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Introduction: Skeletal muscle density (SMD) measurements from imaging scans identify myosteatosis and could screen patients for geriatric assessment. We assessed SMD performance as a screening tool to identify older adults with cancer likely to be frail and who could benefit from in-depth assessment; we compared performance by sex and diabetes status., Materials and Methods: We analyzed patients in the Cancer & Aging Resilience Evaluation (CARE) Registry. Frailty and diabetes were captured using a patient-reported geriatric assessment (CARE tool). Frailty was defined using CARE frailty index (CARE-FI) based on principles of deficit accumulation. SMD was calculated from computed tomography scans (L3 vertebrae). Analyses were conducted by sex and diabetes status. Scatterplots and linear regression described crude associations between SMD and frailty score. Classification performance (frail vs. non-frail) was analyzed with (1) area under the receiver operating characteristic curves (AUC) and confidence intervals (CIs); and (2) sensitivity/specificity for sex-specific SMD quartile cut-offs (Q1, median, Q3). Performance was compared between patients with and without diabetes using differences and estimated CIs (2000 bootstrap replicates). We additionally calculated positive and negative likelihood ratios (LR+, LR-)., Results: The analytic cohort included 872 patients (39% female, median age 68 years, 27% with diabetes) with predominately stage III/IV gastrointestinal cancer; >60% planning to initiate first-line chemotherapy. SMD was negatively associated with frailty score; models were best fit in male patients with diabetes. AUC estimates for female (range: 0.58-0.62) and male (0.58-0.68) patients were low. Q3 cut-offs had high sensitivity (range: 0.76-0.89), but poor specificity (0.25-0.34). Diabetes did not impact estimates for female patients. Male patients with diabetes had greater sensitivity estimates compared to those without (sensitivity differences: 0.23 [0.07, 0.38], 0.08 [-0.07, 0.24], and 0.11 [0.00, 0.22] for Q1, median, Q3, respectively). LR estimates were most notable for male patients with diabetes (LR+ = 2.92, Q1 cut-off; LR- = 0.46, Q3 cut-off)., Discussion: Using SMD alone to screen older patients for geriatric assessment requires improvement. High-sensitivity cut-off points could miss 11-24% of patients with frailty, and many non-frail patients may be flagged. Screening with SMD is practical but work is needed to understand clinical andresource impacts of different cut-off points. Future research should evaluate performance with additional clinical data and in subgroups., Competing Interests: Declaration of Competing Interest ST received dissertation support through the Bristol Meyers Squibb Pre-Doctoral Fellowship in Worldwide Health Economics & Outcomes Research. TS receives investigator-initiated research funding and support as Principal Investigator [R01AG056479] from the National Institute on Aging; and as Co-Investigator [R01CA174453, R01HL118255, R01MD011680], National Institutes of Health. He also receives salary support as Director of Comparative Effectiveness Research (CER), NC TraCS Institute, UNC Clinical and Translational Science Award [UL1TR002489], the Center for Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Takeda, AbbVie, Boehringer Ingelheim), from pharmaceutical companies (Novo Nordisk), and from a generous contribution from Dr. Nancy A. Dreyer to the Department of Epidemiology, UNC-CH. Dr. Stürmer does not accept personal compensation of any kind from any pharmaceutical company. He owns stock in Novartis, Roche, and Novo Nordisk. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Emergency department and urgent care (ED/UC) visits for common conditions can be more expensive with less continuity than office care provided by primary care physicians., Methods: We used quality-improvement methods to enhance telephone triage for pediatric patients by adding additional "Phone First" services including: 1) enhanced office-hours telephone triage and advice with available same-day appointments, 2) follow-up calls to parents of children self-referred to an ED/UC, and 3) parent education to telephone the office for advice prior to seeking acute care. We hypothesized that enhanced office services would reduce ED/UC utilization and cost. We compared changes in ED/UC encounter rates between intervention and regional practices for 4 years (2014-2017) using general linear models, and evaluated balancing measures (after-hour phone calls, acute care phone calls, acute care visits, well child visits) for Medicaid-enrolled and commercially-insured children., Results: The study practices dramatically increased office-hours acute care phone triage and advice which correlated with 23.8% to 80.5% (P < 0.001) reductions in ED/UC rates for Medicaid-enrolled children. Office acute care visits decreased modestly. ED/UC visits did not decrease for children in the comparison region. In phone surveys, 94% of parents indicated satisfaction with the ED/UC follow-up call. The decrease in ED/UC visits resulted in an estimated annual cost of care savings for Medicaid-enrolled children in 2017 of $12.61 per member per month which projected to $169 million cost of care savings in Colorado and $6.8 billion in the United States., Conclusion: "Phone First" services in pediatric practices during office-hours reduced ED/UC encounters and cost of care for Medicaid-enrolled children., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Manual pupillary assessments are an integral part of the neurologic evaluation in critically ill patients. Automated pupillometry provides reliable, consistent, and accurate measurement of the light response. We established a computer interface that allows for direct download of pupillometer information to our hospital electronic medical record (EMR). Here, we report our single-center experience., Methods: An interface allowing direct download of pupillometer data to our EMR was developed. We then performed a prospective study using an electronic survey distributed to nurses that used pupillometers in 2015, 2018, and 2020 using a 5-point Likert-style format to evaluate the acceptance of this implementation., Results: In 2015, 22 nurses were surveyed, with 50% of the respondents citing lack of pupillometers and 41% citing the labor intensity associated with data entry as the reason for the reluctance to use the pupillometer. The number of nurse responses in 2018 increased to 123, with 78% of nurses finding that the direct download to hospital EMR improved the efficiency of their neurologic exams. In 2020, 108 nurses responded with similar responses to those in 2018. We added 3 additional questions regarding utility of the pupillometer during the COVID-19 pandemic. Fifty-eight percent of nurses were reassured of the neurologic exam when using the pupillometer in lieu of a full exam to limit infectious exposure., Conclusions: This is the first report of the implementation of a direct interface to download pupillometer data to the EMR. The positive effect on nursing workflow and documentation of pupillary findings is discussed., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Historical theories on development of professionalism are no longer sufficient in modern radiation therapy or radiography curricula with the focus moving from 'virtues-based professionalism' to 'professional identity formation'. Professional identity formation is a new concept that is described as a transformative journey from being a layperson to 'becoming' a professional. Knowledge, values, and behaviours are transformative and unique to each individual. The overall aim is to produce a consensus statement outlining evidence based programme initiatives to support healthcare students' professional identity formation., Methods: 'Think tank' methodology was used for individual and final combined group reflective tasks to enable the creation of an evidenced based consensus statement. Participants discussed their personal views and beliefs regarding the process of Professional Identity Formation for teaching, learning, assessment, and evaluation. Discussions were recorded, transcribed, and analysed using thematic analysis from an interpretivist perspective. 'Think Tank' participants were asked to attend masterclasses to gain a greater understanding of professional identity formation from leading experts before the final combined 'Think Tanks'., Results: Faculty and students across all Disciplines (N22) within the school of medicine attended the 'Think Tank' sessions., Discussion: During each student's transformative process of professional identity formation, healthcare educators need to create evidence based pedagogic opportunities to support them. It is no longer sufficient to leave to chance within a 'hidden' or 'informal' curriculum. Professional identity is more than a set of learned behaviours that are assessed within the clinical environment., Conclusion: The development of this consensus statement is an innovative educational strategy that will ultimately enhance the education of professionalism in the clinical environment for radiographers and radiation therapists. Through seeking an understanding of the educational needs of students and faculty, the multidisciplinary team were able to create a tailored approach to professional identity formation within the institution. This student-faculty partnership is unique and beneficial to all parties involved and is an effective method of seeking a shared understanding., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: To characterize reasons for hormonal contraceptive (HC) use in 1,455 African-American women, aged 23-35 years., Study Design: The community-based cohort members were recruited from the Detroit, Michigan area in 2010-2012. HC history was collected via telephone interview., Results: Seven percent reported HC use exclusively for non-contraceptive purposes, and 49% reported non-contraceptive reasons in addition to contraception. Non-contraceptive reasons were reported for all HC types, but were most common for combined oral contraceptives. Primary reasons were for irregular cycles, heavy bleeding, and pain., Conclusions: In this large cohort of Black women, HC use to treat menstrual problems was common., Implications: HCs were commonly used for both pregnancy prevention and management of menstrual symptoms, but some women used HCs exclusively for menstrual symptom relief. The importance for women of non-contraceptive reasons for HC use may not be adequately recognized, and published data on Black women's reasons for HC use remain limited., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Virtual learning environments (VLEs) were introduced to progress students from passive to active learners. Active learning promotes the critical thinking skills essential for the transfer/use of classroom-acquired knowledge into the clinical setting. A VLE forms an increasingly vital component of clinical skills development in a range of disciplines., Material and Methods: A randomized control trial was conducted with students randomly attending one of two teaching sessions about radiation therapy. Both sessions were identical except a VLE was used in the second talk with the first being solely didactic. Anonymous questionnaires were distributed. Two weeks after the talks, participants were required to complete the same knowledge questionnaire to determine retention. Mann-Whitney, means, standard deviations, and chi-squared tests were used according to data characteristics. Qualitative data (open-ended questions) were analysed thematically., Results: Virtual learning seemed to significantly improve students' satisfaction/engagement and recall. A total of 40 students attended the teaching sessions. The student group taught using the VLE had higher mean scores for retention than the didactic group; however, this was not statistically significant. Use of VLEs was associated with greater satisfaction/engagement than didactic information (P = .003). Students' learning styles seemed to have no effect on their satisfaction/engagement and ease of learning. Three key themes emerged from the qualitative data: (1) the visuals were good/helpful, (2) the talk was informative, and (3) more details/visuals were required., Discussion and Conclusion: The key findings from this study suggest that there is a role for VLEs in the teaching of students. There is a need for the introduction of advanced technology into health care education as virtual reality, such as Virtual Environment of Radiotherapy, has shown improvement in students' satisfaction, engagement, and recall. Whether VLEs qualify students better than conventional didactic teaching is still undetermined, but these first results are encouraging., (Copyright © 2019. Published by Elsevier Inc.)

