Extreme redox variations in a superdeep diamond from a subducted slab.

The introduction of volatile-rich subducting slabs to the mantle may locally generate large redox gradients, affecting phase stability, element partitioning and volatile speciation1. Here we investigate the redox conditions of the deep mantle recorded in inclusions in a diamond from Kankan, Guinea. Enstatite (former bridgmanite), ferropericlase and a uniquely Mg-rich olivine (Mg# 99.9) inclusion indicate formation in highly variable redox conditions near the 660 km seismic discontinuity. We propose a model involving dehydration, rehydration and dehydration in the underside of a warming slab at the transition zone-lower mantle boundary. Fluid liberated by dehydration in a crumpled slab, driven by heating from the lower mantle, ascends into the cooler interior of the slab, where the H2O is sequestered in new hydrous minerals. Consequent fractionation of the remaining fluid produces extremely reducing conditions, forming Mg-end-member ringwoodite. This fractionating fluid also precipitates the host diamond. With continued heating, ringwoodite in the slab surrounding the diamond forms bridgmanite and ferropericlase, which is trapped as the diamond grows in hydrous fluids produced by dehydration of the warming slab.

Sublithospheric diamond ages and the supercontinent cycle.

Subduction related to the ancient supercontinent cycle is poorly constrained by mantle samples. Sublithospheric diamond crystallization records the release of melts from subducting oceanic lithosphere at 300-700 km depths1,2 and is especially suited to tracking the timing and effects of deep mantle processes on supercontinents. Here we show that four isotope systems (Rb-Sr, Sm-Nd, U-Pb and Re-Os) applied to Fe-sulfide and CaSiO3 inclusions within 13 sublithospheric diamonds from Juína (Brazil) and Kankan (Guinea) give broadly overlapping crystallization ages from around 450 to 650 million years ago. The intracratonic location of the diamond deposits on Gondwana and the ages, initial isotopic ratios, and trace element content of the inclusions indicate formation from a peri-Gondwanan subduction system. Preservation of these Neoproterozoic-Palaeozoic sublithospheric diamonds beneath Gondwana until its Cretaceous breakup, coupled with majorite geobarometry3,4, suggests that they accreted to and were retained in the lithospheric keel for more than 300 Myr during supercontinent migration. We propose that this process of lithosphere growth-with diamonds attached to the supercontinent keel by the diapiric uprise of depleted buoyant material and pieces of slab crust-could have enhanced supercontinent stability.

The genomic landscape of Ménière's disease: a path to endolymphatic hydrops.

BACKGROUND: Ménière's disease (MD) is a disorder of the inner ear that causes episodic bouts of severe dizziness, roaring tinnitus, and fluctuating hearing loss. To date, no targeted therapy exists. As such, we have undertaken a large whole genome sequencing study on carefully phenotyped unilateral MD patients with the goal of gene/pathway discovery and a move towards targeted intervention. This study was a retrospective review of patients with a history of Ménière's disease. Genomic DNA, acquired from saliva samples, was purified and subjected to whole genome sequencing. RESULTS: Stringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell-cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss. CONCLUSION: By enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.

Bridging Culture and Language: Encouraging Bilingual/Multicultural Individuals to Act as Information Navigators for Their Loved-Ones and Communities during the COVID-19 Pandemic.

Linguistically diverse communities face barriers to receiving appropriate health information. COVID-19 exacerbated these health-communication inequities. University of Washington researchers surveyed bilingual staff, students, and medical interpreters - desiring training to become effective communicators of COVID-19 information to their social networks and language communities. In response, the COVID-19 Information Navigator Training was developed and pre-tested with professional networks and members of the target audience. The final training comprised three interactive modules and short quizzes. Evaluation surveys measured Information Navigators' confidence in providing COVID-19 information to their social networks. Surveys included questions on the participants' language or cultural community, the perceived value of the training, and their ability to communicate COVID-19 information. Among 393 participants who enrolled in the training, 284 completed the survey. Significant differences in confidence before and after the course were found in detecting COVID misinformation in the news and social media (pre-course mean: 3.83, post-course mean: 4.63; absolute mean difference was 0.82 points higher in the post-evaluation on the 5-point likert scale, 95% CI: 0.70-0.93, p < .01). Training multicultural volunteers to disseminate information to their social networks is a promising strategy for reaching linguistically diverse communities with up-to-date information during health emergencies.

