Studying harms of interventions with an equity lens in randomized trials.

Equity and health equity are fundamental pillars in fostering a just and inclusive society. While equity underscores fairness in resource allocation and opportunity, health equity aims to eradicate avoidable health disparities among social groups. The concept of harms in interventions-undesirable consequences associated with the use of interventions-often varies across populations due to biological and social factors, necessitating a nuanced understanding. An equity lens reveals disparities in harm distribution, urging researchers and policymakers to address these differences in their decision-making processes. Furthermore, interventions, even well-intentioned ones, can inadvertently exacerbate disparities, emphasizing the need for comprehensive harm assessment. Integrating equity considerations in research practices and trial methodologies, through study design or through practices such as inclusive participant recruitment, is pivotal in advancing health equity. By prioritizing interventions that address disparities and ensuring inclusivity in research, we can foster a more equitable healthcare system.

Social Determinants of Dry Eye in the United States: A Systematic Review.

PURPOSE: To conduct a systematic review to summarize current evidence on associations between social determinants of health (SDOH) indicators and dry eye in the United States. DESIGN: Systematic review. METHODS: We followed a protocol registered on Open Science Framework to include studies that examined associations between SDOH indicators and dry eye. We mapped SDOH indicators to 1 of the 5 domains following the Healthy People 2030 framework and categorized dry eye measures into "dry eye diagnosis and care," "dry eye symptoms," or "ocular surface parameters." We summarized the direction of association between SDOH indicators and dry eye as worsening, beneficial, or null. We used items from the Newcastle Ottawa Scale to assess risk of bias. RESULTS: Eighteen studies reporting 51 SDOH indicators, mostly mapped to the neighborhood and built environment domain, were included. Thirteen studies were judged at high risk of bias. Fifteen of 19 (79%) associations revealed an increase in the diagnosis of dry eye or delayed specialty care for it. Thirty-four of 56 (61%) associations unveiled exacerbated dry eye symptoms. Fifteen of 23 (65%) found null associations with corneal fluorescein staining. Ten of 22 (45%) associations revealed an increased tear break up time (45%) whereas another 10 (45%) showed null associations. CONCLUSIONS: Most SDOH indicators studied were associated with unfavorable dry eye measures, such as a higher disease burden, worse symptoms, or delayed referral, in the United States. Future investigations between SDOH and dry eye should use standardized instruments and address the domains in which there is an evidence gap.

Seminar: Extracellular Vesicles as Mediators of Environmental Stress in Human Disease.

BACKGROUND: Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between cells and tissues, both in normal cellular physiology and as a potential indicator of cellular stress, environmental exposures, and early disease pathogenesis. Extracellular signaling through EVs is a growing field of research for understanding fundamental mechanisms of health and disease and for the potential for biomarker discovery and therapy development. EVs are also known to play important roles in mediating the effects of exposure to environmental stress. OBJECTIVES: This seminar addresses the application of new tools and approaches for EV research, developed in part through the National Institutes of Health (NIH) Extracellular RNA Communication Program, and reflects presentations and discussions from a workshop held 27-28 September 2021 by the National Institute of Environmental Health Sciences (NIEHS) and the National Center for Advancing Translational Sciences (NCATS) on "Extracellular Vesicles, Exosomes, and Cell-Cell Signaling in Response to Environmental Stress." The panel of experts discussed current research on EVs and environmental exposures, highlighted recent advances in EV isolation and characterization, and considered research gaps and opportunities toward identifying and characterizing the roles for EVs in environmentally related diseases, as well as the current challenges and opportunities in this field. DISCUSSION: The authors discuss the application of new experimental models, particularly organ-on-chip (OOC) systems and in vitro approaches and how these have the potential to extend findings in population-based studies of EVs in exposure-related diseases. Given the complex challenges of identifying cell-specific EVs related to environmental exposures, as well as the general heterogeneity and variability in EVs in blood and other accessible biological samples, there is a critical need for rigorous reporting of experimental methods and validation studies. The authors note that these efforts, combined with cross-disciplinary approaches, would ensure that future research efforts in environmental health studies on EV biomarkers are rigorous and reproducible. https://doi.org/10.1289/EHP12980.

Health Research in the Wake of Disasters: Challenges and Opportunities for Sensor Science.

