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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.

Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues. published

Challenges of “Return to Work” in an Ongoing Pandemic The authors discuss the public health challenges faced by commercial establishments in preventing transmission of Covid-19 among their workers ...

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.

SUMMARYThe somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome sequenced tumours from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features with signatures of related aetiologies being similarly affected. Certain signatures exhibit periodic behaviours or cancer-type specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via COSMIC, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer.GRAPHICAL ABSTRACTHIGHLIGHTSComprehensive topography analysis of mutational signatures encompassing 82,890,857 somatic mutations in 5,120 whole-genome sequenced tumours integrated with 516 tissue-matched topographical features from the ENCODE project.The accumulation of somatic mutations from most mutational signatures is affected by nucleosome occupancy, histone modifications, CTCF binding sites, transcribed regions, or replication strand/timing.Mutational signatures with related aetiologies are consistently characterized by similar genome topographies across tissue types.Topography analysis allows both separating signatures from different aetiologies and understanding the genomic specificity of clustered somatic mutations.A comprehensive online resource, disseminate through the COSMIC signatures database, that allows researchers to explore the interactions between somatic mutational processes and genome architecture within and across cancer types.

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.

When the World Health Organization proclaimed 2020 the International Year of the Nurse and Midwife, no one could have predicted that COVID-19 would expose so publicly the extraordinary work of nurses. Their courage, compassion, and skill have elicited gratitude of patients and families internationally. The DAISY Award has been honoring nurses, providing a structured program of ongoing meaningful recognition of nurses since 1999. This article presents the compelling voice of a DAISY nurse whose perspective on 2020 delves into the heart of nursing—nurses’ relationships with their patients that are built on their moments together—the moments DAISY honors.

In 2018, the International Organization for Standardization (ISO) 19867–1 “Harmonized laboratory test protocols” were released for establishing improved quality and comparability for data on cookstove air pollutant emissions, efficiency, safety, and durability. This is the first study that compares emissions [carbon dioxide, carbon monoxide, total hydrocarbons, methane, nitrogen oxides, fine particulate matter (PM(2.5)), organic carbon, elemental carbon, and ultrafine particles] and efficiency data between the ISO protocol and the Water Boiling Test (WBT). The study examines six stove/fuel combinations [liquefied petroleum gas (LPG), pellet, wood fan, wood rocket, three stone fire, and charcoal] tested in the same US EPA laboratory. Evaluation of the ISO protocol shows improvements over previous test protocols and that results are relatively consistent with former WBT data in terms of tier ratings for emissions and efficiency, as defined by the ISO 19867–3 “Voluntary Performance Targets.” Most stove types remain similarly ranked using ISO and WBT protocols, except charcoal and LPG are in higher PM(2.5) tiers with the ISO protocol. Additionally, emissions data including polycyclic aromatic hydrocarbons are utilized to compare between the ISO and Firepower Sweep Test (FST) protocols. Compared to the FST, the ISO protocol results in generally higher PM(2.5) tier ratings.

The Courts of Justice of the European Union (CJEU) held in its July 2020 Schrems II decision that, in order for entities in other countries to import personal data from the European Economic Area (EEA), the importer must be able to provide data protections ‘essentially equivalent’ to those the EEA offers under its General Data Protection Regulation. The CJEU expressed particular concern that United States’ national security intelligence gathering laws prevent U.S.-based entities from providing such protections. This decision has sharply limited the sharing of clinical research data from the EEA to the United States. After describing the pertinent aspects of the Schrems II decision, this article evaluates U.S. national security intelligence gathering frameworks, including Section 702 of the Foreign Intelligence Surveillance Act and Executive Order 12333. The article then leverages recent draft guidance from the European Data Protection Board to explain how entities may be able to adopt widely used contractual and technical measures, such as data pseudonymization, to provide ‘essentially equivalent’ protections in the clinical research context.

Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for

SUMMARYMutational signature analysis is commonly performed in genomic studies surveying cancer and normal somatic tissues. Here we present SigProfilerExtractor, an automated tool for accurate de novo extraction of mutational signatures for all types of somatic mutations. Benchmarking with a total of 34 distinct scenarios encompassing 2,500 simulated signatures operative in more than 60,000 unique synthetic genomes and 20,000 synthetic exomes demonstrates that SigProfilerExtractor outperforms thirteen other tools across all datasets with and without noise. For genome simulations with 5% noise, reflecting high-quality genomic datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true positive signatures while yielding more than 5-fold less false positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome sequenced and 19,184 whole-exome sequenced cancers reveals four previously missed mutational signatures. Two of the signatures are confirmed in independent cohorts with one of these signatures associating with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting mutational signatures, and several novel mutational signatures including a signature putatively attributed to direct tobacco smoking mutagenesis in bladder cancer and in normal bladder epithelium.

