Showing papers by "Research Triangle Park published in 2021"

Per- and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research.

Abstract: Reports of environmental and human health impacts of per- and polyfluoroalkyl substances (PFAS) have greatly increased in the peer-reviewed literature. The goals of the present review are to assess the state of the science regarding toxicological effects of PFAS and to develop strategies for advancing knowledge on the health effects of this large family of chemicals. Currently, much of the toxicity data available for PFAS are for a handful of chemicals, primarily legacy PFAS such as perfluorooctanoic acid and perfluorooctane sulfonate. Epidemiological studies have revealed associations between exposure to specific PFAS and a variety of health effects, including altered immune and thyroid function, liver disease, lipid and insulin dysregulation, kidney disease, adverse reproductive and developmental outcomes, and cancer. Concordance with experimental animal data exists for many of these effects. However, information on modes of action and adverse outcome pathways must be expanded, and profound differences in PFAS toxicokinetic properties must be considered in understanding differences in responses between the sexes and among species and life stages. With many health effects noted for a relatively few example compounds and hundreds of other PFAS in commerce lacking toxicity data, more contemporary and high-throughput approaches such as read-across, molecular dynamics, and protein modeling are proposed to accelerate the development of toxicity information on emerging and legacy PFAS, individually and as mixtures. In addition, an appropriate degree of precaution, given what is already known from the PFAS examples noted, may be needed to protect human health. Environ Toxicol Chem 2021;40:606-630. © 2020 SETAC.

Alcohol Consumption in Response to the COVID-19 Pandemic in the United States.

Abstract: OBJECTIVES: Excessive alcohol use is a serious and growing public health problem. Alcoholic beverage sales in the United States increased greatly immediately after the stay-at-home orders and relaxing of alcohol restrictions associated with the COVID-19 pandemic. However, it is not known to what degree alcohol consumption changed. This study assesses differences in alcohol drinking patterns before and after the enactment of stay-at-home orders. METHODS: In May 2020, a cross-sectional online survey of 993 individuals using a probability-based panel designed to be representative of the US population aged 21 and older was used to assess alcohol drinking patterns before (February, 2020) and after (April, 2020) the enactment of stay-at-home orders among those who consumed alcohol in February, 2020 (n = 555). Reported differences in alcohol consumption were computed, and associations between differences in consumption patterns and individual characteristics were examined. RESULTS: Compared to February, respondents reported consuming more drinks per day in April (+29%, P < 0.001), and a greater proportion reported exceeding recommended drinking limits (+20%, P < 0.001) and binge drinking (+21%, P = 0.001) in April. These differences were found for all sociodemographic subgroups assessed. February to April differences in the proportion exceeding drinking limits were larger for women than men (P = 0.026) and for Black, non-Hispanic people than White, non-Hispanic people (P = 0.028). CONCLUSIONS: There is an association among the COVID-19 pandemic, the public health response to it, changes in alcohol policy, and alcohol consumption. Public health monitoring of alcohol consumption during the pandemic is warranted.

