Establishing achievable benchmarks for quality improvement in systemic therapy for early-stage breast cancer.

BACKGROUND: Setting realistic targets for performance is a consistent challenge in quality improvement. In the current study, the authors used administrative data to define achievable targets for a panel of 15 previously developed quality indicators (QIs) focusing on systemic therapy in patients with early-stage breast cancer. METHODS: Deterministically linked administrative databases were used to identify patients with TNM stage I to stage III breast cancer who were diagnosed between 2006 and 2010 in Ontario, Canada. For each individual indicator, data-driven empirical benchmarks were calculated using the pared-mean benchmark approach. Variation in institution-level performance for each indicator was examined through the construction of funnel plots. RESULTS: A total of 28,303 patients with early-stage breast cancer were identified, 43% of whom received adjuvant chemotherapy. For the 9 QIs for which receiving the service or outcome was desirable (ie, consultation with a medical oncologist), the benchmark varied from 40.9% to 100%. For the 6 indicators for which not receiving the service or outcome was desirable (ie, incidence of febrile neutropenia), the benchmark varied from 0% to 49.0%. There was substantial variation noted with regard to the number of institutions meeting the target and the amount of interinstitution variation between the QIs. Top performing institutions varied by indicator, with no individual institution meeting the benchmark for all indicators. For the majority of indicators, institution size was not found to be correlated with performance. CONCLUSIONS: Data-derived benchmarking can be used to facilitate quality improvement by identifying areas of both good as well as suboptimal performance while defining an achievable target for which to strive. Cancer 2017;123:3772-3780. © 2017 American Cancer Society.

Time to Viremia for Patients Taking their First Antiretroviral Regimen and the Subsequent Resistance Profiles.

BACKGROUND: The resistance profiles for patients on first-line antiretroviral therapy (ART) regimens after viremia have not been well studied in community clinic settings in the modern treatment era. OBJECTIVE: To determine time to viremia and the ART resistance profiles of viremic patients. METHODS: HIV-positive patients aged ≥16 years initiating a three-drug regimen were retrospectively identified from 01/01/06 to 12/31/12. The regimens were a backbone of two nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent: a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor (II). Time to viremia was compared using a proportional hazards model, adjusting for demographic and clinical factors. Resistance profiles were described in those with baseline and follow-up genotypes. RESULTS: For 653 patients, distribution of third-agent use and viremia was: 244 (37%) on PIs with 80 viremia, 364 (56%) on NNRTIs with 84 viremia, and 45 (7%) on II with 11 viremia. Only for NNRTIs, time to viremia was longer than PIs (p = 0.04) for patients with a CD4 count ≥200 cells/mm(3). Of the 175 with viremia, 143 (82%) had baseline and 37 (21%) had follow-up genotype. Upon viremia, emerging ART resistance was rare. One new NNRTI (Y181C) mutation was identified and three patients taking PI-based regimens developed NRTI mutations (M184 V, M184I, and T215Y). CONCLUSIONS: Time to viremia for NNRTIs was longer than PIs. With viremia, ART resistance rarely developed without PI or II mutations, but with a few NRTI mutations in those taking PI-based regimens, and NNRTI mutations in those taking NNRTI-based regimens.

Use and impact of intermittent versus continuous systemic treatment strategies in metastatic colorectal cancer in routine practice.

