Search

PURPOSE This study compared real-world end points extracted from the Cancer Analysis System (CAS), a national cancer registry with linkage to national mortality and other health care databases in England, with those from diverse US oncology data sources, including electronic health care records, insurance claims, unstructured medical charts, or a combination, that participated in the Friends of Cancer Research Real-World Evidence Pilot Project 1.0. Consistency between data sets and between real-world overall survival (rwOS) was assessed in patients with immunotherapy-treated advanced non–small-cell lung cancer (aNSCLC). PATIENTS AND METHODS Patients with aNSCLC, diagnosed between January 2013 and December 2017, who initiated treatment with approved programmed death ligand-1 (PD-[L]1) inhibitors until March 2018 were included. Real-world end points, including rwOS and real-world time to treatment discontinuation (rwTTD), were assessed using Kaplan-Meier analysis. A synthetic data set, Simulacrum, on the basis of conditional random sampling of the CAS data was used to develop and refine analysis scripts while protecting patient privacy. RESULTS Characteristics (age, sex, and histology) of the 2,035 patients with immunotherapy-treated aNSCLC included in the CAS study were broadly comparable with US data sets. In CAS, a higher proportion (46.7%) of patients received a PD-(L)1 inhibitor in the first line than in US data sets (18%-30%). Median rwOS (11.4 months; 95% CI, 10.4 to 12.7) and rwTTD (4.9 months; 95% CI, 4.7 to 5.1) were within the range of US-based data sets (rwOS, 8.6-13.5 months; rwTTD, 3.2-7.0 months). CONCLUSION The CAS findings were consistent with those from US-based oncology data sets. Such consistency is important for regulatory decision making. Differences observed between data sets may be explained by variation in health care settings, such as the timing of PD-(L)1 approval and reimbursement, and data capture.

Background Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications. Materials and methods Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values. Results Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples. Conclusions Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.

In prior work, Friends of Cancer Research convened multiple data partners to establish standardized definitions for oncology real-world end points derived from electronic health records (EHRs) and claims data. Here, we assessed the performance of real-world overall survival (rwOS) from data sets sourced from EHRs by evaluating the ability of the end point to reflect expected differences from a previous randomized controlled trial across five data sources, after applying inclusion/exclusion criteria. The KEYNOTE-189 clinical trial protocol of platinum doublet chemotherapy (chemotherapy) vs. programmed cell death protein 1 (PD-1) in combination with platinum doublet chemotherapy (PD-1 combination) in first-line nonsquamous metastatic non-small cell lung cancer guided retrospective cohort selection. The Kaplan-Meier product limit estimator was used to calculate 12-month rwOS with 95% confidence intervals (CIs) in each data source. Cox proportional hazards models estimated hazard ratios (HRs) and associated 95% CIs, controlled for prognostic factors. Once the inclusion/exclusion criteria were applied, the five resulting data sets included 155 to 1,501 patients in the chemotherapy cohort and 36 to 405 patients in the PD-1 combination cohort. Twelve-month rwOS ranged from 45% to 58% in the chemotherapy cohort and 44% to 68% in the PD-1 combination cohort. The adjusted HR for death ranged from 0.80 (95% CI: 0.69, 0.93) to 1.15 (95% CI: 0.71, 1.85), controlling for age, gender, performance status, and smoking status. This study yielded insights regarding data capture, including ability of real-world data to precisely identify patient populations and the impact of criteria on end points. Sensitivity analyses could elucidate data set-specific factors that drive results.

PURPOSE Immune checkpoint inhibition (ICI) therapy represents one of the great advances in the field of oncology, highlighted by the Nobel Prize in 2018. Multiple predictive biomarkers for ICI benefit have been proposed. These include assessment of programmed death ligand-1 expression by immunohistochemistry, and determination of mutational genotype (microsatellite instability or mismatch repair deficiency or tumor mutational burden) as a reflection of neoantigen expression. However, deployment of these assays has been challenging for oncologists and pathologists alike. METHODS To address these issues, ASCO and the College of American Pathologists convened a virtual Predictive Factor Summit from September 14 to 15, 2021. Representatives from the academic community, US Food and Drug Administration, Centers for Medicare and Medicaid Services, National Institutes of Health, health insurance organizations, pharmaceutical companies, in vitro diagnostics manufacturers, and patient advocate organizations presented state-of-the-art predictive factors for ICI, associated problems, and possible solutions. RESULTS The Summit provided an overview of the challenges and opportunities for improvement in assay execution, interpretation, and clinical applications of programmed death ligand-1, microsatellite instability-high or mismatch repair deficient, and tumor mutational burden-high for ICI therapies, as well as issues related to regulation, reimbursement, and next-generation ICI biomarker development. CONCLUSION The Summit concluded with a plan to generate a joint ASCO/College of American Pathologists strategy for consideration of future research in each of these areas to improve tumor biomarker tests for ICI therapy.