Background: The use of nomograms for predicting clinical endpoints has been well documented. Nomograms provide an individualized prognosis and help clinicians determine the effectiveness of treatment for a given patient. Early identification of potential treatment failure or toxicity allows alternative approaches to be considered, reducing unnecessary treatment, morbidity, and cost. This review aims to evaluate clinical potential of nomogram use for the management of prostate cancer radiotherapy patients., Methods: PubMed, Embase, and Scopus were searched for literature published between 2006 and 2016. The reported correlation between measured and nomogram-predicted probabilities of biochemical control, disease progression, survival and toxicity was reviewed, through an analysis of concordance indexes and areas under the curves., Results: Sixteen studies were reviewed. Outcomes predicted by the nomogram were very close to outcomes measured (concordance index of 0.7 and above) in the majority. But a combination of under and overestimation of outcome was also reported. The predictive accuracy of nomograms was very variable, however, most nomograms had accuracy greater than chance, indicated by a concordance index higher than 0.5., Conclusion: Nomograms can be used as prognostic guides to aid clinical decision-making for prostate cancer patients until further research addresses the limitations presented in this review. Strict definitions of end points should be added to future models and perhaps models could be enhanced with the incorporation of genomic variables or tumor specific parameters., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To explore the impact of increasing interest and investment in patient-centered research, this study sought to describe patterns of comparative effectiveness research (CER) and patient-reported outcomes (PROs) in pharmacologic intervention studies published in widely read medical journals from 2004-2013., Design and Setting: We identified 2335 articles published in five widely read medical journals from 2004-2013 with ≥1 intervention meeting the US Food and Drug Administration's definitions for a drug, biologic, or vaccine. Six trained reviewers extracted characteristics from a 20% random sample of articles (468 studies). We calculated the proportion of studies with CER and PROs. Trends were summarized using locally-weighted means and 95% confidence intervals., Results: Of the 468 sampled studies, 30% used CER designs and 33% assessed PROs. The proportion of studies using CER designs did not meaningfully increase over the study period. However, we observed an increase in the use of PROs., Conclusions: Among pharmacological intervention studies published in widely read medical journals from 2004-2013, we identified no increase in CER. Randomized, placebo-controlled trials continue to be the dominant study design for assessing pharmacologic interventions. Increasing trends in PRO use may indicate greater acceptance of these outcomes as evidence for clinical benefit., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Although epidemiology has an indispensable role in serving public health, the relative emphasis of applications of epidemiology often tend toward individual-level medicine over public health in terms of resources and impact., Methods: We make distinctions between public health and medical applications of epidemiology to raise awareness among epidemiologists, many of whom came to the field with public health in mind. We discuss reasons for the overemphasis on medical epidemiology and suggest ways to counteract these incentives., Results: Public health epidemiology informs interventions that are applied to populations or that confer benefits beyond the individual, whereas medical epidemiology informs interventions that improve the health of treated individuals. Available resources, new biomedical technologies, and existing epidemiologic methods favor medical applications of epidemiology. Focus on public health impact and methods suited to answer public health questions can create better balance and promote population-level improvements in public health., Conclusions: By deliberately reflecting on research motivations and long-term goals, we hope the distinctions presented here will facilitate critical discussion and a greater consciousness of our potential impact on both individual and population-level health. Renewed intentions towards public health can help epidemiologists navigate potential projects and ultimately contribute to an epidemiology of consequence., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Expression of programmed death ligand 1 (PD-L1) in solid tumours has been shown to predict whether patients are likely to respond to anti-PD-L1 therapies. To estimate the therapeutic potential of PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression in a large collection of breast tumours., Patients and Methods: Correlations between CD274 (PD-L1) copy number, transcript and protein levels were evaluated in tumours from 418 patients recruited to the METABRIC genomic study. Immunohistochemistry was used to detect PD-L1 protein in breast tumours in tissue microarrays from 5763 patients recruited to the SEARCH population-based study (N = 4079) and the NEAT randomised, controlled trial (N = 1684)., Results: PD-L1 protein data was available for 3916 of the possible 5763 tumours from the SEARCH and NEAT studies. PD-L1 expression by immune cells was observed in 6% (235/3916) of tumours and expression by tumour cells was observed in just 1.7% (66/3916). PD-L1 was most frequently expressed in basal-like tumours. This was observed both where tumours were subtyped by combined copy number and expression profiling [39% (17/44) of IntClust 10 i.e. basal-like tumours were PD-L1 immune cell positive; P < 0.001] and where a surrogate IHC-based classifier was used [19% (56/302) of basal-like tumours were PD-L1 immune cell positive; P < 0.001]. Moreover, CD274 (PD-L1) amplification was observed in five tumours of which four were IntClust 10. Expression of PD-L1 by either tumour cells or infiltrating immune cells was positively correlated with infiltration by both cytotoxic and regulatory T cells (P < 0.001). There was a nominally significant association between PD-L1 and improved disease-specific survival (hazard ratio 0.53, 95% confidence interval 0.26-1.07; P = 0.08) in ER-negative disease., Conclusions: Expression of PD-L1 is rare in breast cancer, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. PD-L1 inhibition may benefit the 19% of patients with basal-like tumours in which the protein is expressed., Neat Clinicaltrialsgov: NCT00003577., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Since Doll published the first PAF in 1951, it has been a mainstay. Confusion in terminology abounds with regard to these measures. The ability to estimate all of them in case-control studies as well as in cohort studies is not widely appreciated., Methods: This article reviews and comments on the historical development of the population attributable fraction (PAF), the exposed attributable fraction (EAF), the rate difference (ID), the population rate (or incidence) difference (PID), and the caseload difference (CD)., Results: The desire for PAFs to sum to no more than 100% and the interpretation of the complement of a PAF as the proportion of a rate that can be attributed to other causes are shown to stem from the same problem: a failure to recognize the pervasiveness of shared etiologic responsibility among causes. A lack of appreciation that "expected" numbers of cases and deaths are not actually the numbers to be expected when an exposure or intervention appreciably affects person-time denominators for rates, as in the case of smoking and nonnormal body mass, makes many CD estimates inflated. A movement may be gaining momentum to shift away from assuming, often unrealistically, the complete elimination of harmful exposures and toward estimating the effects of realistic interventions. This movement could culminate in a merger of the academic concept of transportability with the applied discipline of risk assessment., Conclusions: A suggestion is offered to pay more attention to absolute measures such as the rate difference, the population rate difference, and the CD, when the latter can be validly estimated and less attention to proportional measures such as the EAF and PAF., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date., Patients and Methods: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival., Results: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1)., Conclusions: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Pertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer., Patients and Methods: Patients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms., Results: A total of 149 patients received either chemotherapy with pertuzumab (arm A, n=74) or chemotherapy alone (arm B, n=75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone., Conclusions: The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.