Screening for Lung Cancer With Low-Dose Computed Tomography: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Abstract: Importance Lung cancer is the leading cause of cancer-related death in the US. Objective To review the evidence on screening for lung cancer with low-dose computed tomography (LDCT) to inform the US Preventive Services Task Force (USPSTF). Data sources MEDLINE, Cochrane Library, and trial registries through May 2019; references; experts; and literature surveillance through November 20, 2020. Study selection English-language studies of screening with LDCT, accuracy of LDCT, risk prediction models, or treatment for early-stage lung cancer. Data extraction and synthesis Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings. Data were not pooled because of heterogeneity of populations and screening protocols. Main outcomes and measures Lung cancer incidence, lung cancer mortality, all-cause mortality, test accuracy, and harms. Results This review included 223 publications. Seven randomized clinical trials (RCTs) (N = 86 486) evaluated lung cancer screening with LDCT; the National Lung Screening Trial (NLST, N = 53 454) and Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON, N = 15 792) were the largest RCTs. Participants were more likely to benefit than the US screening-eligible population (eg, based on life expectancy). The NLST found a reduction in lung cancer mortality (incidence rate ratio [IRR], 0.85 [95% CI, 0.75-0.96]; number needed to screen [NNS] to prevent 1 lung cancer death, 323 over 6.5 years of follow-up) with 3 rounds of annual LDCT screening compared with chest radiograph for high-risk current and former smokers aged 55 to 74 years. NELSON found a reduction in lung cancer mortality (IRR, 0.75 [95% CI, 0.61-0.90]; NNS to prevent 1 lung cancer death of 130 over 10 years of follow-up) with 4 rounds of LDCT screening with increasing intervals compared with no screening for high-risk current and former smokers aged 50 to 74 years. Harms of screening included radiation-induced cancer, false-positive results leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, and increases in distress. For every 1000 persons screened in the NLST, false-positive results led to 17 invasive procedures (number needed to harm, 59) and fewer than 1 person having a major complication. Overdiagnosis estimates varied greatly (0%-67% chance that a lung cancer was overdiagnosed). Incidental findings were common, and estimates varied widely (4.4%-40.7% of persons screened). Conclusions and relevance Screening high-risk persons with LDCT can reduce lung cancer mortality but also causes false-positive results leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, increases in distress, and, rarely, radiation-induced cancers. Most studies reviewed did not use current nodule evaluation protocols, which might reduce false-positive results and invasive procedures for false-positive results.

Evaluation of Cloth Masks and Modified Procedure Masks as Personal Protective Equipment for the Public During the COVID-19 Pandemic.

Abstract: Importance During the coronavirus disease 2019 (COVID-19) pandemic, the general public has been advised to wear masks or improvised face coverings to limit transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there has been considerable confusion and disagreement regarding the degree to which masks protect the wearer from airborne particles. Objectives To evaluate the fitted filtration efficiency (FFE) of various consumer-grade and improvised face masks, as well as several popular modifications of medical procedure masks that are intended to improve mask fit or comfort. Design, Setting, and Participants For this study conducted in a research laboratory between June and August 2020, 7 consumer-grade masks and 5 medical procedure mask modifications were fitted on an adult male volunteer, and FFE measurements were collected during a series of repeated movements of the torso, head, and facial muscles as outlined by the US Occupational Safety and Health Administration Quantitative Fit Testing Protocol. The consumer-grade masks tested included (1) a 2-layer nylon mask with ear loops that was tested with an optional aluminum nose bridge and filter insert in place, (2) a cotton bandana folded diagonally once (ie, “bandit” style) or in a (3) multilayer rectangle according to the instructions presented by the US Surgeon General, (4) a single-layer polyester/nylon mask with ties, (5) a polypropylene mask with fixed ear loops, (6) a single-layer polyester gaiter/neck cover balaclava bandana, and (7) a 3-layer cotton mask with ear loops. Medical procedure mask modifications included (1) tying the mask’s ear loops and tucking in the side pleats, (2) fastening ear loops behind the head with 3-dimensional–printed ear guards, (3) fastening ear loops behind the head with a claw-type hair clip, (4) enhancing the mask/face seal with rubber bands over the mask, and (5) enhancing the mask/face seal with a band of nylon hosiery over the fitted mask. Main Outcomes and Measures The primary study outcome was the measured FFE of common consumer-grade and improvised face masks, as well as several popular modifications of medical procedure masks. Results The mean (SD) FFE of consumer grade masks tested on 1 adult male with no beard ranged from 79.0% (4.3%) to 26.5% (10.5%), with the 2-layer nylon mask having the highest FFE. Unmodified medical procedure masks with ear loops had a mean (SD) FFE of 38.5% (11.2%). All modifications evaluated in this study increased procedure mask FFE (range [SD], 60.3% [11.1%] to 80.2% [3.1%]), with a nylon hosiery sleeve placed over the procedure mask producing the greatest improvement. Conclusions and Relevance While modifications to improve medical procedure mask fit can enhance the filtering capability and reduce inhalation of airborne particles, this study demonstrates that the FFEs of consumer-grade masks available to the public are, in many cases, nearly equivalent to or better than their non-N95 respirator medical mask counterparts.

Predictors of willingness to get a COVID-19 vaccine in the U.S.

