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The Paso del Indio site, discovered and partially mitigated in the midst of a major highway construction project, is the largest and deepest stratified, multi-component prehistoric site found to date on the island of Puerto Rico, and likely the entire Greater Antilles. The site exhibits a number of cultural occupation levels, separated by the deposition of sterile soil levels. This circumstance created a stratigraphic sequence of thousands of years of occupation, over 5 meters deep, representing the four prehistoric culture history periods known for Puerto Rico, as defined in the 1950s. This article is a summary of the work accomplished on this site thus far, analysis of selected material culture, and recent contributions of the site to Caribbean archaeology.

Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1–5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7–9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.

Health care is transitioning from genetics to genomics, in which single-gene testing for diagnosis is being replaced by multi-gene panels, genome-wide sequencing, and other multi-genic tests for disease diagnosis, prediction, prognosis, and treatment. This health care transition is spurring a new set of increased or novel liability risks for health care providers and test laboratories. This article describes this transition in both medical care and liability, and addresses 11 areas of potential increased or novel liability risk, offering recommendations to both health care and legal actors to address and manage those liability risks.

The advent of the European Union’s General Data Protection Regulation (GDPR) has posed several significant difficulties for the secondary research uses of data and associated biospecimens and has led to widespread unease within the international biobanking and databanking community. This disruption of research using personal data and associated biospecimens has gone largely unremarked in the professional literature, including in a recent account of GDPR’s relationship to biobanking practices published in this journal, which instead advocated even more stringent, and in our view, unnecessary restrictions on research uses of banked data and materials. In this article, we describe challenges that GDPR has posed for biobanks and databanks and for researchers who use those banked resources for secondary research. We discuss the limitations inherent in the few pathways that GDPR makes available for secondary research, given that such pathways rely upon complex and varied laws of individual European Union member states. We advocate mitigation of these difficulties through regulatory guidance in order to allow important scientific research to continue.

Title VI of the Civil Rights Act of 1964 and its implementing regulations prohibit federally-funded educational institutions and healthcare centers from engaging in disparate impact discrimination “on the ground of race, color, or national origin” in all of their operations.

In response to researcher noncompliance with ethical and regulatory provisions governing research with humans, protocol deviations, and unanticipated problems with research, institutional review boards (IRBs) or institutions sometimes impose restrictions on the use of research data, although specific cases in which this happens are unlikely to be known publicly. We review IRB policies at top research institutions in the United States about restrictions on the use of research data and describe potential reasons for restricting the use of such data in the context of ensuring compliance with human subjects research standards. We also discuss ethical considerations related to restricting the use of research data and argue that IRBs have limited regulatory authority to take such actions. Finally, we offer recommendations regarding decision-making about restricting the use of research data and call for additional guidance in this area.

As part of ongoing efforts to address the opioid crisis, on June 1, 2018, HSS Journal® convened a multidisciplinary panel of experts for a daylong discussion: Toward Opioid-Free Arthroplasty: A Leadership Forum. Each invited participant presented on a specific aspect of the opioid crisis and/or pain management as it relates to total hip or knee arthroplasty. Representing orthopedics, anesthesiology, psychiatry, bioethics, health information technology, and law, this group crafted a consensus statement on appropriate pain management for total hip or knee arthroplasty. Many have also contributed to this special issue of HSS Journal on “Opioid Prescribing and Pain Management” (February 2019) (Fig. 1). Open in a separate window Fig. 1 Participants in Toward Opioid-Free Arthroplasty: A Leadership Forum, June 1, 2018, at Hospital for Special Surgery (pictured left to right): Travis N. Rieder, PhD, Christopher Lee Wu, MD, Jonathan Avery, MD, Seth Waldman, MD, Charles N. Cornell, MD, Ellen M. Soffin, MD, PhD, William Schairer, MD, Mark Barnes, JD, LLM, Alex Rich, MPH, and Louis A. Shapiro, FACHE. (Not pictured: Todd J. Albert, MD, and E. Carlos Rodriguez-Merchan, MD, PhD.) Photograph by Robert Essel.