Background: Sagopilone, the first fully synthetic epothilone, has shown promising preclinical activity in tumour models. This open-label randomised phase II study investigated two infusion schedules of sagopilone in women with ovarian cancer., Patients and Methods: Women with ovarian cancer recurring within 6 months of end of last platinum-containing treatment received sagopilone 16 mg/m(2) as a 3- or 0.5-h i.v. infusion every 21 days for up to 6 weeks., Results: Sixty-three patients received sagopilone as a 3-h (n=38) or 0.5-h (n=25) infusion. There were nine confirmed tumour responses [by modified RECIST (n=8) and by Gynecologic Cancer Intergroup CA-125 criteria (n=1)] in 57 patients assessable for efficacy overall [three (13%) with 0.5-h and six (18%) with 3-h infusions]. The 0.5-h arm was closed when it failed to meet its target efficacy. Main drug-related adverse events were peripheral sensory neuropathy (73%; 16% grade 3), nausea (37%; 2% grade 3), fatigue (35%; 3% grade 3) and arthralgia (30%; 5% grade 3). Overall incidence of peripheral sensory neuropathy was similar in both treatment arms, with no grade 4 neuropathy events. No acute allergic infusion reactions were observed., Conclusion: Sagopilone is effective, with balanced tolerability, in patients with recurrent platinum-resistant ovarian cancer.