Abstract: As COVID-19 vaccine distribution efforts continue, public health workers can strategize about vaccine promotion in an effort to increase willingness among those who may be hesitant. In April 2020, we surveyed a national probability sample of 2279 U.S. adults using an online panel recruited through address-based sampling. Households received a computer and internet access if needed to participate in the panel. Participants were invited via e-mail and answered online survey questions about their willingness to get a novel coronavirus vaccine when one became available. The survey was completed in English and Spanish. We report weighted percentages. Most respondents were willing to get the vaccine for themselves (75%) or their children (73%). Notably, Black respondents were less willing than White respondents (47% vs. 79%, p < 0.001), while Hispanic respondents were more willing than White respondents (80% vs. 75%, p < 0.003). Females were less likely than makes (72% vs. 79%, p < 0.001). Those without insurance were less willing than the insured (47% vs. 78%, p < 0.001). Willingness to vaccinate was higher for those age 65 and older than for some younger age groups (85% for those 65 and older vs. 75% for those 50–64, p < 0.017; 72% for those 35–49, p < 0.002; 70% for those 25–34, p = NS and 75% for ages 18–24, p = NS), but other groups at increased risk because of underlying medical conditions or morbid obesity were not more willing to get vaccinated than their lower risk counterparts. Most Americans were willing to get a COVID-19 vaccine, but several vulnerable populations reported low willingness. Public health efforts should address these gaps as national implementation efforts continue.

Development and application of a United States-wide correction for PM 2.5 data collected with the PurpleAir sensor

Abstract: . PurpleAir sensors, which measure particulate matter (PM), are widely used by individuals, community groups, and other organizations including state and local air monitoring agencies. PurpleAir sensors comprise a massive global network of more than 10 000 sensors. Previous performance evaluations have typically studied a limited number of PurpleAir sensors in small geographic areas or laboratory environments. While useful for determining sensor behavior and data normalization for these geographic areas, little work has been done to understand the broad applicability of these results outside these regions and conditions. Here, PurpleAir sensors operated by air quality monitoring agencies are evaluated in comparison to collocated ambient air quality regulatory instruments. In total, almost 12 000 24 h averaged PM 2.5 measurements from collocated PurpleAir sensors and Federal Reference Method (FRM) or Federal Equivalent Method (FEM) PM 2.5 measurements were collected across diverse regions of the United States (US), including 16 states. Consistent with previous evaluations, under typical ambient and smoke-impacted conditions, the raw data from PurpleAir sensors overestimate PM 2.5 concentrations by about 40 % in most parts of the US. A simple linear regression reduces much of this bias across most US regions, but adding a relative humidity term further reduces the bias and improves consistency in the biases between different regions. More complex multiplicative models did not substantially improve results when tested on an independent dataset. The final PurpleAir correction reduces the root mean square error (RMSE) of the raw data from 8 to 3 µ g m −3 , with an average FRM or FEM concentration of 9 µ g m −3 . This correction equation, along with proposed data cleaning criteria, has been applied to PurpleAir PM 2.5 measurements across the US on the AirNow Fire and Smoke Map ( https://fire.airnow.gov/ , last access: 14 May 2021) and has the potential to be successfully used in other air quality and public health applications.

Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline.

Abstract: PURPOSETo provide recommendations on the best strategies for the management and on the best timing and treatment (surgical and radiotherapeutic) of the axilla for patients with early-stage breast c...

Telehealth Beyond COVID-19.

Abstract: Because of the COVID-19 pandemic, many mental health care services have been shifted from face-to-face to virtual interactions. Several health policy changes have influenced telehealth uptake during this time, including changes in technology, Internet connectivity, prescriptions, and reimbursement for services. These changes have been implemented for the duration of the pandemic, and it is unclear if all, some, or none of these new or amended policies will be retained after the pandemic has ended. Accordingly, in the wake of changing policies, mental health care providers will need to make decisions about the future of their telehealth programs. This article briefly reviews telehealth policy changes due to the COVID-19 pandemic and highlights what providers should consider for future delivery and implementation of their telehealth programs.

Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis.