BACKGROUND: Disaster events adversely affect the health of millions of individuals each year. They create exposure to physical, chemical, biological, and psychosocial hazards while simultaneously exploiting community and individual-level vulnerabilities that allow such exposures to exert harm. Since 2013, the National Institute of Environmental Health Sciences (NIEHS) has led the development of the Disaster Research Response (DR2) program and infrastructure; however, research exploring the nature and effects of disasters on human health is lacking. One reason for this research gap is the challenge of developing and deploying cost-effective sensors for exposure assessment during disaster events. OBJECTIVES: The objective of this commentary is to synergize the consensus findings and recommendations from a panel of experts on sensor science in support of DR2. METHODS: The NIEHS convened the workshop, "Getting Smart about Sensors for Disaster Response Research" on 28 and 29 July 2021 to discuss current gaps and recommendations for moving the field forward. The workshop invited full discussion from multiple viewpoints, with the goal of identifying recommendations and opportunities for further development of this area of research. The panel of experts included leaders in engineering, epidemiology, social and physical sciences, and community engagement, many of whom had firsthand experience with DR2. DISCUSSION: The primary finding of this workshop is that exposure science in support of DR2 is severely lacking. We highlight unique barriers to DR2, such as the need for time-sensitive exposure data, the chaos and logistical challenges that ensue from a disaster event, and the lack of a robust market for sensor technologies in support of environmental health science. We highlight a need for sensor technologies that are more scalable, reliable, and versatile than those currently available to the research community. We also recommend that the environmental health community renew efforts in support of DR2 facilitation, collaboration, and preparedness. https://doi.org/10.1289/EHP12270.

Are ChatGPT and large language models "the answer" to bringing us closer to systematic review automation?

In this commentary, we discuss ChatGPT and our perspectives on its utility to systematic reviews (SRs) through the appropriateness and applicability of its responses to SR related prompts. The advancement of artificial intelligence (AI)-assisted technologies leave many wondering about the current capabilities, limitations, and opportunities for integration AI into scientific endeavors. Large language models (LLM)-such as ChatGPT, designed by OpenAI-have recently gained widespread attention with their ability to respond to various prompts in a natural-sounding way. Systematic reviews (SRs) utilize secondary data and often require many months and substantial financial resources to complete, making them attractive grounds for developing AI-assistive technologies. On February 6, 2023, PICO Portal developers hosted a webinar to explore ChatGPT's responses to tasks related to SR methodology. Our experience from exploring the responses of ChatGPT suggest that while ChatGPT and LLMs show some promise for aiding in SR-related tasks, the technology is in its infancy and needs much development for such applications. Furthermore, we advise that great caution should be taken by non-content experts in using these tools due to much of the output appearing, at a high level, to be valid, while much is erroneous and in need of active vetting.

Does experience matter? The relationship between nephrologist characteristics and end stage kidney disease patient outcomes.

BACKGROUND: Nephrology offers the unique opportunity to directly link patients to providers, allowing the study of patient outcomes at the provider level. The purpose of this analysis was to determine whether nephrologist experience, defined as years in nephrology practice, was associated with clinical outcomes. DESIGN: Physician data contained within the American Medical Association (AMA) Physician Masterfile was combined with patient and Medicare claims data from the United States Renal Data System (USRDS) for the calendar year 2012, with follow up extending through June 30, 2014. Associations with important healthcare outcomes including mortality in patients receiving maintenance renal replacement therapy (RRT), waitlisting for kidney transplantation, and receipt of a kidney transplant were determined with broad adjustment for both patient and provider level variables, with attention on tertile of provider time in practice. RESULTS: We identified 256,324 patients on maintenance RRT cared for by 6193 nephrologists. Nephrologists with the least experience were more likely to be female, reside in a region with ≥1,000,000 people, have a Doctor of Osteopathic Medicine degree, and have a listed maintenance of certification status as "yes." Overall, 30.2% of the cohort died at a mean follow up of 1.99 years. Compared to those with the 0-10 years of experience, receipt of care from nephrologists with more experience was associated with lower mortality (AHR 0.97 CI 0.94-0.99 for nephrologists with 11-20 years) and increased listing for kidney transplantation (AHR 1.10; CI 1.01-1.21 for nephrologists with >21 years experience). Experience level did not result in a difference in kidney transplantation rates. CONCLUSIONS: Receipt of maintenance RRT from nephrologists with greater experience was associated with decreased mortality and increased listing for kidney transplantation, an effect that remained significant after multiple adjustments for important patient and nephrologist variables.

Time to thrombectomy is associated with increased risk for dialysis catheter placement.