Purpose: To assess the impact of geographic health services factors on the timely diagnosis of autism., Methods: Children residing in central North Carolina were identified by records-based surveillance as meeting a standardized case definition for autism. Individual-level geographic access to health services was measured by the density of providers likely to diagnose autism, distance to early intervention service agencies and medical schools, and residence within a Health Professional Shortage Area. We compared the presence of an autism diagnosis by age 8 and timing of first diagnosis across level of accessibility, using Poisson regression and Cox proportional hazards regression and adjusting for family and neighborhood characteristics., Results: Of 206 identified cases, 23% had no previous documented diagnosis of autism. Most adjusted estimates had confidence limits including the null. Point estimates across analyses suggested that younger age at diagnosis was found for areas with many neurologists and psychiatrists and proximal to a medical school but not areas with many primary care physicians or proximal to early intervention services agencies., Conclusions: Further study of the distribution of medical specialists diagnosing autism may suggest interventions to promote the early diagnosis, and initiation of targeted services, for children with autism spectrum disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To illustrate basic issues that have to be taken into account when study results are presented by means of the number needed to treat (NNT)., Study Design and Setting: This article presents an overview of common problems related to the NNT with corresponding explanations., Results: Without stating the direction of the effect, the alternative treatment, the treatment period, and the follow-up period, information in terms of NNTs is uninterpretable. The naive use of person-time data for the calculation of NNTs is frequently inappropriate. Rounding NNTs to the next upward integer may obscure differences among therapies., Conclusions: The basic information about which treatments are compared, the treatment period, the follow-up period, and the direction of the effect should be given when study results are presented in terms of NNTs. Adequate methods should be used for point and interval estimation of NNTs. Unnecessary rounding of NNTs should be avoided. In more complicated situations of confounding or varying follow-up times, the use of more sophisticated methods is required with increasing potential for misinterpretation., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration., Methods: In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493., Findings: All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272)., Interpretation: This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy., Funding: Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.