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.

Background Performing a statistical test requires a null hypothesis. In cancer genomics, a key challenge is the fast generation of accurate somatic mutational landscapes that can be used as a realistic null hypothesis for making biological discoveries. Results Here we present SigProfilerSimulator, a powerful tool that is capable of simulating the mutational landscapes of thousands of cancer genomes at different resolutions within seconds. Applying SigProfilerSimulator to 2144 whole-genome sequenced cancers reveals: (i) that most doublet base substitutions are not due to two adjacent single base substitutions but likely occur as single genomic events; (ii) that an extended sequencing context of ± 2 bp is required to more completely capture the patterns of substitution mutational signatures in human cancer; (iii) information on false-positive discovery rate of commonly used bioinformatics tools for detecting driver genes. Conclusions SigProfilerSimulator’s breadth of features allows one to construct a tailored null hypothesis and use it for evaluating the accuracy of other bioinformatics tools or for downstream statistical analysis for biological discoveries. SigProfilerSimulator is freely available at https://github.com/AlexandrovLab/SigProfilerSimulator with an extensive documentation at https://osf.io/usxjz/wiki/home/.

Sharing of data for research beyond the EU must improve

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.

High-risk sharing practices among people who inject drugs (PWID) are associated with high rates of HIV transmission in several parts of the world. PWID in these regions face significant barriers to HIV testing and engagement in care, highlighting the need to develop and test interventions aimed at overcoming these barriers. Drug use and HIV are often highly stigmatized in these same settings, which raises safety concerns during the conduct of research. In preparing to address concerns about the safety and well-being of participants in an international research study, HPTN (HIV Prevention Trials Network) 074, we developed participant safety plans (PSPs) at each site to supplement local research ethics committee oversight, community engagement and usual clinical trial procedures. The PSPs were informed by systematic local legal and policy assessments as well as interviews with key stakeholders. Following PSP refinement and implementation, we assessed social impacts at each study visit to ensure continued safety. Throughout the study, five participants reported a negative social impact, with three resulting from study participation. Future research with stigmatized populations should consider using and assessing this approach to enhance participants’ safety and welfare.

Approaches to quantitative equity investing have evolved markedly. Thirty years ago, the focus was on alpha generation, but with the recent decade’s acceptance of smart (alternative) beta, the focus is turning to transparent methods of construction for factor investing. In this article, the authors present an approach for evaluating various methods of portfolio construction that lead to the same factor exposures. Four portfolios are of interest: factor weighted, cap weighted, equal weighted, and risk parity weighted. The authors compare these portfolios based on standard performance statistics as well as new metrics of value-added, such as performance participation rates and portfolio sector concentrations. The results indicate that once the desired factor exposure is achieved, it is beneficial to build the portfolio with the most desirable characteristics in terms of diversification.

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.

Many investors that adopt minimum volatility strategies are inadvertently allowing unnecessary volatility in their minimum volatility allocations by ignoring the underlying currency assumptions used in building their portfolios. Specifically, portfolio country weights can vary widely depending on the currency used in calculating risk. In this article, the authors provide empirical evidence that the currency of the risk calculation should match the currency used in evaluating the portfolio’s performance. In practice, many investors are well aware of the latter but unaware of the former, which can be embedded in commonly available benchmarks and investment vehicles. Any mismatch can lead to increased volatility.

ObjectivesThe National Cancer Institute (NCI) National Clinical Trials Network performs phase II and III clinical trials, which increasingly rely on the submission of diagnostic formalin-fixed, paraffin-embedded tissue blocks for biomarker assessment. Simultaneously, advances in precision oncology require that clinical centers maintain diagnostic specimens for ancillary, standard-of-care diagnostics. This has caused tissue blocks to become a limited resource for advancing the NCI clinical trial enterprise and the practice of modern molecular pathology.MethodsThe NCI convened a 1-day workshop of multidisciplined experts to discuss barriers and strategic solutions to facilitate diagnostic block submission for clinical trial science, from the perspective of patient advocates, legal experts, pathologists, and clinical oncologists.ResultsThe expert views and opinions were carefully noted and reported.ConclusionsRecommendations were proposed to reduce institutional barriers and to assist organizations in developing clear policies regarding diagnostic block submission for clinical trials.