Background Households represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under‐diagnosis and treatment delays. This study aimed to assess the feasibility of an at‐home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery. Methods We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle‐area households with children during the 2019‐2020 influenza season using pre‐positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid‐nasal swabs and used a rapid home‐based influenza immunoassay. An additional home‐collected swab was returned to a laboratory for confirmatory influenza RT‐PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age‐eligible participants, following a telehealth encounter. Results 124 households comprising 481 individuals self‐monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which eight were true positives confirmed by RT‐PCR. The sensitivity and specificity of the home influenza test were 72.7% and 96.2%, respectively. There were eight home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription and all within 48 hours of symptom onset. Conclusions We demonstrate the feasibility of self‐testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics.

Purpose: Restrictive clinical trial eligibility criteria (EC) limit the number of patients who can enroll and potentially benefit from protocol-driven, investigational treatment plans and reduce the generalizability of trial results to the broader population. Following publication of expert stakeholder recommendations for broadening EC in 2017, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) convened working groups to produce additional recommendations and analyze the potential impact on clinical trials using real-world data. Experimental Design: Multistakeholder working groups were appointed by an ASCO-Friends leadership group to propose recommendations for more inclusive EC related to: washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status. Results: The four working groups, ASCO Board of Directors, and Friends leadership support the recommendations included in this statement to modernize EC related to washout periods, concomitant medications, prior therapies, laboratory references ranges and test intervals, and performance status to make trial populations more inclusive and representative of cancer patient populations. Conclusions: Implementation of the recommendations is intended to result in greater ease of determining patient eligibility. Increased opportunities for patient participation in research will help address longstanding underrepresentation of certain groups in clinical trials and produce evidence that is more informative for a broader patient population. More patients eligible will also likely speed clinical trial accrual. See related commentary by Giantonio, p. 2369

Background Tumor mutational burden (TMB) is an emerging biomarker used to identify patients who are more likely to benefit from immuno-oncology therapy. Aside from various unsettled technical aspects, biological variables such as tumor cell content and intratumor heterogeneity may play an important role in determining TMB. Methods TMB estimates were determined applying the TruSight Oncology 500 targeted sequencing panel. Spatial and temporal heterogeneity was analyzed by multiregion sequencing (two to six samples) of 24 pulmonary adenocarcinomas and by sequencing a set of matched primary tumors, locoregional lymph node metastases, and distant metastases in five patients. Results On average, a coding region of 1.28 Mbp was covered with a mean read depth of 609x. Manual validation of the mutation-calls confirmed a good performance, but revealed noticeable misclassification during germline filtering. Different regions within a tumor showed considerable spatial TMB variance in 30% (7 of 24) of the cases (maximum difference, 14.13 mut/Mbp). Lymph node–derived TMB was significantly lower (p = 0.016). In 13 cases, distinct mutational profiles were exclusive to different regions of a tumor, leading to higher values for simulated aggregated TMB. Combined, intratumor heterogeneity and the aggregated TMB could result in divergent TMB designation in 17% of the analyzed patients. TMB variation between primary tumor and distant metastases existed but was not profound. Conclusions Our data show that, in addition to technical aspects such as germline filtering, the tumor content and spatially divergent mutational profiles within a tumor are relevant factors influencing TMB estimation, revealing limitations of single-sample–based TMB estimations in a clinical context.

Glaucoma is one of the leading causes of blindness, and there is an ongoing need for new therapies. Recent studies indicate that cell transplantation using Müller glia may be beneficial, but there is a need for novel sources of cells to provide therapeutic benefit. In this study, we have isolated Müller glia from retinal organoids formed by human induced pluripotent stem cells (hiPSCs) in vitro and have shown their ability to partially restore visual function in rats depleted of retinal ganglion cells by NMDA. Based on the present results, we suggest that Müller glia derived from retinal organoids formed by hiPSC may provide an attractive source of cells for human retinal therapies, to prevent and treat vision loss caused by retinal degenerative conditions. Stem Cells Translational Medicine 2019;8:775–784

Characterization of tumors utilizing next‐generation sequencing methods, including assessment of the number of somatic mutations (tumor mutational burden [TMB]), is currently at the forefront of the field of personalized medicine. Recent clinical studies have associated high TMB with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. However, variability in current methods for TMB estimation and reporting is evident, demonstrating a need for standardization and harmonization of TMB assessment methodology across assays and centers. Two uniquely placed organizations, Friends of Cancer Research (Friends) and the Quality Assurance Initiative Pathology (QuIP), have collaborated to coordinate efforts for international multistakeholder initiatives to address this need. Friends and QuIP, who have partnered with several academic centers, pharmaceutical organizations, and diagnostic companies, have adopted complementary, multidisciplinary approaches toward the goal of proposing evidence‐based recommendations for achieving consistent TMB estimation and reporting in clinical samples across assays and centers. Many factors influence TMB assessment, including preanalytical factors, choice of assay, and methods of reporting. Preliminary analyses highlight the importance of targeted gene panel size and composition, and bioinformatic parameters for reliable TMB estimation. Herein, Friends and QuIP propose recommendations toward consistent TMB estimation and reporting methods in clinical samples across assays and centers. These recommendations should be followed to minimize variability in TMB estimation and reporting, which will ensure reliable and reproducible identification of patients who are likely to benefit from immune checkpoint inhibitors.