The revised Common Rule includes a new option for the conduct of secondary research with identifiable data and biospecimens: regulatory broad consent. Motivated by concerns regarding autonomy and trust in the research enterprise, regulators had initially proposed broad consent in a manner that would have rendered it the exclusive approach to secondary research with all biospecimens, regardless of identifiability. Based on public comments from both researchers and patients concerned that this approach would hinder important medical advances, however, regulators decided to largely preserve the status quo approach to secondary research with biospecimens and data. The Final Rule therefore allows such research to proceed without specific informed consent in a number of circumstances, but it also offers regulatory broad consent as a new, optional pathway for secondary research with identifiable data and biospecimens. In this article, we describe the parameters of regulatory broad consent under the new rule, explain why researchers and research institutions are unlikely to utilize it, outline recommendations for regulatory broad consent issued by the Secretary's Advisory Committee on Human Research Protections (SACHRP), and sketch an empirical research agenda for the sorts of questions about regulatory broad consent that remain to be answered as the research community embarks on Final Rule implementation.

Nearly 19 years have passed since our son Patrick died of complications of idiopathic thrombocytopenia, an autoimmune disease, and we created The DAISY Award for Extraordinary Nurses. AONE has played an important role in our journey—a journey that has brought a meaningful recognition program dedicated to nurses to over 3,200 health care facilities and schools of nursing, throughout the United States and in 18 other countries. This is a story of collaboration between a grieving family and a professional organization that was the first organization to help us see the value in a concept we designed to say thank you to nurses for the extraordinary care we experienced during our Patrick's 8-week hospitalization in late 1999. Today, 30 professional associations support our work. But it was AONE who first provided the guidance of nursing leadership to make our vision a reality. Their support in our early years, when we really needed help, boosted this work and brought DAISY to light for the entire nursing profession.

The scope and severity of the opioid epidemic in the United States has prompted significant legislative intrusion into the patient-physician relationship. These proscriptive regulatory regimes mirror earlier legislation in other politically-charged domains like abortion and gun regulation. We draw on lessons from those contexts to argue that states should consider integrating their responses to the epidemic with existing medical regulatory structures, making physicians partners rather than adversaries in addressing this public health crisis.

There is abundant evidence in support of single fraction (SF) radiation therapy (RT) for uncomplicated bone metastases (BoM). We sought to determine the proportion of BoM that is complicated in a population-based RT program in order to act as a potential guide for assessing SFRT utilization rates.A total of 3200 RT courses were prescribed to 1880 consecutive patients diagnosed with BoM in 2013. Associations between choice of RT fractionation and BoM characterization, whether complicated or not, were assessed with logistic regression.The incidence of complicated BoM was 34.4%, resulting most often from adverse features of actual pathological fracture (42.1%), and neurological compromise (36.3%). Complicated BoM were most common in lung cancers (24.2%) and in the spine (68.5%), followed by extremity (15.2%) and pelvis (14.4%). SFRT was prescribed less commonly in complicated versus un-complicated BoM (39.4% vs. 70.4%; p0.001), which was confirmed on multivariable analysis (OR 0.32; 95% CI 0.28-0.61; p0.001).This study found that 34.4% of BoM are complicated by fracture, or neurological compromise (i.e. 65.6% were un-complicated), and that they were less likely to receive SFRT. A reasonable benchmark for SFRT utilization should be at least 60%.

Investors are increasingly interested in portfolios that are not cap-weighted and that give exposure to specific factor premiums, which we call smart beta portfolios. In this article, we focus on the asset weighting used in smart beta portfolios and show that risk balancing when building factor exposure portfolios yields the most efficient capture of the factor exposure premium. This efficiency comes from both adequate intended factor exposure, which captures positive factor risk premium, and reduced risk concentration in unintended factors, which comes directly from the risk balancing. Other commonly used weighting schemes tend to have less efficient factor premium capture due in part to these unintended risk concentrations, which enter the portfolio because risk is not explicitly taken into account when weighting the assets.