In this work multiple linear regression (MLR) and artificial neural network (ANN) were used to predict the gradient retention times of diverse sets of organic compounds in four separate data sets. Descriptors which were used as inputs of these models are five linear free energy relationship (LFER) solute parameters including E, S, A, B and V. In the first step eight separate multiple linear regression and artificial neural network models were used to predict the gradient retention time for each gradient condition separately. Results obtained in this step reveal that there are significant relations between LFER parameters and gradient retention times of solutes in liquid chromatography. Then MLR and ANN were applied to develop more general models in which several different gradient elution conditions were used. The performances of these models are compared in terms of their standard errors and also correlation analysis. The results obtained reveal that although there are no significant differences between ANN and MLR in separate modeling of the gradient retention times, ANN has a significant superiority over MLR models in developing the general models for various gradient elution conditions. The results of sensitivity analysis on ANN models indicate that the order of importance for input terms in separate ANN models is Vx>B>S>E>A and in the case of combined ANN model is Vx>B>tg>S>E>A, which are in agreement with the order of percentage of significance terms that obtained from the MLR models.

Purpose: To estimate the efficacy of third-generation (3G) chemotherapy agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan) on response and survival in stage IIIB/IV non-small cell lung cancer (NSCLC)., Methods: A meta-analysis was performed using trials identified through MEDLINE. Results on tumor response and survival were collected from randomized trials comparing 3G monotherapy versus best supportive care (BSC), 3G monotherapy versus second-generation (2G) platinum-based regimens, and 3G platinum-based regimens versus 2G platinum-based regimens., Results: Of the 2480 citations screened, 20 randomized controlled trials fulfilled the inclusion and exclusion criteria, and 19 trials were used in the analyses. The data from two, three-arm trials were used in two different comparisons. Five trials (n = 1029 patients) compared 3G monotherapy with BSC. The summary risk difference (RD) for 1-year survival favored 3G agents by 7% (95% confidence interval [CI]: 2%, 12%). Four trials (n = 871 patients) compared treatment with 3G monotherapy versus 2G platinum-based regimens. The response RD was -6% (95% CI: -11%, 0%), and the 1-year survival rate RD was 3% (95% CI: -3%, 10%), suggesting that despite a slightly higher response rate for 2G platinum-based regimens relative to 3G monotherapy, there is equivalency in survival. Twelve trials (n = 3995) compared 3G versus 2G platinum-based regimens. The RD for response was 12% (95% CI: 10%, 15%). A RD for 1-year was not calculated, because of heterogeneity among the trials. A subset analysis of 3G versus 2G platinum-based doublets revealed a 1-year survival-rate RD of 6% (95% CI: 2%, 10%), favoring 3G platinum-based regimens without evidence of heterogeneity., Conclusions: 3G agents have been a significant advance in the treatment of NSCLC.