Background To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). Methods We did a phase 2, open-label, randomised, controlled trial on adults aged 18–60 years, vaccinated with a single dose of ChAdOx1-S 8–12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing. Findings Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84–85·33) at baseline to 7756·68 BAU/mL (7371·53–8161·96) at day 14 (p

Background The COVID-19 pandemic remains a significant global threat. However, despite urgent need, there remains uncertainty surrounding best practices for pharmaceutical interventions to treat COVID-19. In particular, conflicting evidence has emerged surrounding the use of hydroxychloroquine and azithromycin, alone or in combination, for COVID-19. The COVID-19 Evidence Accelerator convened by the Reagan-Udall Foundation for the FDA, in collaboration with Friends of Cancer Research, assembled experts from the health systems research, regulatory science, data science, and epidemiology to participate in a large parallel analysis of different data sets to further explore the effectiveness of these treatments. Methods Electronic health record (EHR) and claims data were extracted from seven separate databases. Parallel analyses were undertaken on data extracted from each source. Each analysis examined time to mortality in hospitalized patients treated with hydroxychloroquine, azithromycin, and the two in combination as compared to patients not treated with either drug. Cox proportional hazards models were used, and propensity score methods were undertaken to adjust for confounding. Frequencies of adverse events in each treatment group were also examined. Results Neither hydroxychloroquine nor azithromycin, alone or in combination, were significantly associated with time to mortality among hospitalized COVID-19 patients. No treatment groups appeared to have an elevated risk of adverse events. Conclusion Administration of hydroxychloroquine, azithromycin, and their combination appeared to have no effect on time to mortality in hospitalized COVID-19 patients. Continued research is needed to clarify best practices surrounding treatment of COVID-19.

The promise of precision medicine as a model to customize health care to the individual patient is heavily dependent upon new genetic tools to classify and characterize diseases and their hosts. Liquid biopsies serve as a safe alternative to solid biopsies and are thus a useful and critical component to fully realizing personalized medicine. The International Liquid Biopsy Standardization Alliance (ILSA) comprises organizations and foundations that recognize the importance of working towards the global use of liquid biopsy in oncology practice to support clinical decision making and regulatory considerations and seek to promote it in their communities. This manuscript provides an overview of the independent liquid biopsy- and standardization-based programs engaged with ILSA, their objectives and progress to date, and the tools and resources each is developing to contribute to the field. It also describes the unique areas of effort as well as synergy found within the group.

Patient reported outcomes (PROs) are the gold standard for assessing patients' experience of treatment in oncology, defined in the 21st Century Cures Act as information about patients' experiences with a disease or condition, including the impact of a disease or condition, or a related therapy or clinical investigation on patients' lives; and patient preferences with respect to treatment of their disease or condition [1]. PROs provide a comprehensive assessment of the benefits and risks of new medical products, as well as essential data to inform real-world use. Although RCTs are the ultimate source for information for evaluating products in development, they are not always feasible for rare diseases with few or no effective treatment options available. Thus, it is important to consider other measures that can help to improve the strength of evidence for cell and gene therapies targeting rare indications. While collection of PROs and other patient experience endpoints does not resolve the difficulty of conducting trials in small populations, doing so contributes empirical evidence that informs both product development and patient access. Additionally, including routine collection of PROs in registries may provide supplemental data to further characterize the benefit:risk profile of cell and gene therapies at follow-up times that would be infeasible to operationalize in a clinical trial setting.

BackgroundTumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms.MethodsEleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits.ResultsStudy results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers.ConclusionsIncreasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.

Introduction: Tumor mutational burden (TMB) is a quan-titative assessment of the number of somatic mutations within a tumor genome. Immunotherapy benefit has been associated with TMB assessed by whole-exome sequencing (wesTMB) and gene panel sequencing (psTMB). The initiatives of Quality in Pathology (QuIP) and Friends of Cancer Research have jointly addressed the need for harmonization among TMB testing options in tissues. This QuIP study identifies critical sources of variation in psTMB assessment. Methods: A total of 20 samples from three tumor types (lung adenocarcinoma, head and neck squamous cell car-cinoma, and colon adenocarcinoma) with available WES data were analyzed for psTMB using six panels across 15 testing centers. Interlaboratory and interplatform variation, including agreement on variant calling and TMB classifica-tion, were investigated. Bridging factors to transform psTMB to wesTMB values were empirically derived. The impact of germline filtering was evaluated. Results: Sixteen samples had low interlaboratory and interpanel psTMB variation, with 87.7% of pairwise com-parisons revealing a Spearman & rsquo;s r greater than 0.6. A wesTMB cut point of 199 missense mutations projected to psTMB cut points between 7.8 and 12.6 mutations per megabase pair; the corresponding psTMB and wesTMB classifications agreed in 74.9% of cases. For three-tier classification with cut points of 100 and 300 mutations, agreement was observed in 76.7%, weak misclassification in 21.8%, and strong misclassification in 1.5% of cases. Confounders of psTMB estimation included fixation arti-facts, DNA input, sequencing depth, genome coverage, and variant allele frequency cut points. Conclusions: This study provides real-world evidence that all evaluated panels can be used to estimate TMB in a routine diagnostic setting and identifies important param-eters for reliable tissue TMB assessment that require careful control. As complex or composite biomarkers beyond TMB are likely playing an increasing role in therapy prediction, the efforts by QuIP and Friends of Cancer Research also delineate a general framework and blueprint for the eval-uation of such assays. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