BACKGROUND: Randomized trials have shown that intermittent treatment may reduce toxicity without compromising survival in patients with metastatic colorectal cancer (mCRC). A population-based study examined patterns of use of chemotherapy-free intervals (CFIs) in routine practice in Ontario and their impact on survival and toxicity. METHODS: Patients treated with first-line intravenous chemotherapy for mCRC in Ontario between 2007 and 2009 were identified from administrative data. A CFI was defined as more than 56 days between 2 chemotherapy doses. A propensity score analysis was used to compare the survival of patients with CFIs and patients without CFIs, stratified by the type of first-line treatment: irinotecan (IRI), irinotecan plus bevacizumab (IRI-B), and oxaliplatin (OX). Toxicity was estimated on the basis of the rate of emergency room visits and hospitalizations. RESULTS: There were 1989 patients who started first-line chemotherapy for mCRC in Ontario between 2007 and 2009, and 489 (25%) had at least 1 CFI. The median time to the first CFI was 155 days (interquartile range, 82-217 days). There was no difference in survival for the propensity score-matched patients with or without CFIs in the IRI (hazard ratio [HR], 0.93; P = .70) and OX groups (HR, 0.73; P = .06). Survival was worse in the CFI group for patients treated with IRI-B (HR, 1.28; P = .03). Toxicity was lower for patients with at least 1 CFI (0.17 vs 0.25 acute visits per person-month of treatment, P = .007), although the magnitude varied with the treatment type. CONCLUSIONS: Intermittent treatment strategies are being used in routine practice for patients with mCRC. The impact on survival and toxicity varies with the type of first-line chemotherapy.

Invasive procedures in the elderly after stage IV cancer diagnosis.

BACKGROUND: Invasive procedures are resource intense and may be associated with substantial morbidity. These harms must be carefully balanced with the benefits gained in life expectancy and quality of life. Prior research has demonstrated an increasing aggressiveness of care in cancer patients at the end-of-life. To better characterize surgical care in this setting, we sought to examine trends in the use of invasive procedures in patients diagnosed with metastatic cancer on presentation. MATERIALS AND METHODS: Using Surveillance Epidemiology and End Results -Medicare data, we identified invasive procedure claims from 1994-2009 for patients diagnosed with incident stage IV breast, colorectal, lung, and prostate cancer patients in 1995-2006. We grouped procedures into surgically relevant categories, using an adaptation of the Clinical Classifications Software, and measured utilization and relative changes over time. RESULTS: Of stage IV patients diagnosed in 2002-2006, 96% underwent a procedure during the course of their cancer care including 63% after the diagnostic period, and 25% in the last month of life. Between 1996 and 2006, minimal change was observed in utilization during the diagnostic period (+1.5%). However, there were significant increases during continuing care (+20.7%) and the last month of life (+21.5%). Procedures consistent with primary tumor resection decreased, whereas those with probable palliative intent and those unrelated to cancer increased. CONCLUSIONS: Nearly all patients who present with metastatic cancer undergo invasive procedures. Although overall utilization is increasing, the specific procedure types indicate that it may be appropriate, enhancing the quality of life in this vulnerable population.

Interinstitutional variation in management decisions for treatment of 4 common types of cancer: A multi-institutional cohort study.

BACKGROUND: When clinical practice is governed by evidence-based guidelines and there is consensus about their validity, practice variation should be minimal. For areas in which evidence gaps exist, greater variation is expected. OBJECTIVE: To systematically assess interinstitutional variation in management decisions for 4 common types of cancer. DESIGN: Multi-institutional, observational cohort study of patients with cancer diagnosed between July 2006 through May 2011 and observed through 31 December 2011. SETTING: 18 cancer centers participating in the formulation of treatment guidelines and systematic outcomes assessment through the National Comprehensive Cancer Network. PATIENTS: 25 589 patients with incident breast cancer, colorectal cancer, lung cancer, or non-Hodgkin lymphoma. MEASUREMENTS: Interinstitutional variation for 171 binary management decisions with varying levels of supporting evidence. For each decision, variation was characterized by the median absolute deviation of the center-specific proportions. RESULTS: Interinstitutional variation was high (median absolute deviation >10%) for 35 of 171 (20%) oncology management decisions, including 9 of 22 (41%) decisions for non-Hodgkin lymphoma, 16 of 76 (21%) for breast cancer, 7 of 47 (15%) for lung cancer, and 3 of 26 (12%) for colorectal cancer. Forty-six percent of high-variance decisions involved imaging or diagnostic procedures and 37% involved choice of chemotherapy regimen. The evidence grade underpinning the 35 high-variance decisions was category 1 for 0%, 2A for 49%, and 2B/other for 51%. LIMITATION: Physician identifiers were unavailable, and results may not generalize outside of major cancer centers. CONCLUSION: The substantial variation in institutional practice manifest among cancer centers reveals a lack of consensus about optimal management for common clinical scenarios. For clinicians, awareness of management decisions with high variation should prompt attention to patient preferences. For health systems, high variation can be used to prioritize comparative effectiveness research, patient-provider education, or pathway development. PRIMARY FUNDING SOURCE: National Cancer Institute and National Comprehensive Cancer Network.

