The evolution of lung adenocarcinoma precursors is associated with chromosomal instability and transition from innate to adaptive immune response/evasion.

Studying lung adenocarcinoma (LUAD) early carcinogenesis is challenging, primarily due to the lack of LUAD precursors specimens. We amassed multi-omics data from 213 LUAD and LUAD precursors to identify molecular features underlying LUAD precancer evolution. We observed progressively increasing mutations, chromosomal aberrations, whole genome doubling and genomic instability from precancer to invasive LUAD, indicating aggravating chromosomal instability (CIN). Telomere shortening, a crucial genomic alteration linked to CIN, emerged at precancer stage. Moreover, later-stage lesions demonstrated increasing cancer stemness and decreasing alveolar identity, suggesting epithelial de-differentiation during early LUAD carcinogenesis. The innate immune cells progressively diminished from precancer to invasive LUAD, concomitant with a gradual recruitment of adaptive immune cells (except CD8+ and gamma-delta T cells that decreased in later stages) and upregulation of numerous immune checkpoints, suggesting LUAD precancer evolution is associated with a shift from innate to adaptive immune response and immune evasion mediated by various mechanisms.

Tumor containment: a more general mathematical analysis.

Clinical and pre-clinical data suggest that treating some tumors at a mild, patient-specific dose might delay resistance to treatment and increase survival time. A recent mathematical model with sensitive and resistant tumor cells identified conditions under which a treatment aiming at tumor containment rather than eradication is indeed optimal. This model however neglected mutations from sensitive to resistant cells, and assumed that the growth-rate of sensitive cells is non-increasing in the size of the resistant population. The latter is not true in standard models of chemotherapy. This article shows how to dispense with this assumption and allow for mutations from sensitive to resistant cells. This is achieved by a novel mathematical analysis comparing tumor sizes across treatments not as a function of time, but as a function of the resistant population size.

Cultural adaptation to quechua and psychometric analysis of the patient health questionnaire (PHQ-9) in a peruvian population. / Adaptación cultural al Quechua y análisis psicométrico del Patient Health Questionnaire (PHQ-9) en población peruana.

OBJECTIVE: . To translate and culturally adapt the Patient Health Questionnaire (PHQ-9) to three varieties of Quechua and analyse their validity, reliability, and measurement invariance. MATERIALS AND METHODS: . 1) Cultural adaptation phase: the PHQ-9 was translated from English into three variants of Quechua (Central, Chanca, Cuzco-Collao) and translated again into English. Then, experts and focus groups allowed the translations to be culturally adapted. 2) Psychometric phase: the unidimensionality of the adapted PHQ-9 was evaluated by using Confirmatory Factor Analysis (CFA), reliability was evaluated by internal consistency (Alpha and Omega), and measurement invariance according to Quechua varieties and sociodemographic variables was evaluated by using CFA, multigroups and MIMIC models (Multiple Indicator Multiple Cause). RESULTS: . Each of the adaptations of the PHQ-9 to the three Quechua varieties reported clear and culturally equivalent items. Subsequently, data from 970 Quechua-speaking adult men and women were analyzed. The general one-dimensional model reported an adequate fit (Comparative fit index = 0.990, Tucker-Lewis index = 0.987, Standardized root mean squared residual= 0.048, Root mean squared error of approximation=0.071); each of the Quechua varieties also showed an adequate fit. Reliability was high for all varieties (α = 0.865 - 0.915; ω = 0.833 - 0.881). The results of the multigroup CFA and MIMIC models confirmed measurement invariance according to Quechua variant, sex, residence, age, marital status and educational level. CONCLUSIONS: . The PHQ-9 adaptations to Central Quechua, Chanca and Cuzco-Collao offer a valid, reliable and invariant measurement, confirming that comparisons can be made between the evaluated groups. Its use will benefit mental health research and care for Quechua-speaking populations.