Abstract: Current antiretroviral therapy (ART) consists of a combination of two or more oral agents from at least two drug classes, such as an integrase strand transfer inhibitor (INSTI) as well as one or two nucleoside reverse transcriptase inhibitors (NRTIs) [1,2]. Cabotegravir (CAB), an INSTI, and rilpivirine (RPV), a non-NRTI (NNRTI), have been developed as the first long-acting, injectable, two-drug ART regimen administered intramuscularly monthly or every 2 months for the maintenance of virologic suppression in people living with HIV-1 [3,4]. Long-acting CAB+RPV is indicated for the treatment of HIV-1 infection in virologically suppressed adults (HIV-1 RNA <50 copies/ml), per positive results from three Phase 3/3b studies. The Phase 3 FLAIR ({"type":"clinical-trial","attrs":{"text":"NCT02938520","term_id":"NCT02938520"}}NCT02938520) and ATLAS ({"type":"clinical-trial","attrs":{"text":"NCT02951052","term_id":"NCT02951052"}}NCT02951052) studies [3,4] demonstrated that long-acting CAB+RPV dosed every 4 weeks (Q4W) was noninferior to daily oral ART in maintaining virologic suppression in stably suppressed participants through 48 weeks; noninferiority was established within each study and in a pooled analysis [5]. In addition, long-acting CAB+RPV dosed every 8 weeks (Q8W) demonstrated noninferior efficacy to Q4W dosing with a similar safety profile in the Phase 3b ATLAS-2M ({"type":"clinical-trial","attrs":{"text":"NCT03299049","term_id":"NCT03299049"}}NCT03299049) study [6]. In the FLAIR, ATLAS and ATLAS-2M studies [3,4,6], confirmed virologic failure (CVF; two consecutive plasma HIV-1 RNA measurements ≥200 copies/ml) was rare, occurring in 1% (n = 17/1636) of participants in the long-acting CAB+RPV arms combined. Similar CVF rates were observed among participants who continued daily oral therapy in FLAIR and ATLAS, with three out of 283 (1.1%) and four out of 308 (1.3%) participants meeting the CVF criterion, respectively. Identifying the factors associated with virologic outcome is important to holistically understand any ART regimen and to assist healthcare professionals/prescribers regarding patient selection. Although few participants experienced CVF across the long-acting CAB+RPV arms of the Phase 3 studies, it is important to identify factors that may have predisposed this minority of participants to CVF. This information will help inform clinicians and patients, allowing them to assess the potential benefits and risks of this novel long-acting therapy. Early analyses in the individual studies sought to identify any participant, viral or pharmacokinetic factors that may warrant further investigation in relation to virologic outcome. One factor that appeared initially to be associated with CVF was the L74I integrase polymorphism [3–5]; however, its role in virologic outcome was unclear. The small number of participants who experienced CVF in the three studies prevented the drawing of meaningful conclusions when the trials were analysed individually. Therefore, a post-hoc multivariable analysis was performed using pooled data from long-acting CAB+RPV participants in FLAIR, ATLAS and ATLAS-2M to explore potential drug (pharmacokinetic and dosing regimen), viral and participant factors predictive of Week 48 virologic failure.

Global transpiration data from sap flow measurements: the SAPFLUXNET database

Abstract: . Plant transpiration links physiological responses of vegetation to water supply and demand with hydrological, energy, and carbon budgets at the land–atmosphere interface. However, despite being the main land evaporative flux at the global scale, transpiration and its response to environmental drivers are currently not well constrained by observations. Here we introduce the first global compilation of whole-plant transpiration data from sap flow measurements (SAPFLUXNET, https://sapfluxnet.creaf.cat/ , last access: 8 June 2021). We harmonized and quality-controlled individual datasets supplied by contributors worldwide in a semi-automatic data workflow implemented in the R programming language. Datasets include sub-daily time series of sap flow and hydrometeorological drivers for one or more growing seasons, as well as metadata on the stand characteristics, plant attributes, and technical details of the measurements. SAPFLUXNET contains 202 globally distributed datasets with sap flow time series for 2714 plants, mostly trees, of 174 species. SAPFLUXNET has a broad bioclimatic coverage, with woodland/shrubland and temperate forest biomes especially well represented (80 % of the datasets). The measurements cover a wide variety of stand structural characteristics and plant sizes. The datasets encompass the period between 1995 and 2018, with 50 % of the datasets being at least 3 years long. Accompanying radiation and vapour pressure deficit data are available for most of the datasets, while on-site soil water content is available for 56 % of the datasets. Many datasets contain data for species that make up 90 % or more of the total stand basal area, allowing the estimation of stand transpiration in diverse ecological settings. SAPFLUXNET adds to existing plant trait datasets, ecosystem flux networks, and remote sensing products to help increase our understanding of plant water use, plant responses to drought, and ecohydrological processes. SAPFLUXNET version 0.1.5 is freely available from the Zenodo repository ( https://doi.org/10.5281/zenodo.3971689 ; Poyatos et al., 2020a). The “sapfluxnetr” R package – designed to access, visualize, and process SAPFLUXNET data – is available from CRAN.

Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study

Abstract: Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1–5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy. Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P < 0.0001) and occurrence of SN (40.6% versus 75.9%; adjusted one-sided P = 0.016), with numerical improvements in additional neutrophil, red blood cell, and platelet measures. Patients receiving trilaciclib had fewer grade ≥ 3 hematologic adverse events than patients receiving placebo, particularly neutropenia (75.0% versus 85.7%) and anemia (28.1% versus 60.7%). Myelopreservation benefits extended to improvements in PROs, specifically in those related to fatigue. Antitumor efficacy was comparable between treatment arms. Compared with placebo, the addition of trilaciclib prior to topotecan for the treatment of patients with previously treated ES-SCLC improves the patient experience of receiving chemotherapy, as demonstrated by a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy. ClinicalTrials.gov: NCT02514447

Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study.

Abstract: Background On the basis of the DREAMM-2 study (ClinicalTrials.gov identifier NCT03525678), single-agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple myeloma (RRMM) who received ≥4 prior therapies, including anti-CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM-2 after 13 months of follow-up among patients who received belamaf 2.5 mg/kg. Methods DREAMM-2 is an ongoing, phase 2, open-label, 2-arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti-CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee. Results As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty-one of 97 patients (32%; 97.5% confidence interval [CI], 21.7%-43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression-free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6-3.6 months), respectively. Response and survival outcomes in patients who had high-risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow-up. Conclusions Extended follow-up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.

Eosinophils in Health and Disease: A State-of-the-Art Review

Abstract: Eosinophils play a homeostatic role in the body's immune responses. These cells are involved in combating some parasitic, bacterial, and viral infections and certain cancers and have pathologic roles in diseases including asthma, chronic rhinosinusitis with nasal polyps, eosinophilic gastrointestinal disorders, and hypereosinophilic syndromes. Treatment of eosinophilic diseases has traditionally been through nonspecific eosinophil attenuation by use of glucocorticoids. However, several novel biologic therapies targeting eosinophil maturation factors, such as interleukin (IL)-5 and the IL-5 receptor or IL-4/IL-13, have recently been approved for clinical use. Despite the success of biologic therapies, some patients with eosinophilic inflammatory disease may not achieve adequate symptom control, underlining the need to further investigate the contribution of patient characteristics, such as comorbidities and other processes, in driving ongoing disease activity. New research has shown that eosinophils are also involved in several homeostatic processes, including metabolism, tissue remodeling and development, neuronal regulation, epithelial and microbiome regulation, and immunoregulation, indicating that these cells may play a crucial role in metabolic regulation and organ function in healthy humans. Consequently, further investigation is needed into the homeostatic roles of eosinophils and eosinophil-mediated processes across different tissues and their varied microenvironments. Such work may provide important insights into the role of eosinophils not only under disease conditions but also in health. This narrative review synthesizes relevant publications retrieved from PubMed informed by author expertise to provide new insights into the diverse roles of eosinophils in health and disease, with particular emphasis on the implications for current and future development of eosinophil-targeted therapies.

MYCN-Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis

Abstract: MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. SIGNIFICANCE: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.

Undetectable equals untransmittable (U = U): awareness and associations with health outcomes among people living with HIV in 25 countries.