The field of cell therapy is rapidly emerging as a priority area for oncology research and drug development. Currently, two chimeric antigen receptor T-cell therapies are approved by the US Food and Drug Administration and other agencies worldwide for two types of hematologic cancers. To facilitate the development of these therapies for patients with life-threatening cancers with limited or no therapeutic options, science- and risk-based approaches will be critical to mitigating and balancing any potential risk associated with either early clinical research or more flexible manufacturing paradigms. Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy convened an expert group of stakeholders to develop specific strategies and proposals for regulatory opportunities to accelerate the development of cell therapies as promising new therapeutics. This meeting took place in Washington, DC on May 17, 2019. As academia and industry expand research efforts and cellular product development pipelines, this report summarizes opportunities to accelerate entry into the clinic for exploratory studies and optimization of cell products through manufacturing improvements for these promising new therapies.

PURPOSE This pilot study examined the ability to operationalize the collection of real-world data to explore the potential use of real-world end points extracted from data from diverse health care data organizations and to assess how these relate to similar end points in clinical trials for immunotherapy-treated advanced non–small-cell lung cancer. PATIENTS AND METHODS Researchers from six organizations followed a common protocol using data from administrative claims and electronic health records to assess real-world end points, including overall survival (rwOS), time to next treatment, time to treatment discontinuation (rwTTD), time to progression, and progression-free survival, among patients with advanced non–small-cell lung cancer treated with programmed death 1/programmed death-ligand 1 inhibitors in real-world settings. Data sets included from 269 to 6,924 patients who were treated between January 2011 and October 2017. Results from contributors were anonymized. RESULTS Correlations between real-world intermediate end points (rwTTD and time to next treatment) and rwOS were moderate to high (range, 0.6 to 0.9). rwTTD was the most consistent end points as treatment detail was available in all data sets. rwOS at 1 year post–programmed death-ligand 1 initiation ranged from 40% to 57%. In addition, rwOS as assessed via electronic health records and claims data fell within the range of median OS values observed in relevant clinical trials. Data sources had been used extensively for research with ongoing data curation to assure accuracy and practical completeness before the initiation of this research. CONCLUSION These findings demonstrate that real-world end points are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision making. Differences observed likely reflect true differences between real-world and protocol-driven practices.

Although outcomes for children with cancer have significantly improved over the past 40 years, there has been little progress in the treatment of some pediatric cancers, particularly when advanced. Additionally, clinical trial options and availability are often insufficient. Improved genomic and immunologic understanding of pediatric cancers, combined with innovative clinical trial designs, may provide an enhanced opportunity to study childhood cancers. Master protocols, which incorporate the use of precision medicine approaches, coupled with the ability to quickly assess the safety and effectiveness of new therapies, have the potential to accelerate early-phase clinical testing of novel therapeutics and which may result in more rapid approval of new drugs for children with cancer. Designing and conducting master protocols for children requires addressing similar principles and requirements as traditional adult oncology trials, but there are also unique considerations for master protocols conducted in children with cancer. The purpose of this paper is to define the key challenges and opportunities associated with this approach in order to ensure that master protocols can be adapted to benefit children and adolescents and ensure that adequate data are captured to advance, in parallel, the clinical development of investigational agents for children with cancer.

The effects of surface water flow system changes caused by constructing water-conservation areas and canals in southeast Florida on groundwater quality under the Atlantic Coastal Ridge was investigated with numerical modeling. Water quality data were used to delineate a zone of groundwater with low total dissolved solids (TDS) within the Biscayne aquifer under the ridge. The delineated zone has the following characteristics. Its location generally coincides with an area where the Biscayne aquifer has high transmissivities, corresponds to a high recharge area of the ridge, and underlies a part of the groundwater mound formed under the ridge prior to completion of the canals. This low TDS groundwater appears to be the result of pre-development conditions rather than seepage from the canals constructed after the 1950s. Numerical simulation results indicate that the time for low TDS groundwater under the ridge to reach equilibrium with high TDS surface water in the water-conservation areas and Everglades National Park are approximately 70 and 60 years, respectively. The high TDS groundwater would be restricted to the water-conservation areas and the park due to its slow eastward movement caused by small hydraulic gradients in Rocky Glades and its mixing with the low TDS groundwater under the high-recharge area of the ridge. The flow or physical boundary conditions such as high recharge rates or low hydraulic conductivity layers may affect how the spatial distribution of groundwater quality in an aquifer will change when a groundwater flow system reaches equilibrium with an associated surface water flow system.

