awareness perceived they had a swallowing problem. Patients with poor awareness experienced numerically more complications at three months. Stroke patients with good awareness of the clinical indicators of dysphagia modify the way they drink by taking smaller volumes per swallow and drink more slowly than those with poor awareness. Dysphagic stroke patients, regardless of good or poor awareness of the clinical indicators of dysphagia, rarely perceive they have a swallowing problem. These findings may have implications for longer-term outcome, patient compliance, and treatment of dysphagia after stroke. This work was presented in abstract form at the Dysphagia Research Society meeting, Burlington, Vermont, 1999     

A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia‐inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis

Cell division plays an important role in animal tissue morphogenesis, which depends, critically, on the orientation of divisions. In isolated adherent cells, the orientation of mitotic spindles is sensitive to interphase cell shape and the direction of extrinsic mechanical forces. In epithelia, the relative importance of these two factors is challenging to assess. To do this, we used suspended monolayers devoid of ECM, where divisions become oriented following a stretch, allowing the regulation and function of epithelial division orientation in stress relaxation to be characterized. Using this system, we found that divisions align better with the long, interphase cell axis than with the monolayer stress axis. Nevertheless, because the application of stretch induces a global realignment of interphase long axes along the direction of extension, this is sufficient to bias the orientation of divisions in the direction of stretch. Each division redistributes the mother cell mass along the axis of division. Thus, the global bias in division orientation enables cells to act collectively to redistribute mass along the axis of stretch, helping to return the monolayer to its resting state. Further, this behavior could be quantitatively reproduced using a model designed to assess the impact of autonomous changes in mitotic cell mechanics within a stretched monolayer. In summary, the propensity of cells to divide along their long axis preserves epithelial homeostasis by facilitating both stress relaxation and isotropic growth without the need for cells to read or transduce mechanical signals.The morphogenesis of animal tissues results from coordinated changes in the shape, size, and packing of their constituent cells (1–3). These include autonomous cell shape changes (4), the response of cells to extrinsic stresses, and the effects of passive tissue deformation (5). When coordinated across a tissue, these active cellular processes and passive responses enable epithelial sheets to undergo shape changes while retaining relatively normal cell packing (6) and help return tissues to their resting state following a perturbation (7). Although the molecular basis of this cooperation is not understood, several studies have suggested a role for mechanical feedback (8, 9). Cell division has been suggested to participate in this feedback (10) because the rate of animal cell proliferation responds to changes in extrinsic forces in several experimental settings (9). Further, division makes an important contribution to tissue morphogenesis in animals (11, 12), accounts for much of the topological disorder observed in epithelia (13), can drive tissue elongation (10), and can facilitate the return to homeostatic cell packing following a deformation (2). Importantly, for each of these functions, the impact of cell division depends critically on the orientation of divisions.At the cellular level, relatively simple rules appear to govern division orientation. These rules were first explored by Hertwig (14), who showed that cells from early embryos divide along their long axis, and were further refined using microfabricated chambers (15). However, by following division orientation in cells adhering to micropatterned substrates, more recent studies identified additional roles for both the geometrical arrangement of integrin-mediated cell–substrate adhesions (16) and extrinsic mechanical forces in orienting divisions (17). Consistent with this, adhesive and mechanical cues have been reported to guide division orientation in vivo (18) and in epithelial monolayers in developing embryos (12, 19). Nevertheless, the respective roles of cell shape and mechanical tension in guiding division orientation in epithelia remain poorly defined, as does the contribution of oriented division to mechanical feedback control.Previously, we established suspended epithelial monolayers lacking ECM as a minimal model system in which to study epithelial biology. Because cell divisions in these monolayers become oriented following a stretch, we were able to explore the regulation and function of division orientation. We found that divisions align better with the long, interphase cell axis than with the monolayer stress axis. This phenomenon, combined with the alignment of cellular long axes induced by stretch, results in a global bias in the orientation of divisions in the direction of extension. Each division redistributes cell mass along the axis of division. Thus, when oriented across a monolayer, divisions act collectively to redistribute mass along the axis of stretch, helping to return the monolayer to its resting state. In summary, this analysis shows that the propensity of cells to divide along their long axis preserves epithelial homeostasis by facilitating both stress relaxation and isotropic growth without the need for cells to read or transduce mechanical signals.     

Decision curve analysis assessing the clinical benefit of NMP22 in the detection of bladder cancer: secondary analysis of a prospective trial

Study Type – Decision analysis (based on alternative scenarios) Level of Evidence 2b What's known on the subject? and What does the study add? Several studies have shown that abnormal levels of nuclear matrix protein 22 (NMP22) are associated with bladder cancer, and NMP22 has been approved by the FDA as a urinary biomarker for bladder cancer detection and surveillance. However, the benefit of adding NMP22 to the clinical care of patients remains unclear. Decision curve analysis incorporates the consequences of clinical decisions, such as an increased number of unnecessary cystoscopies or missed cancers.