Validating billing/encounter codes as indicators of lung, colorectal, breast, and prostate cancer recurrence using 2 large contemporary cohorts.

BACKGROUND: A substantial proportion of cancer-related mortality is attributable to recurrent, not de novo metastatic disease, yet we know relatively little about these patients. To fill this gap, investigators often use administrative codes for secondary malignant neoplasm or chemotherapy to identify recurrent cases in population-based datasets. However, these algorithms have not been validated in large, contemporary, routine care cohorts. OBJECTIVE: To evaluate the validity of secondary malignant neoplasm and chemotherapy codes as indicators of recurrence after definitive local therapy for stage I-III lung, colorectal, breast, and prostate cancer. RESEARCH DESIGN, SUBJECTS, AND MEASURES: We assessed the sensitivity, specificity, and positive predictive value (PPV) of these codes 14 and 60 months after diagnosis using 2 administrative datasets linked with gold-standard recurrence status information: CanCORS/Medicare (diagnoses 2003-2005) and HMO/Cancer Research Network (diagnoses 2000-2005). RESULTS: We identified 929 CanCORS/Medicare patients and 5298 HMO/CRN patients. Sensitivity, specificity, and PPV ranged widely depending on which codes were included and the type of cancer. For patients with lung, colorectal, and breast cancer, the combination of secondary malignant neoplasm and chemotherapy codes was the most sensitive (75%-85%); no code-set was highly sensitive and highly specific. For prostate cancer, no code-set offered even moderate sensitivity (≤ 19%). CONCLUSIONS: Secondary malignant neoplasm and chemotherapy codes could not identify recurrent cancer without some risk of misclassification. Findings based on existing algorithms should be interpreted with caution. More work is needed to develop a valid algorithm that can be used to characterize outcomes and define patient cohorts for comparative effectiveness research studies.

Machine Learning to Allocate Palliative Care Consultations During Cancer Treatment.

PURPOSE: For patients with advanced cancer, early consultations with palliative care (PC) specialists reduce costs, improve quality of life, and prolong survival. However, capacity limitations prevent all patients from receiving PC shortly after diagnosis. We evaluated whether a prognostic machine learning system could promote early PC, given existing capacity. METHODS: Using population-level administrative data in Ontario, Canada, we assembled a cohort of patients with incurable cancer who received palliative-intent systemic therapy between July 1, 2014, and December 30, 2019. We developed a machine learning system that predicted death within 1 year of each treatment using demographics, cancer characteristics, treatments, symptoms, laboratory values, and history of acute care admissions. We trained the system in patients who started treatment before July 1, 2017, and evaluated the potential impact of the system on PC in subsequent patients. RESULTS: Among 560,210 treatments received by 54,628 patients, death occurred within 1 year of 45.2% of treatments. The machine learning system recommended the same number of PC consultations observed with usual care at the 60.0% 1-year risk of death, with a first-alarm positive predictive value of 69.7% and an outcome-level sensitivity of 74.9%. Compared with usual care, system-guided care could increase early PC by 8.5% overall (95% CI, 7.5 to 9.5; P < .001) and by 15.3% (95% CI, 13.9 to 16.6; P < .001) among patients who live 6 months beyond their first treatment, without requiring more PC consultations in total or substantially increasing PC among patients with a prognosis exceeding 2 years. CONCLUSION: Prognostic machine learning systems could increase early PC despite existing resource constraints. These results demonstrate an urgent need to deploy and evaluate prognostic systems in real-time clinical practice to increase access to early PC.