Recent scientific progress is, in some cases, leading to transformative new medicines for diseases that previously had marginal or even no treatment options. This offers great promise for people affected by these diseases, but it has also placed stress on the health care system in terms of the growing cost associated with some new interventions. Effort has been taken to create tools to help patients and health care providers assess the value of new medical innovations. These tools may also provide the basis for assessing the price associated with new medical products. Given the growing expenditures in health care, value frameworks present an opportunity to evaluate new therapeutic options in the context of other treatments and potentially lead to a more economically sustainable health care system. In summary, the contribution to meaningful improvements in health outcomes is the primary focus of any assessment of the value of a new intervention. A component of such evaluations, however, should factor in timely access to new products that address an unmet medical need, as well as the magnitude of that beneficial impact. To achieve these goals, value assessment tools should allow for flexibility in clinical end points and trial designs, incorporate patient preferences, and continually evolve as new evidence, practice patterns, and medical progress advance.

Strong evidence suggests that patient-reported outcomes (PROs) aid in managing chronic conditions, reduce omissions in care, and improve patient-provider communication. However, provider acceptability of PROs and their use in clinical HIV care is not well known. We interviewed providers (n = 27) from four geographically diverse HIV and community care clinics in the US that have integrated PROs into routine HIV care, querying perceived value, challenges, and use of PRO data. Perceived benefits included the ability of PROs to identify less-observable behaviors and conditions, particularly suicidal ideation, depression, and substance use; usefulness in agenda setting prior to a visit; and reduction of social desirability bias in patient-provider communication. Challenges included initial flow integration issues and ease of interpretation of PRO feedback. Providers value same-day, electronic patient-reported measures for use in clinical HIV care with the condition that PROs are (1) tailored to be the most clinically relevant to their population; (2) well integrated into clinic flow; and (3) easy to interpret, highlighting chief patient concerns and changes over time.

To describe the mental health service use of Haitian, African-American, and non-Latino White youth in a community mental health setting. Groups are compared on adherence to treatment guidelines for attention-deficit/hyperactivity disorder (ADHD) and depressive disorders.Retrospective review of outpatient mental health charts (n = 252) from five community sites in an urban area of the Northeastern United States. We recorded the total number and treatment type of sessions during the first six months of treatment. Guideline-adherent treatments were compared and predicted after controlling for clinical need.Most Haitian and African-American youth stopped treatment by six months, with the majority attending less than eight sessions. One third of Haitian and African-American patients attended just one session. Haitian patients who presented with less severe symptoms and dysfunction were more likely to have single-session treatments. Guideline-adherent treatment for ADHD and depression was less likely for Haitians. Older patients were more likely to receive adequate depression treatment. Haitian youth were relatively underinsured, had more family separations documented, and received Adjustment Disorder diagnoses more often.Haitian youth use outpatient mental health services in similar proportion to African-American youth and at lower rates than White youth. Guideline-adherent treatment for ADHD and depression is limited by low retention in care for Black youth. Low insurance coverage is likely an important contributor to reduced use of services, especially for Haitians. These findings are discussed in the context of providing culturally sensitive mental health care to diverse communities.

We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.

Whiplash-associated disorders are common and incur considerable expense in social and economic terms. There are no known effective treatments for those people whose pain and disability persist beyond 3 months. We conducted a randomized, assessor-blinded, controlled trial at two centres in Australia. All participants received 3 advice sessions. In addition the experimental group participated in 12 exercise sessions over 6 weeks. Primary outcomes were pain intensity, pain bothersomeness and function measured at 6 weeks and 12 months. Exercise and advice was more effective than advice alone at 6 weeks for all primary outcomes but not at 12 months. The effect of exercise on the 0-10 pain intensity scale was -1.1 (95%CI -1.8 to -0.3, p=0.005) at 6 weeks and -0.2 (0.6 to -1.0, p=0.59) at 12 months; on the bothersomeness scale the effect was -1.0 (-1.9 to -0.2, p=0.003) at 6 weeks and 0.3 (-0.6 to 1.3, p=0.48) at 12 months. The effect on function was 0.9 (0.3 to 1.6, p=0.006) at 6 weeks and 0.6 (-0.1 to 1.4, p=0.10) at 12 months. High levels of baseline pain intensity were associated with greater treatment effects at 6 weeks and high levels of baseline disability were associated with greater treatment effects at 12 months. In the short-term exercise and advice is slightly more effective than advice alone for people with persisting pain and disability following whiplash. Exercise is more effective for subjects with higher baseline pain and disability.

Prospective inception cohort study of 62 consecutive patients seen in 2 orthopaedic clinics following ankle fracture.To investigate 4 putative predictors (age, fracture classification, acute management [surgical or nonsurgical], and ankle dorsiflexion range of motion measured at the time of cast removal) of outcome after ankle fracture and to develop simple predictive models of outcome after ankle fracture.Ankle fracture is a common condition. However, few studies have investigated factors that predict outcome after ankle fracture.Sixty-two consecutive subjects aged 17 or older with ankle fractures were recruited from 2 hospital orthopaedic clinics. Outcome measures recorded at 6 weeks and 6 months after cast removal included 2 functional questionnaires, patients' ratings of global improvement, and a measure of ankle dorsiflexion. The predictive value of 4 variables selected a priori was analyzed using bivariate and stepwise multiple linear regression.Ankle dorsiflexion and fracture classification predicted outcome 6 weeks and 6 months after cast removal for all outcome measures used (P.05, r2 = 0.09-0.47). Fracture management (surgical or nonsurgical) inconsistently predicted outcome at both 6 weeks and 6 months, and age did not predict outcome at either 6 weeks or 6 months after cast removal. The predictive models explain between 19% and 58% of the variance in outcomes 6 weeks after cast removal and 19% to 52% of the variance in outcomes 6 months after cast removal.Ankle dorsiflexion measured at the time of cast removal and fracture classification are clinically significant predictors of outcome after ankle fracture; however, much unexplained variation in outcomes still exists.