Primary cilia are highly conserved organelles found on almost all eukaryotic cells. Tg737(orpk) (orpk) mice carry a hypomorphic mutation in the Tg737 gene resulting in the loss of polaris, a protein essential for ciliogenesis. Orpk mice have an array of skeletal patterning defects and show stunted growth after birth, suggesting defects in appositional and endochondral development. This study investigated the association between orpk tibial long bone growth and chondrocyte primary cilia expression using histomorphometric and immunohistochemical analysis. Wild-type chondrocytes throughout the developing epiphysis and growth plate expressed primary cilia, which showed a specific orientation away from the articular surface in the first 7-10 cell layers. In orpk mice, primary cilia were identified on very few cells and were significantly shorter. Orpk chondrocytes also showed significant increases in cytoplasmic tubulin, a likely result of failed ciliary assembly. The growth plates of orpk mice were significantly smaller in length and width, with marked changes in cellular organization in the presumptive articular cartilage, proliferative and hypertrophic zones. Cell density at the articular surface and in the hypertrophic zone was significantly altered, suggesting defects in both appositional and endochondral growth. In addition, orpk hypertrophic chondrocytes showed re-organization of the F-actin network into stress fibres and failed to fully undergo hypertrophy, while there was a marked reduction in type X collagen sequestration. These data suggest that failure to form a functional primary cilium affects chondrocyte differentiation and results in delayed chondrocyte hypertrophy within the orpk growth plate.

Purpose: In case-control studies, when odds ratios estimate rate ratios or risk ratios, trends in odds ratios can reflect trends in incidence in the underlying population., Methods and Results: In this report, we use an empirical example and hypothetical data to compare two methods ("common referent" and "shifting referent") for calculating odds ratios from case-control data across multiple exposure variables. With common referent methods, a single independent variable is constructed from the joint distribution of all exposure variables. With shifting referent methods, each stratum-specific trend has its own referent., Conclusions: Using examples involving a single ordinal "trend" variable and a dichotomous "stratification" variable, we show that common referent odds ratios will reflect the pattern of incidence in the underlying population, whereas odds ratios calculated using shifting referent methods will not.

Objective: To understand how Helicobacter pylori infection is acquired and the role that herpes simplex virus type 1 (HSV-1) may have, we determined whether an association between HSV and H pylori exists at the individual level and for what reason., Study Design: Data were collected from 1,090 participants aged 12-19 years during phase 1 (1988-1991) of the NHANES III. Generalized estimating equations were used to estimate prevalence ratios (PR)., Results: The crude overall PR and 95% CI for H pylori seropositivity comparing HSV+ to HSV- individuals was 2.20 (1.69-2.85). In large urban households the PR adjusted for poverty level and race/ethnicity was twice that in small nonurban households (2.27 versus 1.15, respectively)., Conclusions: Overall, HSV-1 seropositivity is associated with a higher H pylori seroprevalence. The negligible association found in some strata suggests that shared environmental factors or routes of transmission rather than biologic reasons may be primarily responsible for this association.

The solvation parameter model is used to characterize the retention properties of a 3-aminopropylsiloxane-bonded (Alltima amino), three 3-cyanopropylsiloxane-bonded (Ultrasphere CN, Ultremex-CN and Zorbax SB-CN), a spacer bonded propanediol (LiChrospher DIOL) and a multifunctional macrocyclic glycopeptide (Chirobiotic T) silica-based stationary phases with mobile phases containing 10 and 20% (v/v) methanol-water. The low retention on the polar chemically bonded stationary phases compared with alkylsiloxane-bonded silica stationary phases arises from the higher cohesion of the polar chemically bonded phases and an unfavorable phase ratio. The solvated polar chemically bonded stationary phases are considerably more hydrogen-bond acidic and dipolar/polarizable than solvated alkylsiloxane-bonded silica stationary phases. Selectivity differences are not as great among the polar chemically bonded stationary phases as they are between the polar chemically bonded phases and alkylsiloxane-bonded silica stationary phases.

This paper describes temporal changes in the metabolism and distribution of newly synthesized aggrecan and the organization of the extracellular matrix when explant cultures of articular cartilage maintained in the presence of fetal calf serum were exposed to retinoic acid for varying periods of time. Explant cultures of articular cartilage were incubated with radiolabeled sulfate prior to exposure to retinoic acid. The radiolabeled and chemical aggrecan present in the tissue and appearing in the culture medium was studied kinetically. Changes in the localization of radiolabeled aggrecan within the extracellular matrix were monitored by autoradiography in relation to type VI collagen distribution in the extracellular matrix. In control cultures where tissue levels of aggrecan remain constant the newly synthesized aggrecan remained closely associated with the territorial matrix surrounding the chondrocytes. Exposure of cultures to retinoic acid for the duration of the experiment, resulted in the extensive loss of aggrecan from the tissue and the redistribution of the remaining radiolabeled aggrecan from the chondron and territorial matrix into the inter-territorial matrix. These changes preceded alterations in the organization of type VI collagen in the extracellular matrix that involved the remodeling of the chondron and the appearance of type VI collagen in the inter-territorial matrix; there was also evidence of chondrocyte proliferation and clustering. In cartilage explant cultures exposed to retinoic acid for 24 h there was no loss of aggrecan from the matrix but there was an extensive redistribution of the radiolabeled aggrecan into the inter-territorial matrix. This work shows that maintenance of the structure and organization of the extracellular matrix that comprises the chondron and pericellular microenvironment of chondrocytes in articular cartilage is important for the regulation of the distribution of newly synthesized aggrecan monomers within the tissue.