Impact of oncology-related direct-to-consumer advertising: association with appropriate and inappropriate prescriptions.

BACKGROUND: Little is known about the impact of direct-to-consumer advertising (DTCA) on appropriate versus inappropriate prescribing. Aromatase inhibitor (AI) therapy for breast cancer provides an ideal paradigm for studying this issue, because AIs have been the focus of substantial DTCA, and because they should only be used in postmenopausal women, age can serve as a simple surrogate marker of appropriateness. METHODS: Data regarding national DTCA spending for the AIs were obtained from TNS Multimedia; hormonal therapy prescription data were obtained from IMS Health. Time series analyses were performed to characterize the association between monthly changes in DTCA spending for the AIs and monthly changes in the proportion of all new hormonal therapy prescriptions represented by the AIs from October 2005 to September 2007. Analyses were stratified by age, considering prescriptions for women ≤ 40 (likely premenopausal) to be inappropriate and those for women > 60 (likely postmenopausal) to be appropriate. RESULTS: Monthly dollars spent on AI-associated DTCA varied considerably ($118,600 to $22,019,660). Time series analysis revealed that for every million dollars spent on DTCA for the AIs, there was an associated increase 3 months later in the new AI prescription proportion of 0.15% for all ages (P < .0001) and 0.18% for those > 60 years (P < .0001), but no significant change for those ≤ 40 at any time from 0 to 6 months. CONCLUSIONS: DTCA for the AIs was associated with increases in appropriate prescriptions with no significant effect on inappropriate prescriptions, suggesting that DTCA may not foster inappropriate medication use for certain drug classes.

End-of-life care discussions among patients with advanced cancer: a cohort study.

BACKGROUND: National guidelines recommend that physicians discuss end-of-life (EOL) care planning with patients with cancer whose life expectancy is less than 1 year. OBJECTIVE: To evaluate the incidence of EOL care discussions for patients with stage IV lung or colorectal cancer and where, when, and with whom these discussions take place. DESIGN: Prospective cohort study of patients diagnosed with lung or colorectal cancer from 2003 to 2005. SETTING: Participants lived in Northern California, Los Angeles County, North Carolina, Iowa, or Alabama or received care in 1 of 5 large HMOs or 1 of 15 Veterans Health Administration sites. PATIENTS: 2155 patients with stage IV lung or colorectal cancer. MEASUREMENTS: End-of-life care discussions reported in patient and surrogate interviews or documented in medical records through 15 months after diagnosis. RESULTS: 73% of patients had EOL care discussions identified by at least 1 source. Among the 1470 patients who died during follow-up, 87% had EOL care discussions, compared with 41% of the 685 patients who were alive at the end of follow-up. Of the 1081 first EOL care discussions documented in records, 55% occurred in the hospital. Oncologists documented EOL care discussions with only 27% of their patients. Among 959 patients with documented EOL care discussions who died during follow-up, discussions took place a median of 33 days before death. LIMITATIONS: The depth and quality of EOL care discussions was not evaluated. Much of the information about discussions came from surrogates of patients who died before baseline interviews could be obtained. CONCLUSION: Although most patients with stage IV lung or colorectal cancer discuss EOL care planning with physicians before death, many discussions occur during acute hospital care, with providers other than oncologists, and late in the course of illness. PRIMARY FUNDING SOURCE: National Cancer Institute and Department of Veterans Affairs.

Medical oncologists' and palliative care physicians' opinions towards thromboprophylaxis for inpatients with advanced cancer: a cross-sectional study.