BACKGROUND: Arteriovenous dialysis access, fistulae (AVF) or grafts (AVG), are associated with significant rates of thrombosis. Timely thrombectomy may have a significant impact on immediate and long-term access survival. However, switching to a catheter is associated with higher rates of morbidity and mortality compared with those who have an AVF or AVG. OBJECTIVES: The goal of this study was to evaluate whether time to thrombectomy increases the risk for loss of dialysis access and subsequent placement of a dialysis catheter at hospital discharge, at 6 months, 12 months, and data at any time after discharge. METHODS: Using retrospective data, 444 patients were identified as having undergone thrombectomy for dialysis access dysfunction between January 2008 and April 2015, with 122 hospital admissions primarily for thrombectomy. RESULTS: The mean age was 60.4 years, 65% were male, and 44.3% had an arteriovenous fistula as their dialysis access. The mean time to thrombectomy was 10.8 hours, and 14 patients utilised a catheter for haemodialysis as primary access upon discharge. After adjustment for prior access intervention, access type, and time to thrombectomy, the adjusted odds ratios (AOR) of a one-day delay in thrombectomy was associated with a twofold increase in requirement for catheter at discharge and at 6 months. This association remained present at any time after discharge. CONCLUSION: In this study of patients cared for within an academic health system, a single day delay in thrombectomy nearly doubled the risk of needing a dialysis catheter at hospital discharge, 6 months, or any time after discharge.

CK2 Pro-Survival Role in Prostate Cancer Is Mediated via Maintenance and Promotion of Androgen Receptor and NFκB p65 Expression.

The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, and AR and NFκB are involved in the development and progression of prostate cancer, we investigated their interaction in benign and malignant prostate cells in the presence of altered CK2 expression. Our results show that elevation of CK2 levels caused increased levels of AR and NFκB p65 in prostate cells of different phenotypes. Analysis of TCGA PCa data indicated that AR and CK2α RNA expression are strongly correlated. Small molecule inhibition or molecular down-regulation of CK2 caused reduction in AR mRNA expression and protein levels in PCa cells and in orthotopic xenograft tumors by various pathways. Among these, regulation of AR protein stability plays a unifying role in CK2 maintenance of AR protein levels. Our results show induction of various endoplasmic reticulum stress signals after CK2 inhibition, which may play a role in the PCa cell death response. Of note, CK2 inhibition caused loss of cell viability in both parental and enzalutamide-resistant castrate-resistant PCa cells. The present work elucidates the specific link of CK2 to the pathogenesis of PCa in association with AR and NFκB expression; further, the observation that inhibition of CK2 can exert a growth inhibitory effect on therapy-resistant PCa cells emphasizes the potential utility of CK2 inhibition in patients who are on enzalutamide treatment for advanced cancer.

CDK11 Loss Induces Cell Cycle Dysfunction and Death of BRAF and NRAS Melanoma Cells.

Cyclin dependent kinase 11 (CDK11) is a protein kinase that regulates RNA transcription, pre-mRNA splicing, mitosis, and cell death. Targeting of CDK11 expression levels is effective in the experimental treatment of breast and other cancers, but these data are lacking in melanoma. To understand CDK11 function in melanoma, we evaluated protein and RNA levels of CDK11, Cyclin L1 and Cyclin L2 in benign melanocytes and BRAF- as well as NRAS-mutant melanoma cell lines. We investigated the effectiveness of reducing expression of this survival kinase using RNA interference on viability, clonal survival, and tumorsphere formation in melanoma cell lines. We examined the impact of CDK11 loss in BRAF-mutant melanoma on more than 700 genes important in cancer signaling pathways. Follow-up analysis evaluated how CDK11 loss alters cell cycle function in BRAF- and NRAS-mutant melanoma cells. We present data on CDK11, CCNL1 and CCNL2 mRNA expression in melanoma patients, including prognosis for survival. In sum, we found that CDK11 is necessary for melanoma cell survival, and a major impact of CDK11 loss in melanoma is to cause disruption of the cell cycle distribution with accumulation of G1- and loss of G2/M-phase cancer cells.

Towards quality assurance and quality control in untargeted metabolomics studies.

We describe here the agreed upon first development steps and priority objectives of a community engagement effort to address current challenges in quality assurance (QA) and quality control (QC) in untargeted metabolomic studies. This has included (1) a QA and QC questionnaire responded to by the metabolomics community in 2015 which recommended education of the metabolomics community, development of appropriate standard reference materials and providing incentives for laboratories to apply QA and QC; (2) a 2-day 'Think Tank on Quality Assurance and Quality Control for Untargeted Metabolomic Studies' held at the National Cancer Institute's Shady Grove Campus and (3) establishment of the Metabolomics Quality Assurance and Quality Control Consortium (mQACC) to drive forward developments in a coordinated manner.

Towards precision prevention: Technologies for identifying healthy individuals with high risk of disease.