The solvation parameter model is used to study the influence of composition and temperature on the selectivity of two poly(siloxane) stationary phases used for open-tubular capillary column gas chromatography. The poly(methyltrifluoropropyldimethylsiloxane) stationary phase, DB-200, has low cohesion, intermediate dipolarity/polarizability, low hydrogen-bond basicity, no hydrogen-bond acidity, and repulsive electron lone pair interactions. The DB-VRX stationary phase has low cohesion, low dipolarity/polarizability, low hydrogen-bond basicity and no hydrogen-bond acidity and no capacity for electron lone pair interactions. The selectivity of the two stationary phases is complementary to those in a database of 11 stationary phase chemistries determined under the same experimental conditions.

The solvation parameter model is used to study the influence of temperature and composition on the selectivity of nine poly(siloxane) and two poly(ethylene glycol) stationary phase chemistries for open-tubular column gas chromatography. A database of system constants for the temperature range 60-140 degrees C was constructed from literature values with additional results determined for HP-50+, DB-210, DB-1701, DB-225 and SP-2340 columns. The general contribution of monomer composition (methyl, phenyl, cyanopropyl, and trifluoropropyl substituents) on the capacity of poly(siloxane) stationary phases for dispersion, electron lone pair, dipole-type and hydrogen-bond interactions is described. The selectivity coverage of the open-tubular column stationary phases is compared with a larger database for packed column stationary phases at a reference temperature of 120 degrees C. The open-tubular column stationary phases provide reasonable coverage of the range of dipole-type and hydrogen-bond base interactions for non-ionic packed column stationary phases. Deficiencies are noted in the coverage of electron lone pair interactions. None of the open-tubular column stationary phases are hydrogen-bond acids. The system constants are shown to change approximately linearly with temperature over the range 60-140 degrees C. The intercepts and slopes of these plots are used to discuss the influence of temperature on stationary phase selectivity.

Purpose: To examine the activity and safety of two sequentially scheduled chemotherapy regimens comprising four cycles of paclitaxel (pctx) 200 mg/m2/3 hours then four cycles ofcisplatin (cisDDP) 100 mg/m2, and vice versa, in patients with previously untreated advanced ovarian cancer., Patients and Methods: Between January 1994 and February 1996, we recruited 30 patients to the pctx-then-cisDDP regimen and 29 to cisDDP-then-pctx, in parallel phase II trials., Results: Both regimens were predictably active with responses seen in 22 of 30 patients (OR 74%; CR 27%, PR 47%) treated with pctx-then-cisDDP, as against 13 of 21 patients (OR 62%; CR 38%, PR 24%) treated with cisDDP-then-pctx. The OR rate to four cycles of pctx (induction) was 43%, with 27% disease progression; the OR to four cycles of cisDDP (induction) was 57%, with 5% progression. However, progression rates across both induction and consolidation phases were 16% (pctx-then-cisDDP) and 29% (cisDDP-then-pctx). Both regimens were unacceptably neurotoxic. II patients suffering grade 3 sensory neurotoxicity (5 on pctx-then-cisDDP, 6 on cisDDP-then-pctx) and 20 having grade 3 deafness (9 on pctx- then-cisDDP, 11 on cisDDP-then-pctx)., Conclusion: The activity of these sequential regimens justifies their further development using the less neurotoxic platinum analogue carboplatin, perhaps combining paclitaxel with other platinum non-cross resistant drugs.

The solvation parameter model is used to study differences in selectivity for poly(ethylene glycol) stationary phases for packed column (Carbowax 20M) and fused-silica, open-tubular column (HP-20M, AT-Wax, HP-INNOWax and DB-FFAP) gas chromatography. All phases are dipolar, strongly hydrogen-bond basic with no hydrogen-bond acidity and of moderate cohesion. No two phases are exactly alike, however, and selectivity differences identified with cavity formation and dispersion interactions, n- and pi-electron pair interactions, dipole-type interactions and hydrogen-bond interactions are quantified by differences in the system constants at a fixed temperature where retention occurs solely by gas-liquid partitioning. The system constants vary linearly with temperature over the range 60-140 degrees C (except for n- and pi-electron pair interactions which are temperature invariant) facilitating a general comparison of the importance of temperature on selectivity differences for compared phases. From a mechanistic point of view it is demonstrated that selectivity differences can result from chemical differences between the poly(ethylene glycol) stationary phases and from differences in the relative contribution of interfacial adsorption to the retention mechanism. The latter depends on both system properties and solute characteristics.