BACKGROUND: Patients with advanced cancer are increasingly discharged from inpatient settings following focused symptom management admissions. Thromboprophylaxis (TP) is recommended for patients with cancer admitted to acute care settings; less is known about TP use in palliative care (PC) settings. This study explored the opinions of Canadian medical oncologists (MO) and PC physicians regarding the use of TP for inpatients with advanced cancer. METHODS: A fractional factorial survey designed to evaluate the impact of patient factors (age, clinical setting, reason for admission, pre-admission performance status (Eastern Cooperative Oncology Group; ECOG), and risk of bleeding on anticoagulation) and physician demographics on recommending TP was administered by email to Canadian MO and PC physicians. Each respondent received eight vignettes randomly selected from a set of 32. Hierarchical regression was used to evaluate the odds of prescribing TP adjusted for patient factors. RESULTS: 606 MO and 491 PC physicians were surveyed; response rates were 11.1% and 15.0%, respectively. MO were predominantly male (59.7%); PC female (60.3%); most worked in academic environments (90.3% MO; 73.9% PC). Multivariable hierarchical logistic regression demonstrated that all patient factors except age were associated with prescribing TP (ORs range: from 1.34 (95% CI 1.01 to 1.77) for good ECOG, to 2.53 (95% CI 1.9 to 3.37), for reversible reason for admission). Controlling for these factors, medical specialty was independently associated with recommending TP (OR for MO 2.09 (95% CI 1.56 to 2.8)). CONCLUSIONS: MO have higher odds of recommending TP for inpatients with advanced cancer than PC physicians. Further research exploring the drivers of these differing practices is warranted.

Adverse pregnancy outcomes among foreign-born Canadians.

OBJECTIVE: Numerous non-Canadian studies have shown that immigrant women experience higher rates of adverse maternal and perinatal events than the general non-immigrant population. Limited information about the pregnancy outcomes of immigrant Canadian women is available. METHODS: We conducted a retrospective cohort study at St. Michael's Hospital between October 2002 and June 2006 to estimate the risk of adverse obstetrical and perinatal outcomes among foreign-born women residing in Toronto. The main study outcomes were the incidences of preterm delivery between 32 and 36 completed weeks' gestation, low infant birth weight, and delivery by Caesarean section. RESULTS: Compared with Canadian-born women, those who were foreign-born had an associated adjusted odds ratio of 0.85 (95% CI 0.64 to 1.14) for preterm delivery, 1.92 (95% CI 1.29 to 2.85) for low infant birth weight, and 1.16 (95% CI 1.01 to 1.34) for delivery by Caesarean section. CONCLUSION: In this study, foreign-born women had a non-significantly lower risk of preterm birth, but a significantly higher risk of low birth weight infants and Caesarean section than Canadian-born women. In this urban setting, recent immigrant women have worse pregnancy outcomes, warranting increased attention to this group during antenatal and intrapartum care.

Evaluation of Adolescents' and Young Adults' Attitudes Toward Participation in Cancer Clinical Trials.

PURPOSE: Participation in cancer clinical trials (CCTs) for adolescents and young adults (AYAs) remains the lowest of any patient group with cancer. Little is known about the personal barriers to AYA accrual. The aim of this study was to explore AYA attitudes that influence CCT participation. METHODS: A mixed-methods approach was used. AYAs and non-AYAs (≥ 40 years) completed the Cancer Treatment subscale of the Attitudes Toward Cancer Trials Scales and 9 supplementary questions formed from interview analysis. Differences between AYA and non-AYA cohorts were analyzed using the Mann-Whitney U test, and logistic regression models were constructed to evaluate the effect of demographics on perceptions of CCTs. RESULTS: Surveys were distributed to 61 AYAs (median age, 29 years; range, 17-39 years) and 74 non-AYAs (median age, 55 years; range, 40-88 years). Compared with non-AYAs, AYAs perceived CCTs to be unsafe/more difficult (Personal Barrier/Safety domain; P = .01). There were no differences based on age in other domains. AYAs were also more concerned with CCT interference in their long-term goals (P = .04). Multivariable ordered logistic regression identified increased personal barriers in the Personal Barrier/Safety domain for AYAs (P = .01), in patients with English as a second language (ESL; P < .01), and in patients previously not offered a clinical trial (P = .03). Long-term goals were identified as a barrier in particular tumor types (P = .01) and in patients with ESL (P < .01), with a trend identified in AYAs (P = .12). CONCLUSION: Age-related differences in attitudes toward CCTs suggest that tailored approaches to CCT accrual are warranted. Patient-centered delivery of information regarding CCTs, particularly in patients with ESL and who are trial naïve, may improve accrual.