Abstract: Objectives ‘Undetectable equals Untransmittable’ (U=U) is an empowering message that may enable people living with HIV (PLHIV) to reach and maintain undetectability. We estimated the percentage of PLHIV who ever discussed U=U with their main HIV care provider, and measured associations with health-related outcomes. Secondarily, we evaluated whether the impact of the U=U message varied between those who heard it from their healthcare provider (HCP) vs from elsewhere. Methods Data were from the 25-country 2019 Positive Perspectives Survey of PLHIV on treatment (n=2389). PLHIV were classified as having discussed U=U with their HCP if they indicated that their HCP had ever told them about U=U. Those who had not discussed U=U with their HCP but were nonetheless aware that ‘My HIV medication prevents me from passing on HIV to others’ were classified as being made aware of U=U from non-HCP sources. Multivariable logistic regression was used to measure associations between exposure to U=U messages and health outcomes. Results Overall, 66.5% reported ever discussing U=U with their HCP, from 38.0% (South Korea) to 87.3% (Switzerland). Prevalence was lowest among heterosexual men (57.6%) and PLHIV in Asia (51.3%). Compared with those unaware of U=U, those reporting U=U discussions with their HCP had lower odds of suboptimal adherence (AOR=0.59, 95% CI 0.44 to 0.78) and higher odds of self-reported viral suppression (AOR=2.34, 95% CI 1.72 to 3.20), optimal sexual health (AOR=1.48, 95% CI 1.14 to 1.92) and reporting they ‘always shared’ their HIV status (AOR=2.99, 95% CI 1.42 to 6.28). While exposure to U=U information from non-HCP sources was beneficial too, the observed associations were attenuated relative to those seen with reported discussions with HCPs. Conclusion HCP discussion of U=U with PLHIV was associated with favourable health outcomes. However, missed opportunities exist since a third of PLHIV reported not having any U=U discussion with their HCP. U=U discussions with PLHIV should be considered as a standard of care in clinical guidelines.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Nuclear hormone receptors

Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15540. Nuclear hormone receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Land-based measures to mitigate climate change: Potential and feasibility by country.

Abstract: Land-based climate mitigation measures have gained significant attention and importance in public and private sector climate policies. Building on previous studies, we refine and update the mitigation potentials for 20 land-based measures in >200 countries and five regions, comparing “bottom-up” sectoral estimates with integrated assessment models (IAMs). We also assess implementation feasibility at the country level. Cost-effective (available up to $100/tCO2eq) land-based mitigation is 8–13.8 GtCO2eq yr−1 between 2020 and 2050, with the bottom end of this range representing the IAM median and the upper end representing the sectoral estimate. The cost-effective sectoral estimate is about 40% of available technical potential and is in line with achieving a 1.5°C pathway in 2050. Compared to technical potentials, cost-effective estimates represent a more realistic and actionable target for policy. The cost-effective potential is approximately 50% from forests and other ecosystems, 35% from agriculture, and 15% from demand-side measures. The potential varies sixfold across the five regions assessed (0.75–4.8 GtCO2eq yr−1) and the top 15 countries account for about 60% of the global potential. Protection of forests and other ecosystems and demand-side measures present particularly high mitigation efficiency, high provision of co-benefits, and relatively lower costs. The feasibility assessment suggests that governance, economic investment, and socio-cultural conditions influence the likelihood that land-based mitigation potentials are realized. A substantial portion of potential (80%) is in developing countries and LDCs, where feasibility barriers are of greatest concern. Assisting countries to overcome barriers may result in significant quantities of near-term, low-cost mitigation while locally achieving important climate adaptation and development benefits. Opportunities among countries vary widely depending on types of land-based measures available, their potential co-benefits and risks, and their feasibility. Enhanced investments and country-specific plans that accommodate this complexity are urgently needed to realize the large global potential from improved land stewardship.

Criteria pollutant impacts of volatile chemical products informed by near-field modeling.

Abstract: Consumer, industrial, and commercial product usage is a source of exposure to potentially hazardous chemicals. In addition, cleaning agents, personal care products, coatings, and other volatile chemical products (VCPs), evaporate and react in the atmosphere producing secondary pollutants. Here, we show high air emissions from VCP usage (≥ 14 kg person-1 yr-1, at least 1.7× higher than current operational estimates) are supported by multiple estimation methods and constraints imposed by ambient levels of ozone, hydroxyl radical (OH) reactivity, and the organic component of fine particulate matter (PM2.5) in Pasadena, California. A near-field model, which estimates human chemical exposure during or in the vicinity of product use, indicates these high air emissions are consistent with organic product usage up to ~75 kg person-1 yr-1, and inhalation of consumer products could be a non-negligible exposure pathway. After constraining the PM2.5 yield to 5% by mass, VCPs produce ~41% of the photochemical organic PM2.5 (1.1 ± 0.3 μg m-3) and ~17% of maximum daily 8-hr average ozone (9 ± 2 ppb) in summer Los Angeles. Therefore, both toxicity and ambient criteria pollutant formation should be considered when organic substituents are developed for VCPs in pursuit of safer and sustainable products and cleaner air.