The present research tested relations between extraversion and emergent leadership among men in situations that differed in potential reward availability. Four-person groups of men engaged in a Leaderless Group Discussion (LGD) task and were randomly assigned to be evaluated by an attractive female observer, an attractive male observer, or not be evaluated. Evolutionary theories suggest that impressing a female evaluator in an intrasexually competitive situation should hold greater reward potential for men than impressing either a male evaluator or no evaluator. Accordingly, more extraverted men (who are more sensitive to reward cues) should display more group leadership when being evaluated by a woman than either a man or no one. Self-and peer ratings confirmed that more extraverted men were significantly more likely to emerge as leaders, but only in the female-evaluator condition. The results are discussed in terms of the interplay between personality, situational factors, and evolutionary principles.

The feasibility and acceptability of computerized screening and patient-reported outcome measures have been demonstrated in the literature. However, patient-centered management of health information entails two challenges: gathering and presenting data using “patient-tailored” methods and supporting “patient-control” of health information. The design and development of many symptom and quality-of-life information systems have not included opportunities for systematically collecting and analyzing user input. As part of a larger clinical trial, the Electronic Self-Report Assessment for Cancer–II project, participatory design approaches were used to build and test new features and interfaces for patient/caregiver users. The research questions centered on patient/caregiver preferences with regard to the following: (a) content, (b) user interface needs, (c) patient-oriented summary, and (d) patient-controlled sharing of information with family, caregivers, and clinicians. Mixed methods were used with an emphasis on qualitative approaches; focus groups and individual usability tests were the primary research methods. Focus group data were content analyzed, while individual usability sessions were assessed with both qualitative and quantitative methods. We identified 12 key patient/caregiver preferences through focus groups with 6 participants. We implemented seven of these preferences during the iterative design process. We deferred development for some of the preferences due to resource constraints. During individual usability testing (n = 8), we were able to identify 65 usability issues ranging from minor user confusion to critical errors that blocked task completion. The participatory development model that we used led to features and design revisions that were patient centered. We are currently evaluating new approaches for the application interface and for future research pathways. We encourage other researchers to adopt user-centered design approaches when building patient-centered technologies.

Pulmonary vein isolation with phased radiofrequency current and use of a pulmonary vein ablation catheter (PVAC) has recently been associated with a high incidence of clinically silent brain infarcts on diffusion-weighted magnetic resonance imaging, and a high microembolic signal (MES) count detected by transcranial Doppler. We investigated the potential effects of the ongoing rhythm and the target vein during energy delivery (ED) on MES generation during PVAC ablations.A total of 735 EDs during 48 PVAC ablations were analyzed. MES counts were recorded for each ED and time-stamped for correlation with the ongoing rhythm and the target vein for each ED. Significantly higher MES counts were observed during ablations of the left-sided as compared with the right-sided pulmonary veins (P = 0.0003). Similarly, higher MES counts were detected during EDs in atrial fibrillation as compared with sinus rhythm when the temperature was56°C (P0.0001). The ongoing rhythm had no effect on the number of MESs at lower temperatures during ablation.Both the ongoing rhythm during ED and the site of ablation influence microembolus generation during PVAC ablation procedures.

Objectives Many technologies intended for patient use are never developed or evaluated with principles of user-centered design. In this review, we explore different approaches to assessing usability and acceptability, drawn from selected exemplar studies in the health sciences literature. Data Sources Peer-reviewed research manuscripts were selected from Medline and other data sources accessible through pubmed.gov . We also present a framework for developing patient-centered technologies that we recently employed. Conclusion While there are studies using principles of user-centered design, many more do not report formative usability testing results and may only report post-hoc satisfaction surveys. Consequently, adoption by user groups may be limited. Implications for Nursing Practice We encourage nurses in practice to look for and examine usability testing results before considering implementation of any patient-centered technology.

The small AO (Synthes, Paoli, Pa) external fixator is a valuable tool for the treatment of distal radius fractures. The construct has many possible bar and pin configurations. However, there are no data regarding which construct is optimal with respect to strength and versatility. We tested 10 configurations to determine bending stiffness, rotation, and axial loading. Although slight variations were found between constructs for bending and rotation forces, there were marked differences between constructs during axial loading. A frame design without bar-to-bar clamps was determined stiffest. However, this configuration may be more difficult to apply and adjust in the clinical setting. Although an "ideal" construct applicable to all fracture types does not exist, knowledge of the strengths of various configurations may allow for optimization of fixator assembly to meet specific clinical needs.