A survey of abstracts of high-impact clinical journals indicated most statistical methods presented are summary statistics.

OBJECTIVES: To assess what statistical methods are commonly used in high-impact clinical research and how they are presented in abstracts of articles published in high-impact medical journals. STUDY DESIGN AND SETTING: A cross-sectional survey of abstracts of original articles published in July 2003 in four high-impact medical journals was conducted. The primary outcome was the distribution of statistical methods used in study results presented in the abstract of articles. RESULTS: Seventy articles met inclusion criteria. One hundred twenty-five unique statistical method presentations were analyzed. Sixty-eight percent of statistical methods used summary statistics, and 27.2% used regression analysis. When summary statistics were used, clinical evidence was presented with a P-value or confidence interval (CI) in 51.8% of statistical methods compared to 72.5% when summary statistics were not used (P=0.0282). Clinical evidence was presented verbally in 7.1% of statistical methods when summary statistics were used and in 20.0% when summary statistics were not used (P=0.0323). CONCLUSIONS: Summary statistics are the most frequently used statistical method to generate high-impact clinical evidence presented in the abstract of a medical article. Evidence described by summary statistics is significantly associated with less frequent reporting of a P-value or CI, and less frequent verbal presentations.

National evaluation of policies on individual financial conflicts of interest in Canadian academic health science centers.

BACKGROUND: Conflicts of interest (COI) in research are an important emerging topic of investigation and are frequently cited as a serious threat to the integrity of human participant research. OBJECTIVE: To study financial conflicts of interest (FCOI) policies for individual investigators working in Canadian academic health centers. DESIGN: Survey instrument containing 61 items related to FCOI. SETTING: All Canadian academic health science centers (universities with faculties of medicine, faculties of medicine and teaching hospitals) were requested to provide their three primary FCOI policies. MEASUREMENTS: Number of all centers and teaching hospitals with policies addressing each of the 61 items related to FCOI. MAIN RESULTS: Only one item was addressed by all 74 centers. Thirteen items were present in fewer than 25% of centers. Fewer than one-quarter of hospitals required researchers to disclose FCOI to research participants. The role of research ethics boards (REBs) in hospitals was marginal. LIMITATIONS: Asking centers to identify only three policies may not have inclusively identified all FCOI policies in use. Additionally, policies at other levels might apply. For instance, all institutions receiving federal grant money must comply with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. CONCLUSIONS: Canadian centers within the same level (for instance, teaching hospitals) differ significantly in the areas that their policies address and these policies differ widely in their coverage. Presently, no single policy in any Canadian center informs researchers about the broad range of individual FCOI issues. Canadian investigators need to understand the environment surrounding FCOI, be able to access and follow the relevant policies and be confident that they can avoid entering into a FCOI.

The science of human security.

During the 1990s medical studies using public health methodologies about injury and death due to weapons in conflict began to appear in the medical literature. The 1990s was also the period when the concept of human security was materialising in the development and humanitarian communities. Nowadays it is common for global organisations, governmental and non-governmental agencies, and academics to conduct scientific studies of human security. Many such studies gather evidence about human insecurity and these in turn lead to policy recommendations pertaining to improving human security. The data-to-policy process applies in this domain. In this article we propose that conceptual developments in human security and methods which generate scientific evidence of human security or insecurity have combined to create a new science: the science of human security. We describe key problems inherent in this new multidisciplinary science, some unique methodological challenges and new scientific opportunities.