Expanding the scope of plant genome engineering with Cas12a orthologs and highly multiplexable editing systems.

Abstract: CRISPR-Cas12a is a promising genome editing system for targeting AT-rich genomic regions. Comprehensive genome engineering requires simultaneous targeting of multiple genes at defined locations. Here, to expand the targeting scope of Cas12a, we screen nine Cas12a orthologs that have not been demonstrated in plants, and identify six, ErCas12a, Lb5Cas12a, BsCas12a, Mb2Cas12a, TsCas12a and MbCas12a, that possess high editing activity in rice. Among them, Mb2Cas12a stands out with high editing efficiency and tolerance to low temperature. An engineered Mb2Cas12a-RVRR variant enables editing with more relaxed PAM requirements in rice, yielding two times higher genome coverage than the wild type SpCas9. To enable large-scale genome engineering, we compare 12 multiplexed Cas12a systems and identify a potent system that exhibits nearly 100% biallelic editing efficiency with the ability to target as many as 16 sites in rice. This is the highest level of multiplex edits in plants to date using Cas12a. Two compact single transcript unit CRISPR-Cas12a interference systems are also developed for multi-gene repression in rice and Arabidopsis. This study greatly expands the targeting scope of Cas12a for crop genome engineering.

Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial.

Abstract: Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naive and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml−1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naive and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naive participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naive participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naive participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population. A first-in-human study of an antisense oligonucleotide targeting hepatitis B virus (HBV) RNA provides initial insights into this potential new therapeutic modality for individuals with chronic HBV infection.

Characterization of HIV infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083

Abstract: Author(s): Marzinke, Mark A; Grinsztejn, Beatriz; Fogel, Jessica M; Piwowar-Manning, Estelle; Li, Maoji; Weng, Lei; McCauley, Marybeth; Cummings, Vanessa; Ahmed, Shahnaz; Haines, Casey D; Bushman, Lane R; Petropoulos, Christos; Persaud, Deborah; Adeyeye, Adeola; Kofron, Ryan; Rinehart, Alex; St Clair, Marty; Rooney, James F; Pryluka, Daniel; Coelho, Lara; Gaur, Aditya; Middelkoop, Keren; Phanuphak, Nittaya; Cohen, Myron S; Hendrix, Craig W; Anderson, Peter; Hanscom, Brett; Donnell, Deborah; Landovitz, Raphael J; Eshleman, Susan H | Abstract: IntroductionThe HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV prevention in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083.MethodsRetrospective testing included HIV testing, viral load testing, quantification of study drugs and HIV drug resistance testing.ResultsFifty-eight infections were evaluated, including 51 incident infections (12 CAB, 39 TDF/FTC). In many cases (5 CAB, 37 TDF/FTC), infection was associated with low or unquantifiable study drug concentrations. In four cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral treatment (ART), and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing.ConclusionsEarly detection of HIV infection and prompt ART initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.

Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation

Abstract: The SARS-CoV-2 coronavirus responsible for the global pandemic contains a unique furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation. Here, we show that O-glycosylation near the furin cleavage site is mediated by specific members of the GALNT enzyme family and is dependent on the novel proline at position 681 (P681). We further demonstrate that O-glycosylation of S decreases furin cleavage. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the potential role of P681 mutations in the recently identified, highly transmissible B.1.1.7 variant.

Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non-small cell lung cancer (NSCLC).