This review examines studies that detail the effects of weather and climate on urban transit systems and ridership. The aim is to help revitalize a hazards geography research agenda to support stakeholder decision-making on hazard risk and disaster vulnerability for US transit systems and ridership. Largely representative of the literature are field perspectives outside of hazards geography whose predispositions to positivism neglect equity concerns of vital importance to hazard risk mitigation, vulnerability reduction, adaptation, and resilience research and practitioner communities. The article argues for hazards geography's perspectival insight to fill this void. Themes discussed in the article include hazards geography value, transit system vulnerability to meteorological and non-meteorological factors, place-based climate change vulnerability assessments, policymaker and managerial perceptions of climate change, and transit ridership choice. The article concludes with a call to hazards geographers to conduct critical assessments of structural and non-structural adaptation measures, investigate mobility decision-making and coping strategies, and develop theoretical understandings on adaptation policymaking and practice in relation to hazard risk and disaster vulnerability.

In contrast to factor-based smart beta, diversification-based smart beta assumes that, seemingly naively, all investments are the same in some dimension. The four possible dimensions—portfolio weight, expected return, risk-adjusted return, and risk contribution—lead respectively to four naive beta portfolios: equally weighted, minimum-variance, maximum-diversification, and risk parity portfolios. In this article, the authors show how these four portfolios outperform the capitalization-weighted S&P 500 Index due to their sector differences and, especially, the index’s aggressive shifts into specific sectors. Among the three naive beta portfolios that use risk inputs as part of their portfolio construction, both minimum-variance and maximum-diversification portfolios tend to be highly concentrated in certain sectors. The authors develop an analytic framework based on a partitioned correlation matrix, modeling sectors as two groups (mostly defensive versus cyclical). The results shed light on material differences between the risk parity and optimized portfolios in their level of diversification. Empirical examples of sector portfolios within the universe of the S&P 500 Index show the triumph of naive beta over the index, which suffers from strong sector biases and ill-timed allocation shifts.

Purpose There is abundant evidence that a single fraction (SF) of palliative radiation therapy (RT) for bone metastases is equivalent to more protracted and costly multiple fraction courses. Despite this, there is low utilization of SFRT internationally. We sought to determine the utilization of SFRT in a population-based, publicly funded health care system. Methods and Materials All consecutive patients with bone metastases treated with RT during 2007 to 2011 in British Columbia (BC) were identified. Associations between utilization of SFRT and patient and provider characteristics were investigated. Results A total of 16,898 courses of RT were delivered to 8601 patients. SFRT was prescribed 49% of the time. There were positive relationships among SFRT utilization and primary tumor group ( P P P P P P Conclusions The large variability in SFRT utilization across BC Cancer Agency (BCCA) cancer centers suggests there is a strong cultural effect, where physicians' use of SFRT is influenced by their colleagues' practice. SFRT use in BC was similar to that in other Canadian and western European reports but strikingly higher than in the United States. Further work is needed to standardize SFRT prescribing practices internationally for this common indication for RT, with the potential for huge health system cost savings and substantial improvements in patients' quality of life.

Over the past three decades, two separate federal regulatory structures have emerged, each seeking to assure separate aspects of the integrity and ethics of research conducted using federal funding. One set of regulations is described in the Public Health Service Policies on Research Misconduct and relates to research misconduct, defined as consisting of fabrication of data or results, falsification of data and results, or plagiarism, in accordance with the federal-wide definition adopted by the Office of Science and Technology Policy. The second set of regulations, set forth in the Department of Health and Human Services regulations on the protection of human subjects (known as the “Common Rule”), prescribes a set of ethical and procedural protections for research involving human subjects. These two sets of research regulations are distinguished from each other by having different foci of enforcement, priorities of protection, oversight officials, oversight procedures, seizure of evidence, standards of proof, expectations of privacy, and appeal procedures for researchers who are subject to adverse findings and penalties. These differences are significant and fundamental. They complicate the process of compliance for institutions and researchers, who are expected to adhere to both sets of standards for the same federally funded research activities in research with human subjects. Compliance is especially complicated when suspected violations of both sets of standards must be investigated and resolved concurrently. This document represents an effort to provide institutions and individuals with practical suggestions as they try to comply with both sets of regulations.