OBJECTIVE

• ? To employ decision curve analysis to determine the impact of nuclear matrix protein 22 (NMP22) on clinical decision making in the detection of bladder cancer using data from a prospective trial.

PATIENTS AND METHODS

• ? The study included 1303 patients at risk for bladder cancer who underwent cystoscopy, urine cytology and measurement of urinary NMP22 levels.
• ? We constructed several prediction models to estimate risk of bladder cancer. The base model was generated using patient characteristics (age, gender, race, smoking and haematuria); cytology and NMP22 were added to the base model to determine effects on predictive accuracy.
• ? Clinical net benefit was calculated by summing the benefits and subtracting the harms and weighting these by the threshold probability at which a patient or clinician would opt for cystoscopy.

RESULTS

• ? In all, 72 patients were found to have bladder cancer (5.5%). In univariate analyses, NMP22 was the strongest predictor of bladder cancer presence (predictive accuracy 71.3%), followed by age (67.5%) and cytology (64.3%).
• ? In multivariable prediction models, NMP22 improved the predictive accuracy of the base model by 8.2% (area under the curve 70.2–78.4%) and of the base model plus cytology by 4.2% (area under the curve 75.9–80.1%).
• ? Decision curve analysis revealed that adding NMP22 to other models increased clinical benefit, particularly at higher threshold probabilities.

CONCLUSIONS

• ? NMP22 is a strong, independent predictor of bladder cancer.
• ? Addition of NMP22 improves the accuracy of standard predictors by a statistically and clinically significant margin.
• ? Decision curve analysis suggests that integration of NMP22 into clinical decision making helps avoid unnecessary cystoscopies, with minimal increased risk of missing a cancer.

     

Venous thromboembolism after radical prostatectomy: the effect of surgical caseload

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Several risk factors increase VTE after RP: advanced age, comorbidities such as cardiopulmonary disease, rheumatologic diseases, prior history of VTE, more advanced prostate cancer, and simultaneous pelvic lymph node dissection. To date, the effect of annual surgical caseload (ASC), an established determinant of various RP outcomes, has not been tested. A previous study showed in adjusted analyses that patients operated for colorectal cancer by very high ASC surgeons were 60% less likely to suffer a VTE than those operated by low ASC surgeons. Moreover, some authors hypothesized that laparoscopy may contribute to a higher risk of VTE, due to peritoneal insufflation, reverse Trendelenburg position and prolonged operative time. The VTE rates reported in the current population‐based study closely reflect those reported in institutional series. Moreover, we validated the practice‐makes‐perfect concept, since ASC was linked to VTE. We could not detect statistically significantly differences between minimally invasive radical prostatectomy (MIRP) patients and others. Our results indicate that lower rates of VTE should be expected in patients treated by high ASC surgeons. Our findings suggest that VTE‐specific processes of care need to be improved, with the intent of reaching the level recorded in patients treated by high ASC surgeons. Finally, MIRP seems to be no risk factor for VTE.

OBJECTIVE

• ? To examine the effect of annual surgical caseload (ASC) on the likelihood of venous thromboembolism (VTE) after radical prostatectomy (RP).

PATIENTS AND METHODS

• ? Between 1999 and 2008, 36 699 RPs were performed in the state of Florida. Logistic regression models predicting the likelihood of VTE were fitted.
• ? Covariates included year of surgery, age, race, baseline Charlson Comorbidity Index (CCI), lymph node dissection, ASC and surgical approach.

RESULTS

• ? The overall VTE rate was 0.3%. It was higher in patients operated within the low (0.4%) and intermediate (0.3%) ASC tertile than in those operated within the high‐ASC tertile (0.1%, P < 0.001).
• ? Mortality rate was 6.0% in patients with VTE vs 0.1% in others (P < 0.001). Median length of stay and median total hospital charges were 9 vs 3 days (P < 0.001) and $51 571 vs $24 943 (P < 0.001) in patients with VTE vs others, respectively.
• ? In multivariable analyses predicting VTE, patients operated on by low‐ASC surgeons were at higher risk of VTE than those operated on by high‐ASC surgeons (odds ratio [OR]= 3.78, P < 0.001). Additionally, black patients were more likely to experience a VTE (OR = 1.80, P= 0.023). Patients with CCI ≥ 1 were also more likely to experience a VTE than others (OR = 1.65, P= 0.016). Conversely, patients who had undergone minimally invasive radical prostatectomy were not more likely to experience a VTE than those who had undergone open RP (OR = 1.97, P= 0.086).

CONCLUSIONS

• ? RP by high‐ASC surgeons exerts a protective effect on the likelihood of VTE.
• ? Additionally, VTE is associated with higher mortality, prolonged length of stay and increased hospital charges.