An issue that arises when selecting therapy is whether patient or clinician preferences for treatment moderate the effect of treatment. To evaluate this question we conducted a secondary analysis of the results of a randomized controlled trial of exercise treatment of chronic whiplash. Immediately prior to randomization, treatment preference ratings were collected from each patient and from the physiotherapist who assessed each patient. Patients were then randomized to receive advice alone or exercise and advice with the primary treatment outcomes of pain and function measured immediately after conclusion of treatment. Treatment effect modification was evaluated with a treatment group by preference interaction term in the regression analyses. The analysis revealed that neither patient nor therapist treatment preferences moderated the effect of exercise treatment for chronic whiplash. The interaction effect of treatment group by patient preference was 0.1 (-0.3 to 0.5, p=0.68) on the 0-10 pain intensity scale and -0.1 (-0.5 to 0.3, p=0.64) on the 0-10 function scale. The interaction effect of treatment group by therapist preference was 0.0 (-0.3 to 0.4, p=0.786) on the 0-10 pain intensity scale and -0.2 (-0.4 to 0.1, p=0.296) on the 0-10 function scale. Our findings do not provide evidence that patient or therapist treatment preferences moderate the effect of exercise treatment for chronic whiplash.

STUDY DESIGN Reanalysis of data derived from longitudinal cohort studies. OBJECTIVE To comprehensively evaluate the psychometric properties of a 5-item version of the Core Outcome Measure in people with whiplash. SUMMARY OF BACKGROUND DATA The 7-item Core Outcome Measure was initially proposed as a brief health outcome measure for use in low back pain. To date, this measure has not been comprehensively assessed in a whiplash population. METHOD.: Data were sourced from 3 separate whiplash cohorts (total 481) encompassing acute, early chronic, and late-chronic whiplash among primary care and insurance populations. Subjects completed a 5-item version of the Core Outcome Measure for whiplash (Core Whiplash Outcome Measure [CWOM]), the Functional Rating Index, Neck Disability Index, SF-36, and perceived recovery questionnaires at baseline and short and long-term follow-up periods. Psychometric evaluation of the CWOM included assessing questionnaire responses, internal consistency, construct validity, and internal and external responsiveness. RESULTS Internal consistency was excellent at all stages of whiplash (Cronbach alpha = 0.76 in the acute stage and 0.83 in the late-chronic stage). Convergent validity was observed between the CWOM and Functional Rating Index (Pearson r = 0.81), Neck Disability Index (Pearson r = 0.76), and SF-36 physical health summary measure (Pearson r = -0.65). Divergent validity was observed between the CWOM and SF-36 mental health summary measure (Pearson r = -0.45). The internal and external responsiveness of the CWOM was similar to other neck-specific outcome measures. CONCLUSIONS We recommend the 5-item CWOM as a brief clinical measure for whiplash because it is quick to administer and score, and has excellent measurement properties. The CWOM may need to be supplemented with other questionnaires (e.g., when assessment of psychological or emotional health is required).

We report a case of Lyme borreliosis. Culture of skin biopsy was positive for Borrelia garinii, despite repeated prior treatment with antibiotics. The patient had travelled in Europe 17 months before the onset of symptoms, but the clinical details indicate that the organism could have been acquired in Australia. The results of conventional serological and histopathological tests were negative, despite an illness duration of at least two years.

Only a minority of Australian graduates are interested in careers in general practice. The factors influencing medical students toward general practice as a career choice are poorly understood, even though this is important to the makeup of the medical workforce.We ran 10 focus groups involving 82 first and final year medical students from three Australian medical schools in 2002, and analysed factors influencing participants' interest in working in general practice.About half the students were interested in general practice. Attractive factors were: the nature of the work (including its diversity), continuity of care, community context, and working conditions (including flexibility of training and work, availability of part time work and portability of qualifications). Negative factors included: the breadth of knowledge needed, boring work (in urban general practice), having to run a business, and working conditions (including relatively poor remuneration, overwork in rural general practice, and poor status of general practitioners). Some students were strongly influenced by negative attitudes of the GPs they were taught by, deciding against general practice as a career.Medical educators and GPs should be aware of this important influence.

The Royal Australian College of General Practitioners Fellowship (FRACGP) examination remains the sole point of entry to Fellowship of the RACGP for registrars in the Australian General Practice Training Program. It is also used by 'practice eligible route' candidates. It may have been some time since candidates studied for any exam, and the prospect is often daunting. Like ally examination, the FRACGP has its own attendant myths and legends on what you must do to pass.This article recounts the study habits of a group of three general practice registrars who sat the FRACGP examination at the end of 2003. It attempts to give a light hearted account of their study techniques in the hope of dispelling some of the fear and mystery surrounding the exam.Despite the seemingly casual approach described below, all the authors passed without suffering grievous psychological injury, and most of their patients seem to have survived as well.