Trends in Varenicline Use for Tobacco Cessation, and Their Implications.

BACKGROUND: Tobacco use remains a leading cause of death in the U.S. Varenicline is a preferred medication for tobacco cessation, and a prior report in the literature showed its use fell dramatically after the voluntary recall of Chantix (name-brand varenicline) in July 2021. OBJECTIVES: Working with data on prescriptions for varenicline and nicotine-replacement therapy (NRT), we studied use from 2018 to 2023 to determine if varenicline use had recovered or if there had been a compensatory increase in NRT use. METHODS: Data are yearly from state employees and their dependents who were aged >18 years and were health-insurance beneficiaries of the Washington Public Employees Benefits Board from July 2018 through June 2023. Data include numbers of tobacco users and numbers of prescriptions filled. RESULTS: The 5-year prevalence of tobacco use among 224,816 beneficiaries was 4.6%. The percentage of tobacco users who filled a prescription for varenicline fell from highs of 9.5% and 9.6% in the 2018-2019 and 2019-2020 year to lows of 5.3% and 6.4% in the 2021-2022 and 2022-2023 years. For nicotine replacement therapy, prescriptions rose modestly over the 5 years, from 4.5% in 2018-2019 to 6.0% in 2022-2023. DISCUSSION: Varenicline use dropped after the voluntary recall of Chantix by Pfizer in mid-2021 and has not returned to pre-recall levels. CONCLUSION: Pharmacists and other clinicians should address this drop, in addition to addressing longer-term challenges to increasing varenicline use; these include the requirement for a prescription and the black-box warning by the Food and Drug Administration, rescinded in 2016.

What happens in Vegas, stays in your lungs: an assessment of fine particulate matter in casinos that prohibit and allow smoking in Las Vegas, Nevada, USA.

INTRODUCTION: Despite progress in adoption of smoke-free policies, smoking in casinos is allowed in some US states, including Nevada. In 2020, for the first time, a resort-style casino in Las Vegas prohibited smoking voluntarily. This study is the first to assess air quality in this casino and compare results with similar casinos that allow smoking. METHODS: A real-time personal aerosol monitor evaluated particulate matter with a diameter <2.5 µm (PM2.5), a surrogate for secondhand smoke (SHS). PM2.5 was measured at eight Las Vegas casinos, including the smoke-free casino. Each casino was visited twice, and PM2.5 was assessed in smoking-permitted gaming areas and areas where smoking is otherwise prohibited. RESULTS: Average PM2.5 levels were significantly higher in casinos that allow smoking, for both casino gaming areas and areas where smoking is otherwise prohibited (p<0.05). Mean PM2.5 in gaming areas was 164.9 µg/m3 in casinos that allow smoking and 30.5 µg/m3 in the smoke-free casino. Mean PM2.5 in areas where smoking is otherwise prohibited was 83.2 µg/m3 in casinos which allowed smoking in gaming areas, and 48.1 µg/m3 in the smoke-free casino. CONCLUSION: Despite robust evidence about the harms of SHS, tens of thousands of casino employees and tens of millions of tourists are exposed to high levels of SHS in Las Vegas casinos annually, with PM2.5 levels 5.4 times higher in gaming areas when compared with a smoke-free casino. The only way to protect people from SHS exposure is to prohibit smoking in all indoor areas.

Development and maturation of the occupational health services research field in the United States over the past 25 years: Challenges and opportunities for the future.