Background: Animal and in vitro studies have provided evidence of an anticarcinogenic effect of active ingredients in garlic., Objective: The objective was to conduct meta-analyses of the epidemiologic literature on the association between garlic consumption and risk of stomach, colon, head and neck, lung, breast, and prostate cancers., Design: Meta-analyses were conducted for all cancers mutually and separately for colorectal and stomach cancers in relation to consumption of exclusively raw garlic, cooked garlic, or both (RC garlic). Eighteen studies reported a relative risk estimate for RC garlic consumption and cancer risk., Results: In the meta-analyses of colorectal and stomach cancer, the reference categories ranged from no consumption to consumption of 3.5 g/wk, whereas the highest categories ranged from any consumption to >28.8 g/wk. The average difference between the highest and lowest categories was 16 g/wk. The random-effects relative risk (RR) estimate of colorectal cancer and RC garlic consumption, excluding garlic supplements, was 0.69 (95% CI: 0.55, 0.89). For stomach cancer, the random-effects RR estimate was 0.53 (95% CI: 0.31, 0.92). The heterogeneity among studies for the latter outcome (P: = 0.0002) indicates the questionableness of the generalizability of this summary estimate. An indication of publication bias for all cancers combined is evident from a funnel plot of RC garlic consumption and cancer risk and from the results of the Begg and Mazumdar test (P: = 0.049)., Conclusions: High intake of RC garlic may be associated with a protective effect against stomach and colorectal cancers. Heterogeneity of effect estimates, differences in dose estimation, publication bias, and possible alternative hypotheses (eg, confounding by total vegetable consumption) preclude sole reliance on summary effect estimates.

The authors provide a personal perspective of method development in thin-layer chromatography for the novice and more experienced chromatographer alike. No attempt has been made at a comprehensive survey of the literature. Instead we provide an overview with insights into a smaller number of approaches that the authors have found useful in their own work and indicate the factors responsible for the variation in retention and their control. The main topics covered are the relationship between sorbent chemistry and retention, the selection of primary solvents for mobile phase optimization and mobile phase optimization using the PRISMA and solvation parameter models.

Background: Phase II studies have shown primary (neo-adjuvant) chemotherapy with bleomycin, ifosfamide and cisplatin (BIP) is active against inoperable cervical cancer. We present here results of a randomised phase III multicentre trial comparing radical radiotherapy with neo-adjuvant BIP chemotherapy followed by radical radiotherapy in patients with inoperable cervical cancer, designed to discover whether this combination might improve survival., Patients and Methods: Patients with inoperable cervical carcinoma were randomised to pelvic radiotherapy alone [RT] or two to three cycles of bleomycin 30 units/24-hour infusion, ifosfamide 5 g/m2/24 hours, and cisplatin 50 mg/m2) chemotherapy followed by pelvic radiotherapy (BIP + RT). Randomisation was stratified by stage and radiotherapy centre., Results: One hundred seventy-two eligible women were randomised into this trial; eighty-six to RT and eighty-six to BIP + RT. A total of 190 cycles of chemotherapy were given. Median follow-up for the 47 patients still alive is 9 years with a minimum follow-up of 3 years. Complete or partial response occurred in 51 of 86 (59%) of those randomised to RT and 60 of 86 (69%) of those randomised to BIP + RT. The difference between response rates does not reach statistical significance (chi2 = 2.06, P = 0.15). Median survival is two years with an actuarial survival at five years of 32% (95% confidence interval (95% CI): 25%-39%). There is no significant difference between the treatment groups (chi2log-rank = 0.11, P = 0.74)., Conclusions: This study does not show any survival benefit from the use of neo-adjuvant BIP chemotherapy in advanced cervical cancer.

The kinetic and retention properties of solid-phase extraction devices are reviewed from the perspective of method development strategies. Models based on frontal analysis are used to correct retention properties of solid-phase extraction devices to account for the fact that too few theoretical plates are provided for retention to be independent of kinetic factors. The available pressure drop for the sampling device largely dictates the choice of useful particle sizes and maximum bed length. The use of octanol--water partition coefficients and extrapolated values of the retention factor obtained by liquid chromatography are poor empirical models for the estimation of breakthrough volumes with water as the sample solvent. The solvation parameter model provides an adequate description of sorbent retention for the estimation of breakthrough volumes, rinse solvent volume and composition, and elution solvent volume and composition. Combining the frontal analysis and solvation parameter models offers a comprehensive approach to computer-aided method development in solid-phase extraction. This is the first step in the development of a structure-driven approach to method development in solid-phase extraction that should be more reliable and less tedious than traditional trial and error approaches.