A remarkable feature of motor cortical organization in higher mammals is that a brief electrical stimulus elicits in the pyramidal tract and corticospinal tract an unrelayed direct (D) wave followed by multiple indirect (I) waves at frequencies as high as 500-700 Hz. This review presents some conclusions regarding very high frequency synchronous activity in mammalian cortex: (1) Synchrony in repetitive I discharges is extraordinary in humans and monkeys, less in cats and still less in rats, being there represented by a delayed broad wave; such phylogenetic trends have important implications for the suitability of lower mammalian species for studies of high frequency cortical networks in the human brain; (2) The evidence from microstimulation at different cortical depths and pial cooling favors a vertically oriented chain of interneurons that centripetally excite corticospinal neurons as the basis for inter-I wave periodicity and synchrony; (3) Significantly, the I wave periodicity is conserved despite wide changes in stimulus parameters; (4) Synchronous high frequency activity similar to that of I waves can be recorded from other neocortical areas such as visual and somatosensory cortex; however, evidence is still lacking that the output neurons of these cortical regions have synchronized discharges comparable to I waves; (5) In limbic cortices, the frequency of synchronous neural activity is lower than that in motor cortex or related cortices and periodicity is not conserved with changes in stimulus parameters, indicating a lack of the neocortical interneuronal substrate in limbic cortex; (6) We propose that the very high frequency synchronous activity of motor cortical output reflects a computational function such as a "clock," quantizing times at which inputs would interact preferentially yielding synchronous output discharges. Such circuitry, if a general feature of neocortex, would facilitate rapid communication of significant computations between cortical regions.

A cross-sectional analytic study was conducted.To collect normative data on back extensor endurance holding times and evaluate the discriminative validity of the Biering-Sorensen test in a group of coal miners in Australia.Low back pain is a common complaint among those working in the Australian coal mining industry. One test that may be predictive of first-time episodes of low back pain is the Biering-Sorensen test of back extensor endurance strength. While this test has been evaluated in overseas sedentary populations, normative data and the discriminative ability of the test have not been evaluated with coal miners.Eighty-eight coal miners completed a questionnaire for known risk factors for low back pain, performed the Biering-Sorensen test, and undertook a test of aerobic fitness. Data analysis was performed to describe the groups and to determine whether any significant difference existed between those with a past history of low back pain and those without.Significantly lower than expected holding times were found in this group of coal miners (mean 113 s). This result was significantly lower than demonstrated in previous studies (mean 138 s, t87 = 6.32, p0.001). When holding times for those with a past history of low back pain were compared with times for those with no history of low back pain, the difference was not statistically significant (t86 = 1.56, p = 0.12), nor was there a significant difference in fitness between those with a past history of low back pain and those without (t86 = 0.47, p = 0.64).Coal miners in Australia have lower than normal Biering-Sorensen holding times. This lower back holding time does not differ between coal miners with a past history of low back pain and those without.

Fifteen patients (9 male and 6 female) with a mean age of 32.8 years (range, 17-44 years) were examined at a mean follow-up of 64 months (range, 33-118 months) after undergoing pectoralis major transfer with a fascia lata autograft for scapular winging. Ten patients were treated as part of a worker's compensation claim. Twelve reported that they would undergo the procedure again. The mean Rowe score was 66 (range, 41-92), the mean Constant-Murley score was 74 (range, 32-95), the mean Simple Shoulder Test score was 8 of 12 positive responses, and the mean American Shoulder and Elbow Surgeons score was 63 (range, 10-87). Pain decreased in 11 patients, whereas function improved in 10 patients. According to the Rowe scoring system, the results were excellent in 2 patients, good in 5, fair in 4, and poor in 4. Better results occur in patients attaining at least 60° of external rotation postoperatively. Although complete relief of pain and full function were not always achieved, most patients returned to their preoperative level of activity with minor adaptations. (J Shoulder Elbow Surg 2002;11:345-350)

Intelligence, school achievement, and perceptual-motor performance were studied in 32 children with the hyperactive child syndrome, behaviorally defined, and 34 matched controls. Patients had significantly lower WISC IQs, but scores on school achievement and perceptual-motor tests did not differ from those of controls when adjusted for WISC Full-Scale IQ. Results indicate that hyperactive children have an intellectual as well as behavioral handicap, but that they do learn schoolwork at the rate normal for their level of intelligence.

The physiology of excitable membranes is a fundamental topic in neuroscience and physiology courses at graduate and undergraduate levels. From the building blocks of ionic gradients and membrane channels whose permeability is selective and variable, we build the concepts of resting potential, action potential, and propagation in neurons and muscle fibers. Many students have an intuitive understanding of the movements of ions and the associated changes in membrane potential. For example, potassium ions leaving a cell through potassium-selective channels become unbalanced positive charges on the outside of the cell (and leave unbalanced negative charges on the inside), thus producing a potential across the membrane with the inside negative with respect to the outside. Later, when we discuss the local circuit currents that underlie propagation or the basis for extracellular stimulation, we make the general statement that "outward currents depolarize cells." Students respond with utter disbelief. Two simple additions to a discussion of membranes are suggested that permit the formulation of a consistent set of rules that apply to everything from the resting and action potentials of nerve and muscle through synaptic potentials and stimulation techniques.