Abstract: BACKGROUND Currently available biomarkers are imperfect in their ability to predict responses to the multiple first-line treatment options available for patients with advanced non-small cell lung cancer (NSCLC). Having an early pharmacodynamic marker of treatment resistance may help redirect patients onto more effective alternative therapies. We sought to determine if changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in NSCLC would enable early prediction of response prior to radiological assessment. METHODS Plasma collected from patients with advanced NSCLC prior to and serially after starting first-line pembrolizumab±platinum doublet chemotherapy was analyzed by next-generation sequencing using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes. Early change in ctDNA allele fraction (AF) was correlated with radiographic responses and long-term clinical outcomes. RESULTS Among 62 patients who received first-line pembrolizumab±platinum/pemetrexed and underwent ctDNA assessment, 45 had detectable ctDNA alterations at baseline. The median change in AF at the first follow-up (at a median of 21 days after treatment initiation) was -90.1% (range -100% to +65%) among patients who subsequently had a radiologic response (n=18), -19.9% (range: -100% to +1884%) among stable disease cases (n=15), and +28.8% (range: -100% to +410%) among progressive disease cases (n=12); p=0.003. In addition, there was a significant correlation between the percent change in ctDNA at the first follow-up and the percent change in tumor target lesions from baseline (R=0.66, p<0.001). AF decrease between the pretreatment and first on-treatment blood draw was associated with significantly higher response rate (60.7% vs 5.8%, p=0.0003), and significantly longer median progression-free survival (8.3 vs 3.4 months, HR: 0.29 (95% CI: 0.14 to 0.60), p=0.0007) and median overall survival (26.2 vs 13.2 months, HR: 0.34 (95% CI: 0.15 to 0.75), p=0.008) compared with cases with an AF increase. CONCLUSION In patients with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.

Development and Application of Liquid Chromatographic Retention Time Indices in HRMS-Based Suspect and Nontarget Screening.

Abstract: There is an increasing need for comparable and harmonized retention times (tR) in liquid chromatography (LC) among different laboratories, to provide supplementary evidence for the identity of compounds in high-resolution mass spectrometry (HRMS)-based suspect and nontarget screening investigations. In this study, a rigorously tested, flexible, and less system-dependent unified retention time index (RTI) approach for LC is presented, based on the calibration of the elution pattern. Two sets of 18 calibrants were selected for each of ESI+ and ESI-based on the maximum overlap with the retention times and chemical similarity indices from a total set of 2123 compounds. The resulting calibration set, with RTI set to range between 1 and 1000, was proposed as the most appropriate RTI system after rigorous evaluation, coordinated by the NORMAN network. The validation of the proposed RTI system was done externally on different instrumentation and LC conditions. The RTI can also be used to check the reproducibility and quality of LC conditions. Two quantitative structure-retention relationship (QSRR)-based models were built based on the developed RTI systems, which assist in the removal of false-positive annotations. The applicability domains of the QSRR models allowed completing the identification process with higher confidence for substances within the domain, while indicating those substances for which results should be treated with caution. The proposed RTI system was used to improve confidence in suspect and nontarget screening and increase the comparability between laboratories as demonstrated for two examples. All RTI-related calculations can be performed online at http://rti.chem.uoa.gr/.

A multicenter study benchmarking single-cell RNA sequencing technologies using reference samples

Abstract: Comparing diverse single-cell RNA sequencing (scRNA-seq) datasets generated by different technologies and in different laboratories remains a major challenge. Here we address the need for guidance in choosing algorithms leading to accurate biological interpretations of varied data types acquired with different platforms. Using two well-characterized cellular reference samples (breast cancer cells and B cells), captured either separately or in mixtures, we compared different scRNA-seq platforms and several preprocessing, normalization and batch-effect correction methods at multiple centers. Although preprocessing and normalization contributed to variability in gene detection and cell classification, batch-effect correction was by far the most important factor in correctly classifying the cells. Moreover, scRNA-seq dataset characteristics (for example, sample and cellular heterogeneity and platform used) were critical in determining the optimal bioinformatic method. However, reproducibility across centers and platforms was high when appropriate bioinformatic methods were applied. Our findings offer practical guidance for optimizing platform and software selection when designing an scRNA-seq study. A comprehensive comparison of 20 single-cell RNA-seq datasets derived from the two cell lines analyzed using six preprocessing pipelines, eight normalization methods and seven batch-correction algorithms derived from four different sequencing platforms at different centers.