Purpose: This study assesses the incidence of distal bone metastases in palliative radiotherapy (RT) patients. Material and methods: All courses of RT for bone metastases from 2007–2011 for patient living in British Columbia (BC) were identified in a provincial RT programme. Treated bone metastases (BoM) were categorized as distal if the BoM was located within or distal to the elbow or knee. Patients were grouped by primary tumour site as breast, lung, prostate gastrointestinal, haematological, melanoma, and other. The incidence of distal bone metastases and associations with primary tumour types were determined. Results: From 2007 to 2011, 8008 patients were treated with 16,277 courses of RT, of which 425 (3%) were courses of RT for distal BoM. The incidence of distal BoM in decreasing order by primary tumour type was melanoma (5%), haematological (3%), lung (2%), other (2%), prostate (2%), breast (1%) and gastrointestinal (1%). Distal BoM where more commonly identified in the lower extremity (87%, p

This study assessed the impact of the distance a patient travelled to the treatment centre on the use of single fraction RT for bone metastases. There was significant variability in the prescription of SFRT by distance at which the patient lives from a cancer centre (p < 0.001).

Savannah River Site (SRS) personnel have completed construction and assembly of the Modular Caustic Side Solvent Extraction Unit (MCU) facility. Following assembly, they conducted testing to evaluate the ability of the process to remove non-radioactive cesium and to separate the aqueous and organic phases. They conducted tests at salt solution flow rates of 3.5, 6.0, and 8.5 gpm. During testing, the MCU Facility collected samples and submitted them to Savannah River National Laboratory (SRNL) personnel for analysis of cesium, Isopar{reg_sign} L, and Modifier [1-(2,2,3,3-tetrafluoropropoxy)-3-(4-sec-butylphenoxy)-2-propanol]. SRNL personnel analyzed the aqueous samples for cesium by Inductively-Coupled Plasma Mass Spectroscopy (ICP-MS) and the solvent samples for cesium using a Parr Bomb Digestion followed by ICP-MS. They analyzed aqueous samples for Isopar{reg_sign} L and Modifier by gas chromatography (GC).

Objective: Smoking rate is disproportionately high among patients with schizophrenia, resulting in significant morbidity and mortality. However, cigarette smoking has been reported to have beneficial effects on negative symptoms, extrapyramidal symptoms, cognitive functioning and mood symptoms. Therefore, smoking cessation may worsen disability in schizophrenia. The association between smoking and these key clinical parameters was examined. Additionally, severity of smoking across four different antipsychotic treatment groups was explored. Method: One hundred and forty-six patients with schizophrenia were assessed for smoking using expired carbon monoxide and smoking history. They were administered the Positive and Negative Symptom Scale, The Extrapyramidal Symptom Rating Scale, the Barnes Akathisia Rating Scale, Reitans Trail-making Test (A and B) and General Health Questionnaire-28. Results: There was no difference in the chlorpromazine equivalent dose of any of the medications studied. Atypical agents were associated with significantly lower levels of smoking when compared with typical medications. There was no difference in smoking severity between the individual atypical medications examined. Similarly, there were no significant differences between smoking and non-smoking groups with regard to Positive and Negative Symptom Scale, Extrapyramidal Symptom Rating Scale, Trail-making Test and General Health Questionnaire-28. However, there was a significant difference between these groups with the smoking group demonstrating less akathisia. Conclusions: Smoking is not associated with positive, negative cognitive and mood symptoms in schizophrenia. Smoking is associated with lower levels of antipsychotic induced akathisia. Clinicians should not be discouraged from helping patients stop smoking for fear of worsening symptoms. However, akathisia may emerge upon cessation of smoking. Switching patients from typical to atypical antipsychotics may assist patients with schizophrenia to give up smoking.