Work is an important social determinant of health; unfortunately, work-related injuries remain prevalent, can have devastating impact on worker health, and can impose heavy economic burdens on workers and society. Occupational health services research (OHSR) underpins occupational health services policy and practice, focusing on health determinants, health services, healthcare delivery, and health systems affecting workers. The field of OHSR has undergone tremendous expansion in both definition and scope over the past 25 years. In this commentary, focusing on the US, we document the historical development and evolution of OHSR as a research field, describe current doctoral-level OHSR training, and discuss challenges and opportunities for the OHSR field. We also propose an updated definition for the OHSR field: Research and evaluation related to the determinants of worker health and well-being; to occupational injury and illness prevention and surveillance; to healthcare, health programs, and health policy affecting workers; and to the organization, access, quality, outcomes, and costs of occupational health services and related health systems. Researchers trained in OHSR are essential contributors to improvements in healthcare, health systems, and policy and programs to improve worker health and productivity, as well as equity and justice in job and employment conditions. We look forward to the continued growth of OHSR as a field and to the expansion of OHSR academic training opportunities.

Interpersonal Firearm Injury and Death in Portland, Oregon: 2018 Through 2021.

The annual number of firearm injuries in Portland, Oregon has been higher in the years since 2020 than in any prior year in the city's history. This descriptive study analyzed data from Gun Violence Archives (GVA) from January 1, 2018, to December 31, 2021. All incidents in GVA of interpersonal firearm injury that occurred in Portland during this period were analyzed for location, number of people injured or killed, and demographic information for those injured or killed. Comparisons in firearm injury rates were made with Seattle and San Francisco. Interpersonal firearm injuries began to rise after the first COVID-19 case in Oregon; July 2020 had the most injuries in the four-year period. Black men suffered the highest rate of interpersonal fatalities, with more than 11-fold higher rate per 100,000 than White men in every year studied. Portland had a higher rate of total interpersonal firearm injuries and a higher rate of firearm fatalities from 2018 through 2021 compared to Seattle and San Francisco. Neighborhoods near Downtown and those on the Eastside of the city had the highest rates of interpersonal injuries and deaths from firearms, whereas those in the Southwest had the lowest. Defining the burden of disease from interpersonal firearm injuries is a fundamental step in designing future public health research and implementing interventions to curb the trauma brought by interpersonal firearm injury.

Evidence for complex iron oxides in the deep mantle from FeNi(Cu) inclusions in superdeep diamond.

The recent discovery in high-pressure experiments of compounds stable to 24-26 GPa with Fe4O5, Fe5O6, Fe7O9, and Fe9O11 stoichiometry has raised questions about their existence within the Earth's mantle. Incorporating both ferric and ferrous iron in their structures, these oxides if present within the Earth could also provide insight into diamond-forming processes at depth in the planet. Here we report the discovery of metallic particles, dominantly of FeNi (Fe0.71Ni0.24Cu0.05), in close spatial relation with nearly pure magnetite grains from a so-called superdeep diamond from the Earth's mantle. The microstructural relation of magnetite within a ferropericlase (Mg0.60Fe0.40)O matrix suggests exsolution of the former. Taking into account the bulk chemistry reconstructed from the FeNi(Cu) alloy, we propose that it formed by decomposition of a complex metal M oxide (M4O5) with a stoichiometry of (Fe3+2.15Fe2+1.59Ni2+0.17Cu+0.04)Σ=3.95O5 We further suggest a possible link between this phase and variably oxidized ferropericlase that is commonly trapped in superdeep diamond. The observation of FeNi(Cu) metal in relation to magnetite exsolved from ferropericlase is interpreted as arising from a multistage process that starts from diamond encapsulation of ferropericlase followed by decompression and cooling under oxidized conditions, leading to the formation of complex oxides such as Fe4O5 that subsequently decompose at shallower P-T conditions.

Tisotumab vedotin in Japanese patients with recurrent/metastatic cervical cancer: Results from the innovaTV 206 study.