The rise of advanced technologies for characterizing human populations at the molecular level, from sequence to function, is shifting disease prevention paradigms toward personalized strategies. Because minimization of adverse outcomes is a key driver for treatment decisions for diseased populations, developing personalized therapy strategies represent an important dimension of both precision medicine and personalized prevention. In this commentary, we highlight recently developed enabling technologies in the field of DNA damage, DNA repair, and mutagenesis. We propose that omics approaches and functional assays can be integrated into population studies that fuse basic, translational and clinical research with commercial expertise in order to accelerate personalized prevention and treatment of cancer and other diseases linked to aberrant responses to DNA damage. This collaborative approach is generally applicable to efforts to develop data-driven, individualized prevention and treatment strategies for other diseases. We also recommend strategies for maximizing the use of biological samples for epidemiological studies, and for applying emerging technologies to clinical applications.

Biomonitoring in the Era of the Exposome.

BACKGROUND: The term "exposome" was coined in 2005 to underscore the importance of the environment to human health and to bring research efforts in line with those on the human genome. The ability to characterize environmental exposures through biomonitoring is key to exposome research efforts. OBJECTIVES: Our objectives were to describe why traditional and nontraditional (exposomic) biomonitoring are both critical in studies aiming to capture the exposome and to make recommendations on how to transition exposure research toward exposomic approaches. We describe the biomonitoring needs of exposome research and approaches and recommendations that will help fill the gaps in the current science. DISCUSSION: Traditional and exposomic biomonitoring approaches have key advantages and disadvantages for assessing exposure. Exposomic approaches differ from traditional biomonitoring methods in that they can include all exposures of potential health significance, whether from endogenous or exogenous sources. Issues of sample availability and quality, identification of unknown analytes, capture of nonpersistent chemicals, integration of methods, and statistical assessment of increasingly complex data sets remain challenges that must continue to be addressed. CONCLUSIONS: To understand the complexity of exposures faced throughout the lifespan, both traditional and nontraditional biomonitoring methods should be used. Through hybrid approaches and the integration of emerging techniques, biomonitoring strategies can be maximized in research to define the exposome.

CK2 targeted RNAi therapeutic delivered via malignant cell-directed tenfibgen nanocapsule: dose and molecular mechanisms of response in xenograft prostate tumors.

CK2, a protein serine/threonine kinase, promotes cell proliferation and suppresses cell death. This essential-for-survival signal demonstrates elevated expression and activity in all cancers examined, and is considered an attractive target for cancer therapy. Here, we present data on the efficacy of a tenfibgen (TBG) coated nanocapsule which delivers its cargo of siRNA (siCK2) or single stranded RNA/DNA oligomers (RNAi-CK2) simultaneously targeting CK2α and α' catalytic subunits. Intravenous administration of TBG-siCK2 or TBG-RNAi-CK2 resulted in significant xenograft tumor reduction at low doses in PC3-LN4 and 22Rv1 models of prostate cancer. Malignant cell uptake and specificity in vivo was verified by FACS analysis and immunofluorescent detection of nanocapsules and PCR detection of released oligomers. Dose response was concordant with CK2αα' RNA transcript levels and the tumors demonstrated changes in CK2 protein and in markers of proliferation and cell death. Therapeutic response corresponded to expression levels for argonaute and GW proteins, which function in oligomer processing and translational repression. No toxicity was detected in non-tumor tissues or by serum chemistry. Tumor specific delivery of anti-CK2 RNAi via the TBG nanoencapsulation technology warrants further consideration of translational potential.

Mitochondria, energetics, epigenetics, and cellular responses to stress.

BACKGROUND: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria-nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. OBJECTIVES: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function. METHODS: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25-26 March 2013. Here, we summarize key points and ideas emerging from this meeting. DISCUSSION: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways. CONCLUSIONS: Understanding mitochondria-cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors.

Harnessing genomics to identify environmental determinants of heritable disease.

Next-generation sequencing technologies can now be used to directly measure heritable de novo DNA sequence mutations in humans. However, these techniques have not been used to examine environmental factors that induce such mutations and their associated diseases. To address this issue, a working group on environmentally induced germline mutation analysis (ENIGMA) met in October 2011 to propose the necessary foundational studies, which include sequencing of parent-offspring trios from highly exposed human populations, and controlled dose-response experiments in animals. These studies will establish background levels of variability in germline mutation rates and identify environmental agents that influence these rates and heritable disease. Guidance for the types of exposures to examine come from rodent studies that have identified agents such as cancer chemotherapeutic drugs, ionizing radiation, cigarette smoke, and air pollution as germ-cell mutagens. Research is urgently needed to establish the health consequences of parental exposures on subsequent generations.

Identification of novel positive-strand RNA viruses by metagenomic analysis of archaea-dominated Yellowstone hot springs.