Setting Quality Improvement Priorities for Women Receiving Systemic Therapy for Early-Stage Breast Cancer by Using Population-Level Administrative Data.

Purpose Routine evaluation of quality measures (QMs) can drive improvement in cancer systems by highlighting gaps in care. Targeting quality improvement at QMs that demonstrate substantial variation has the potential to make the largest impact at the population level. We developed an approach that uses both variation in performance and number of patients affected by the QM to set priorities for improving the quality of systemic therapy for women with early-stage breast cancer (EBC). Patients and Methods Patients with EBC diagnosed from 2006 to 2010 in Ontario, Canada, were identified in the Ontario Cancer Registry and linked deterministically to multiple health care databases. Individual QMs within a panel of 15 QMs previously developed to assess the quality of systemic therapy across four domains (access, treatment delivery, toxicity, and safety) were ranked on interinstitutional variation in performance (using interquartile range) and the number of patients who were affected; then the two rankings were averaged for a summative priority ranking. Results We identified 28,427 patients with EBC who were treated at 84 institutions. The use of computerized physician electronic order entry for chemotherapy, emergency room visits or hospitalizations during chemotherapy, and timely receipt of chemotherapy were identified as the QMs that had the largest potential to improve quality of care at a system level within this cohort. Conclusion A simple ranking system based on interinstitutional variation in performance and patient volume can be used to identify high-priority areas for quality improvement from a population perspective. This approach is generalizable to other health care systems that use QMs to drive improvement.

Towards collation and modelling of the global cost of armed violence on civilians.

A method is described which translates qualitative reports about armed violence into meaningful quantitative data allowing an evidence-based approach to the causes and effects of the global health impact of armed violence on unarmed people. Analysis of 100 randomly selected news reports shows that the type of weapon used, the psychological aspect of the violence, the number of weapons in use and the victims' vulnerability independently influence the mortality of victims. Data collated by the same method could be analysed together with indicators of poverty, development and health so illuminating the relationship between such indicators and degradation of peoples' physical security through acts of armed violence. The method could also help uphold the laws of war and human rights.

Palliative care and the aggressiveness of end-of-life care in patients with advanced pancreatic cancer.

BACKGROUND: We examined the impact of palliative care (PC) on aggressiveness of end-of-life care for patients with advanced pancreatic cancer. Measures of aggressive care included chemotherapy within 14 days of death; and at least one intensive care unit (ICU) admission, more than one emergency department (ED) visit, and more than one hospitalization, all within 30 days of death. METHODS: A retrospective population-based cohort study using administrative data was conducted in patients with advanced pancreatic cancer from 2005 to 2010 in Ontario, Canada. Multivariable logistic regression was performed with the above measures of aggressive care as the outcomes of interest and PC as the main exposure, adjusting for covariables. Secondary analyses examined intensity of PC as the main exposure defined in two ways: 1) absolute number of PC visits before the outcome of interest (0, 1, 2, 3+ visits) and 2) monthly rate of PC visits. RESULTS: The cohort included 5381 patients (median survival 75 days); 2816 (52.3%) had received a PC consultation. PC consultation was associated with decreased use of chemotherapy near death (odds ratio [OR] = 0.34, 95% confidence interval [CI] = 0.25 to 0.46); lower risk of ICU admission: OR = 0.12, 95% CI = 0.08 to 0.18; multiple ED visits: OR = 0.19, 95% CI = 0.16 to 0.23; multiple hospitalizations near death: OR = 0.24, 95% CI = 0.19 to 0.31). A per-unit increase in the monthly rate of PC visits was associated with lower odds of aggressive care for all four outcomes. CONCLUSION: PC consultation and a higher intensity of PC were associated with less aggressive care near death in patients with advanced pancreatic cancer.