Objective: The aim was to develop a psychiatric assessment and advisory service for local general practitioners (GPs). Method: In July 2001, five full-time psychiatrists at Royal Brisbane Hospital each dedicated a 1-h appointment per week in their hospital private practice clinic to assess patients referred by local GPs. The ‘Psych Opinion’ clinic was advertised through the Division of General Practice Newsletter. After 12 months, the referrals to the clinic had been disappointing so two surveys were carried out: one to the GPs who had used the service and the other to those who had not referred. Results: Feedback from the GPs who had used the service showed a high level of satisfaction with the service. The second survey of the GPs who had not referred showed a strong endorsement of the concept but there was poor awareness of the service's existence. Conclusions: This model offers a way for public sector psychiatrists to provide timely assessments to local GPs without additional funding. There is strong support and willingness from the GPs to refer. However, the need to actively market the service both initially and on an ongoing basis is highlighted.

The ongoing globalization of world economies and introduction of the euro have prompted the reevaluation of country and sector effects on security returns. Here is research on the relative importance of countries and sectors and the changes over time. While sectors seem to be growing in importance, country effects remain significant. Given a belief that this situation will persist for some time, the authors argue that active strategies cannot afford to ignore country effects.

The anti-inflammatory effects of globular adiponectin (gAcrp) are mediated by IL-10/heme oxygenase 1 (HO-1)-dependent pathways. Although full-length (flAcrp) adiponectin also suppresses LPS-induced pro-inflammatory signaling, its signaling mechanisms are not yet understood. The aim of this study was to examine the differential mechanisms by which gAcrp and flAcrp suppress pro-inflammatory signaling in macrophages. Chronic ethanol feeding increased LPS-stimulated TNF-α expression by Kupffer cells, associated with a shift to an M1 macrophage polarization. Both gAcrp and flAcrp suppressed TNF-α expression in Kupffer cells; however, only the effect of gAcrp was dependent on IL-10. Similarly, inhibition of HO-1 activity or siRNA knockdown of HO-1 in RAW264.7 macrophages only partially attenuated the suppressive effects of flAcrp on MyD88-dependent and -independent cytokine signatures. Instead, flAcrp, acting via the adiponectin R2 receptor, potently shifted the polarization of Kupffer cells and RAW264.7 macrophages to an M2 phenotype. gAcrp, acting via the adiponectin R1 receptor, was much less effective at eliciting an M2 pattern of gene expression. M2 polarization was also partially dependent on AMP-activated kinase. flAcrp polarized RAW264.7 macrophages to an M2 phenotype in an IL-4/STAT6-dependent mechanism. flAcrp also increased the expression of genes involved in oxidative phosphorylation in RAW264.7 macrophages, similar to the effect of flAcrp on hepatocytes. In summary, these data demonstrate that gAcrp and flAcrp utilize differential signaling strategies to decrease the sensitivity of macrophages to activation by TLR4 ligands, with flAcrp utilizing an IL-4/STAT6-dependent mechanism to shift macrophage polarization to the M2/anti-inflammatory phenotype.

In June of 2002, the US Supreme Court upheld a regulation that allows employers, under the Americans with Disabilities Act, to make disability-related employment decisions based on risks to an employee’s own personal health or safety. Previous judicial decisions had allowed employers to make employment decisions based on the threat that a worker’s medical condition posed to others but had not addressed the issue of risk posed to an employee’s health by his or her own disability. The authors comment on the potential effects of the court’s decision for occupational health practitioners charged with assessing the degree of risk and harm of a particular workplace environment and for public health efforts aimed at curbing workplace injury and sickness.

In both academic literature and the media, financial conflicts of interest in human subjects research have come center-stage. The cover of a recent edition ofTimemagazine features a research subject in a cage with the caption human guinea pigs, signifying perhaps that human research subjects are no more protected from research abuses than are laboratory animals. That magazine issue highlights three well-publicized cases of human subjects research violations that occurred at the University of Oklahoma, the University of Pennsylvania, and Johns Hopkins University.At St. John Medical Center in Tulsa, Oklahoma, a study that was co-sponsored by the University of Oklahoma Health Sciences Center investigated an experimental vaccine for malignant melanoma. In that case, the chair of the university's institutional review board (IRB) — the committee within each medical institution charged with ethics review of human research projects undertaken at that institution — and the dean of the University's College of Medicine allegedly concealed from both the IRB and the United States Food and Drug Administration (FDA) a report by an outside consulting firm that had found severe deficiencies with the melanoma vaccine study being conducted at the medical center.