New treatments, particularly second-line options, are needed to improve outcomes for patients with recurrent/metastatic cervical cancer (r/mCC). Tisotumab vedotin (TV) is an antibody-drug conjugate directed to tissue factor, a transmembrane protein commonly expressed in cancer cells, to deliver cytotoxic monomethyl auristatin E. This single-arm, open-label phase 1/2 trial evaluated the consistency of safety and efficacy outcomes of TV in Japanese patients with r/mCC to bridge the current findings with those reported in previous trials in non-Japanese patients in the United States and Europe. In part 1 (dose escalation; N = 6), patients with advanced solid tumors received TV 1.5 or 2.0 mg/kg once every 3 weeks to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 (dose expansion; N = 17) evaluated the RP2D in r/mCC patients with 1-2 prior lines of therapy. In part 1, no dose-limiting toxicities were observed, the MTD was not reached, and TV 2.0 mg/kg was established as the RP2D. In part 2, the most common treatment-emergent adverse events were anemia (58.8%), nausea (58.8%), alopecia (47.1%), epistaxis (47.1%), and diarrhea (35.3%); adverse events of special interest were bleeding (76.5%), ocular events (35.3%), and peripheral neuropathy (17.6%), and were mostly grade 1/2. In part 2, confirmed objective response rate was 29.4%, median duration of response was 7.1 months, and median time to response was 1.2 months. In Japanese patients with r/mCC, TV demonstrated a manageable and tolerable safety, pharmacokinetics, and efficacy profile consistent with that observed in non-Japanese patients.

Mobility was a significant determinant of reported COVID-19 incidence during the Omicron Surge in the most populous U.S. Counties.

BACKGROUND: Significant immune escape by the Omicron variant, along with the emergence of widespread worry fatigue, have called into question the robustness of the previously observed relation between population mobility and COVID-19 incidence. METHODS: We employed principal component analysis to construct a one-dimensional summary indicator of six Google mobility categories. We related this mobility indicator to case incidence among 111 of the most populous U.S. counties during the Omicron surge from December 2021 through February 2022. RESULTS: Reported COVID-19 incidence peaked earlier and declined more rapidly among those counties exhibiting more extensive decline in mobility between December 20 and January 3. Based upon a fixed-effects, longitudinal cohort model, we estimated that every 1% decline in mobility between December 20 and January 3 was associated with a 0.63% decline in peak incidence during the week ending January 17 (95% confidence interval, 0.40-0.86%). Based upon a cross-sectional analysis including mean household size and vaccination participation as covariates, we estimated that the same 1% decline in mobility was associated with a 0.36% decline in cumulative reported COVID-19 incidence from January 10 through February 28 (95% CI, 0.18-0.54%). CONCLUSION: Omicron did not simply sweep through the U.S. population until it ran out of susceptible individuals to infect. To the contrary, a significant fraction managed to avoid infection by engaging in risk-mitigating behaviors. More broadly, the behavioral response to perceived risk should be viewed as an intrinsic component of the natural course of epidemics in humans.

Timely epidemic monitoring in the presence of reporting delays: anticipating the COVID-19 surge in New York City, September 2020.

BACKGROUND: During a fast-moving epidemic, timely monitoring of case counts and other key indicators of disease spread is critical to an effective public policy response. METHODS: We describe a nonparametric statistical method, originally applied to the reporting of AIDS cases in the 1980s, to estimate the distribution of reporting delays of confirmed COVID-19 cases in New York City during the late summer and early fall of 2020. RESULTS: During August 15-September 26, the estimated mean delay in reporting was 3.3 days, with 87% of cases reported by 5 days from diagnosis. Relying upon the estimated reporting-delay distribution, we projected COVID-19 incidence during the most recent 3 weeks as if each case had instead been reported on the same day that the underlying diagnostic test had been performed. Applying our delay-corrected estimates to case counts reported as of September 26, we projected a surge in new diagnoses that had already occurred but had yet to be reported. Our projections were consistent with counts of confirmed cases subsequently reported by November 7. CONCLUSION: The projected estimate of recently diagnosed cases could have had an impact on timely policy decisions to tighten social distancing measures. While the recent advent of widespread rapid antigen testing has changed the diagnostic testing landscape considerably, delays in public reporting of SARS-CoV-2 case counts remain an important barrier to effective public health policy.