Time scale and other invariants of integrative mechanical behavior in living cells.

In dealing with systems as complex as the cytoskeleton, we need organizing principles or, short of that, an empirical framework into which these systems fit. We report here unexpected invariants of cytoskeletal behavior that comprise such an empirical framework. We measured elastic and frictional moduli of a variety of cell types over a wide range of time scales and using a variety of biological interventions. In all instances elastic stresses dominated at frequencies below 300 Hz, increased only weakly with frequency, and followed a power law; no characteristic time scale was evident. Frictional stresses paralleled the elastic behavior at frequencies below 10 Hz but approached a Newtonian viscous behavior at higher frequencies. Surprisingly, all data could be collapsed onto master curves, the existence of which implies that elastic and frictional stresses share a common underlying mechanism. Taken together, these findings define an unanticipated integrative framework for studying protein interactions within the complex microenvironment of the cell body, and appear to set limits on what can be predicted about integrated mechanical behavior of the matrix based solely on cytoskeletal constituents considered in isolation. Moreover, these observations are consistent with the hypothesis that the cytoskeleton of the living cell behaves as a soft glassy material, wherein cytoskeletal proteins modulate cell mechanical properties mainly by changing an effective temperature of the cytoskeletal matrix. If so, then the effective temperature becomes an easily quantified determinant of the ability of the cytoskeleton to deform, flow, and reorganize.

Time to virologic failure for patients taking their first antiretroviral regimen and the subsequent resistance profiles.

INTRODUCTION: The resistance profiles of first-line antiretroviral therapy (ART) regimens after virologic failure have yet to be studied in a clinic setting in the modern treatment era. Time to virologic failure among three standard first-line regimens and the resistance profiles of these failures were compared. MATERIALS AND METHODS: All HIV-positive persons aged 16 and over starting a three-drug first-line ART regimen were retrospectively identified at a Toronto community clinic (1 January 2006-1 January 2013). The regimens included a backbone of two NRTIs and a third agent; a PI, an NNRTI, or an II. Patients must have been on treatment for at least 14 days and have at least one VL test within 6 months after starting treatment. The primary outcome was virologic failure defined as either: no suppression by 6 months, or after suppression, two consecutive, detectable VL200 copies/mL at least 14 days apart or one VL>200 copies/mL. Time to failure was compared using a proportional hazards model adjusting for demographic and clinical factors. Resistance profiles of NRTIs and third agents are described in patients with virologic failure who had both baseline and virologic failure genotypes. RESULTS: Six hundred sixty patients (93% male) were included with a mean age of 38.9 and a median follow-up period of 35.3 (32.2-39.3) months. Distribution of third agent use was: PI 37.3% (n=246), NNRTI 55.9% (n=369) and II 6.8% (n=45). Virologic failures occurred in 81/246 (33%) with PI, 87/369 (24%) with NNRTI and 11/45 (24%) with II. Compare to PIs, time to failure was longer with NNRTIs (p=0.0013) and similar for IIs (p=0.1562). No evidence that failure with NNRTIs was different from IIs (p=0.9139). Of the 660 patients, 567 (86%) had a baseline genotype. Of the 567 patients, 179 had virological failure. Of the 179, 145(81%) had a baseline genotype and only 37 (21%) had both a baseline and follow-up genotype. Upon failure, emerging ART resistance was rare. No new PI or II mutations were identified and one new NNRTI (Y181C) mutation was identified. Three patients taking PI-based regimens developed NRTI mutations (M184V, M184I, T215Y). CONCLUSIONS: Time to virologic failure was significantly greater in the NNRTI group compared to the PI group. If failure did occur, ART resistance rarely developed with no PI mutations but a few NRTI mutations in those taking PI-based regimens, and NNRTI mutations in those taking NNRTI-based regimen.