There are no known RNA viruses that infect Archaea. Filling this gap in our knowledge of viruses will enhance our understanding of the relationships between RNA viruses from the three domains of cellular life and, in particular, could shed light on the origin of the enormous diversity of RNA viruses infecting eukaryotes. We describe here the identification of novel RNA viral genome segments from high-temperature acidic hot springs in Yellowstone National Park in the United States. These hot springs harbor low-complexity cellular communities dominated by several species of hyperthermophilic Archaea. A viral metagenomics approach was taken to assemble segments of these RNA virus genomes from viral populations isolated directly from hot spring samples. Analysis of these RNA metagenomes demonstrated unique gene content that is not generally related to known RNA viruses of Bacteria and Eukarya. However, genes for RNA-dependent RNA polymerase (RdRp), a hallmark of positive-strand RNA viruses, were identified in two contigs. One of these contigs is approximately 5,600 nucleotides in length and encodes a polyprotein that also contains a region homologous to the capsid protein of nodaviruses, tetraviruses, and birnaviruses. Phylogenetic analyses of the RdRps encoded in these contigs indicate that the putative archaeal viruses form a unique group that is distinct from the RdRps of RNA viruses of Eukarya and Bacteria. Collectively, our findings suggest the existence of novel positive-strand RNA viruses that probably replicate in hyperthermophilic archaeal hosts and are highly divergent from RNA viruses that infect eukaryotes and even more distant from known bacterial RNA viruses. These positive-strand RNA viruses might be direct ancestors of RNA viruses of eukaryotes.

Inhibition of fried meat-induced colorectal DNA damage and altered systemic genotoxicity in humans by crucifera, chlorophyllin, and yogurt.

UNLABELLED: Dietary exposures implicated as reducing or causing risk for colorectal cancer may reduce or cause DNA damage in colon tissue; however, no one has assessed this hypothesis directly in humans. Thus, we enrolled 16 healthy volunteers in a 4-week controlled feeding study where 8 subjects were randomly assigned to dietary regimens containing meat cooked at either low (100°C) or high temperature (250°C), each for 2 weeks in a crossover design. The other 8 subjects were randomly assigned to dietary regimens containing the high-temperature meat diet alone or in combination with 3 putative mutagen inhibitors: cruciferous vegetables, yogurt, and chlorophyllin tablets, also in a crossover design. Subjects were nonsmokers, at least 18 years old, and not currently taking prescription drugs or antibiotics. We used the Salmonella assay to analyze the meat, urine, and feces for mutagenicity, and the comet assay to analyze rectal biopsies and peripheral blood lymphocytes for DNA damage. Low-temperature meat had undetectable levels of heterocyclic amines (HCAs) and was not mutagenic, whereas high-temperature meat had high HCA levels and was highly mutagenic. The high-temperature meat diet increased the mutagenicity of hydrolyzed urine and feces compared to the low-temperature meat diet. The mutagenicity of hydrolyzed urine was increased nearly twofold by the inhibitor diet, indicating that the inhibitors enhanced conjugation. Inhibitors decreased significantly the mutagenicity of un-hydrolyzed and hydrolyzed feces. The diets did not alter the levels of DNA damage in non-target white blood cells, but the inhibitor diet decreased nearly twofold the DNA damage in target colorectal cells. To our knowledge, this is the first demonstration that dietary factors can reduce DNA damage in the target tissue of fried-meat associated carcinogenesis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00340743.

Gene-environment interplay in common complex diseases: forging an integrative model­recommendations from an NIH workshop.

Although it is recognized that many common complex diseases are a result of multiple genetic and environmental risk factors, studies of gene-environment interaction remain a challenge and have had limited success to date. Given the current state-of-the-science, NIH sought input on ways to accelerate investigations of gene-environment interplay in health and disease by inviting experts from a variety of disciplines to give advice about the future direction of gene-environment interaction studies. Participants of the NIH Gene-Environment Interplay Workshop agreed that there is a need for continued emphasis on studies of the interplay between genetic and environmental factors in disease and that studies need to be designed around a multifaceted approach to reflect differences in diseases, exposure attributes, and pertinent stages of human development. The participants indicated that both targeted and agnostic approaches have strengths and weaknesses for evaluating main effects of genetic and environmental factors and their interactions. The unique perspectives represented at the workshop allowed the exploration of diverse study designs and analytical strategies, and conveyed the need for an interdisciplinary approach including data sharing, and data harmonization to fully explore gene-environment interactions. Further, participants also emphasized the continued need for high-quality measures of environmental exposures and new genomic technologies in ongoing and new studies.