Worksite tobacco control - a qualitative study on perspectives from employers and employees at small worksites.

BACKGROUND: Evidence-based interventions (EBIs) for tobacco control can be implemented in worksite settings to reduce tobacco use. Small worksites are less likely to adopt tobacco control EBIs than large worksites. The purpose of this qualitative study was to 1) explore factors that impact small employers' decisions to offer tobacco control EBIs, and 2) understand employees' perceptions of tobacco control at small worksites. METHODS: Working with staff from small worksites (20-250 employees), we analyzed data from 12 semi-structured interviews with employers (via key informants) and four focus groups with employees. We recruited employers and employees through a purchased business list and market research company, respectively. Interview and focus group topics included perceptions of worksite tobacco control; internal and external forces shaping worksite tobacco control implementation; and perceived worksite support for cessation. We conducted thematic data analysis. RESULTS: Key themes from the employer interviews included: the local environment played an important role in implementation of tobacco control EBIs; tobacco control was perceived as important but not a priority; and tobacco control decisions were driven by worksite culture. Key themes from the employee focus groups included: perceived employer support for tobacco cessation was limited although there was interest from employees; employees who currently used tobacco were stigmatized for their behavior; and incentives and coaching were considered ideal tobacco control EBIs. CONCLUSIONS: Tobacco control has not been prioritized at small worksites, despite employees welcoming additional cessation support. This study contributes important information on contextual factors and employee preferences that could be targeted to improve tobacco control EBI implementation. Worksites should implement comprehensive tobacco-free policies, minimize stigma when promoting cessation, establish equitable break policies, and involve employees in decision-making related to tobacco control.

By the Seat of Our Pants: the Experience of Small Businesses in the COVID-19 Pandemic, Washington State, March-October 2020.

INTRODUCTION: Most US businesses are small, yet they employ almost half of the nation's workforce. Literature is limited about how small employers (those with 20-250 employees) have made decisions about operating their businesses during the COVID-19 pandemic. We sought to learn how employers made these decisions, what information sources they used, what information they wanted, and to what extent they worked with or used information from their local health department. METHODS: We conducted qualitative, semistructured interviews with 26 employers in Washington State, from August through October 2020. Employers were recruited from 7 counties (4 urban and 3 rural) that were experiencing either higher or lower COVID-19 case rates than Washington State overall. RESULTS: Employers relied heavily on national government resources to make decisions about how to operate their businesses during the COVID-19 pandemic. Few employers had relationships with or turned to their local health departments for information or support. Employers wanted information about COVID-19 safety that was specific to their business operations and industry. Employers also described the emotional toll of COVID-19 and the challenge of trying to make high-stakes decisions with rapidly evolving information. CONCLUSION: Small employers showed little awareness of their local health departments and the information and assistance they could provide. Local health departments could increase their visibility and build relationships with small employers by partnering with them on value-added services such as workplace health promotion. Establishing these relationships could support more rapid collaboration between local health departments and small employers during future public health crises.

Loss of ß-catenin triggers oxidative stress and impairs hematopoietic regeneration.

Accidental or deliberate ionizing radiation exposure can be fatal due to widespread hematopoietic destruction. However, little is known about either the course of injury or the molecular pathways that regulate the subsequent regenerative response. Here we show that the Wnt signaling pathway is critically important for regeneration after radiation-induced injury. Using Wnt reporter mice, we show that radiation triggers activation of Wnt signaling in hematopoietic stem and progenitor cells. ß-Catenin-deficient mice, which lack the ability to activate canonical Wnt signaling, exhibited impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. We found that, as part of the mechanism, hematopoietic stem cells lacking ß-catenin fail to suppress the generation of reactive oxygen species and cannot resolve DNA double-strand breaks after radiation. Consistent with the impaired response to radiation, ß-catenin-deficient mice are also unable to recover effectively after chemotherapy. Collectively, these data indicate that regenerative responses to distinct hematopoietic injuries share a genetic dependence on ß-catenin and raise the possibility that modulation of Wnt signaling may be a path to improving bone marrow recovery after damage.

Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population. METHODS: This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. FINDINGS: 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. INTERPRETATION: Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. FUNDING: Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

Utility of droplet digital polymerase chain reaction for TERT and BRAF mutational profiling of thyroid nodules.

BACKGROUND: Mutations involving BRAF and TERT are important predictors of disease severity in thyroid cancer, but molecular testing is limited by cost and lack of adequate tissue sample. This study aimed to assess the utility of BRAFV600E and TERT testing using droplet digital PCR (ddPCR) as a diagnostic and prognostic tool for thyroid fine needle aspirate biopsy (FNAB). METHODS: Patients with thyroid nodules were prospectively enrolled from March 2015 to September 2018. Pre-operative FNAB was collected for standard cytology and molecular testing. BRAFV600E and TERT levels were analyzed by ddPCR. Cytology (Bethesda system) and ddPCR results were correlated to surgical pathology. RESULTS: A total of 222 patients were enrolled, of which 124 received thyroid surgery. Pre-operative cytology alone with Bethesda ≥5 was 100% specific and 70% sensitive for malignancy on final surgical pathology. BRAFV600E positivity or TERT overexpression was 100% specific and 60.0% sensitive. Combining cytology (Bethesda ≥5) with BRAFV600E and TERT testing increased the sensitivity of a malignant diagnosis to 80.0%. High TERT levels and/or BRAFV600E was associated with aggressive or advanced stage pathology. CONCLUSIONS: Combining cytology with ddPCR analysis of BRAFV600E and TERT can improve the diagnostic accuracy of thyroid FNAB, and help predict aggressive pathology.

A phase 1, randomized study to evaluate safety, tolerability, and pharmacokinetics of GDC-3280, a potential novel anti-fibrotic small molecule, in healthy subjects.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Although anti-fibrotic treatments, such as pirfenidone, are available that reduce the rate of disease progression, these medications have limitations in tolerability, and IPF patients still have poor prognoses. GDC-3280, an orally available small molecule that was designed to improve upon pirfenidone's activity, has anti-fibrotic activity in animal models. This first-in-human, phase 1 trial evaluated GDC-3280 to determine its safety, tolerability, and pharmacokinetics (PK). METHODS: Single and multiple ascending-doses of GDC-3280 were administered to healthy volunteers in two parts. Part A consisted of 6 treatment groups, each receiving a single, oral dose of GDC-3280 (25-1600 mg) or placebo in the fasted state. Part A also assessed the effect of food and coadministration of a proton pump inhibitor (rabeprazole) on the tolerability and PK of single doses of 400- and 800-mg GDC-3280. Part B consisted of 3 treatment groups who received either 200- or 275-mg GDC-3280 twice daily or 525-mg once daily after a low-fat meal for 7 days. The trial monitored treatment-emergent adverse events (TEAEs) and assessed the pharmacokinetics of GDC-3280 in blood and urine samples. RESULTS: Fifty-six subjects (42 GDC-3280, 14 placebo) in Part A and 24 subjects (18 GDC-3280, 6 placebo) in Part B received treatment. No deaths, serious adverse events, or dose-limiting adverse events occurred, and no subjects withdrew due to a TEAE. In both Parts A and B, most TEAEs were mild. The most frequent TEAEs in Part A were headache and nausea. TEAEs occurred more often when GDC-3280 was administered with food. Pretreatment and coadministration with rabeprazole had no effect on GDC-3280 tolerability. In Part B, the most frequent TEAEs were nausea, dizziness, nasal congestion, and cough. Transient, treatment-related increases in serum creatinine occurred at doses greater than 400 mg in Part A (12%-18% from baseline) and after multiple doses in each group in Part B (20%-34% from baseline). GDC-3280 was generally readily absorbed with a median tmax < 4.0 h following single- or repeat-dose oral administration. In Part A, less-than-dose-proportional increases in systemic exposure occurred, and in Part B, dose-proportional increases occurred within the dose range tested. At doses of 200 mg or lower, more than 50%-70% of orally administered doses were recovered in urine as unchanged GDC-3280 when subjects received a single dose of GDC-3280, suggesting renal excretion is one of the major routes of elimination. Administration of single doses of 400- and 800-mg GDC-3280 after a meal caused statistically significant increases in exposure due to increased rates of absorption compared to the fasted state. Pretreatment and coadministration of rabeprazole dosing led to decreases in exposure compared to GDC-3280 alone, indicating a weak drug-drug interaction. Following repeat dose administration, steady-state plasma concentrations of GDC-3280 were achieved within 2 days with an apparent terminal half-life (t1/2) between 5 and 6 h. CONCLUSIONS: Single and multiple doses of GDC-3280 were generally well tolerated, with acceptable safety and pharmacokinetic profiles that support twice-daily, oral administration with food in future clinical trials.

Local Health Departments' Capacity for Workplace Health Promotion Programs to Prevent Chronic Disease: Comparison of Rural, Micropolitan, and Urban Contexts.

OBJECTIVE: To examine local health department (LHD) contexts, capacity for, and interest in partnering with employers on workplace health promotion programs (WHPPs) for chronic disease prevention. DESIGN: Qualitative interviews with LHD directors. SETTING: LHDs from 21 counties in 10 states. PARTICIPANTS: Twenty-one LHD directors. MAIN OUTCOME MEASURESS: Experiences and perceptions of existing partnerships, decision making, funding, data needs, and organizational capacity for WHPP partnerships with employers. RESULTS: We identified 3 themes: (1) LHDs see the value of partnering with employers but lack the capacity to do so effectively; (2) while LHDs base priorities on community need, funding ultimately drives decision making; and (3) rural, micropolitan, and urban LHDs differ in their readiness and capacity to work with employers. CONCLUSIONS: Understanding LHDs' partnership capacity and context is essential to the successful implementation of WHPP partnerships with employers. Expanding these partnerships may require additional financial investments, particularly among rural LHDs.

Local Health Jurisdiction Staff Deliver Health Promotion to Small Worksites, Washington.

CONTEXT: Worksites can serve as community sites for local health jurisdictions (LHJs) to assist with implementation of evidence-based interventions (EBIs) to prevent and control chronic diseases. OBJECTIVE: To assess the feasibility and effectiveness of using LHJ staff to disseminate Connect to Wellness (CtW), an effective dissemination package for increasing implementation of EBIs for chronic disease control by small worksites. DESIGN: Single-arm, multisite intervention trial, with measurement at baseline, after 6 months of intervention, and after a maintenance period of 6 months. SETTING: Six geographically dispersed counties in Washington State. Target worksites had 20 to 250 employees. PARTICIPANTS: Nine staff members from 6 LHJs delivered CtW to 35 worksites. INTERVENTION: Connect to Wellness seeks to increase worksites' implementation of 14 EBIs classified as communication, policy, or program approaches to increasing 4 behaviors: cancer screening, healthy eating, physical activity, and tobacco cessation. MAIN OUTCOME MEASURE: Evidence-based intervention implementation measured on a scale from 0% to 100%. RESULTS: Participating worksites showed a significant increase (P < .001, t test) in total mean implementation scores from baseline (33%) to 6-month follow-up (47%). Increases in implementation for communications, policy, healthy eating, and tobacco EBIs were statistically significant at 6 months and maintained at 12 months. Increased implementation at 6 months of a group physical activity program was not sustained after the program became unavailable, and total implementation scores at 12 months (38%) showed little change from baseline. CONCLUSIONS: Local health jurisdiction-delivered CtW increased worksites' implementation of EBIs at 6 months, and increased implementation in communication, policy, healthy eating, and tobacco was maintained at 12 months. This package, delivered by LHJ staff working part-time on CtW, was nearly as successful as prior delivery by staff working full-time on CtW.