OBJETIVO: . Traducir y adaptar culturalmente el Patient Health Questionnaire (PHQ-9) a tres variedades del quechua y analizar su validez, confiabilidad e invarianza. MATERIALES Y MÉTODOS: . 1) Fase de adaptación cultural: el PHQ-9 fue traducido del inglés a tres variantes del quechua (Central, Chanca, Cuzco-Collao) y traducido nuevamente al inglés, posteriormente expertos y grupos focales permitieron adaptar culturalmente las traducciones. 2) Fase psicométrica: se evaluó la uni-dimensionalidad del PHQ-9 adaptado mediante un Análisis Factorial Confirmatorio (CFA), la confiabilidad se evaluó mediante consistencia interna (Alpha y Omega), y la invarianza de medida según variedades del quechua y variables sociodemográficas se evaluó empleando CFA multigrupos y modelos MIMIC (Múltiples Indicadores y Múltiples Causas). RESULTADOS: . Cada una de las adaptaciones del PHQ-9 a las tres variedades de quechua reportaron ítems claros y culturalmente equivalentes. Posteriormente, con 970 datos de quechuahablantes adultos varones y mujeres, el modelo general unidimensional reportó un ajuste adecuado (índice de ajuste comparativo: 0,990, índice de Tucker-Lewis: 0,987, residuo estandarizado cuadrático medio: 0,048, raíz del error cuadrático medio de aproximación: 0,071), lo mismo ocurrió para cada variedad del quechua. La confiabilidad fue alta para todas las variedades (α = 0,865 - 0,915; ω = 0,833 - 0,881). Los resultados del CFA multigrupos y modelos MIMIC confirmaron invarianza de medida según variante del quechua, sexo, residencia, edad, estado civil y nivel educativo. CONCLUSIONES: . Las adaptaciones del PHQ-9 a Quechua Central, Chanca y Cuzco-Collao ofrecen una medición válida, confiable e invariante, confirmando que se pueden hacer comparaciones en los grupos evaluados. Su uso beneficiará a la investigación y a la atención en salud mental de poblaciones quechuahablantes.

Targeting immunosuppressive Ly6C+ classical monocytes reverses anti-PD-1/CTLA-4 immunotherapy resistance.

Introduction: Despite significant clinical advancement with the use of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) there are still a major subset of patients that develop adaptive/acquired resistance. Understanding resistance mechanisms to ICB is critical to developing new therapeutic strategies and improving patient survival. The dynamic nature of the tumor microenvironment and the mutational load driving tumor immunogenicity limit the efficacy to ICB. Recent studies indicate that myeloid cells are drivers of ICB resistance. In this study we sought to understand which immune cells were contributing to resistance and if we could modify them in a way to improve response to ICB therapy. Results: Our results show that combination anti-PD-1/CTLA-4 produces an initial antitumor effect with evidence of an activated immune response. Upon extended treatment with anti-PD-1/CTLA-4 acquired resistance developed with an increase of the immunosuppressive populations, including T-regulatory cells, neutrophils and monocytes. Addition of anti-Ly6C blocking antibody to anti-PD-1/CTLA-4 was capable of completely reversing treatment resistance and restoring CD8 T cell activity in multiple KP lung cancer models and in the autochthonous lung cancer KrasLSL-G12D/p53fl/fl model. We found that there were higher classical Ly6C+ monocytes in anti-PD-1/CTLA-4 combination resistant tumors. B7 blockade illustrated the importance of dendritic cells for treatment efficacy of anti-Ly6C/PD-1/CTLA-4. We further determined that classical Ly6C+ monocytes in anti-PD-1/CTLA-4 resistant tumors are trafficked into the tumor via IFN-γ and the CCL2-CCR2 axis. Mechanistically we found that classical monocytes from ICB resistant tumors were unable to differentiate into antigen presenting cells and instead differentiated into immunosuppressive M2 macrophages or myeloid-derived suppressor cells (MDSC). Classical Ly6C+ monocytes from ICB resistant tumors had a decrease in both Flt3 and PU.1 expression that prevented differentiation into dendritic cells/macrophages. Conclusions: Therapeutically we found that addition of anti-Ly6C to the combination of anti-PD-1/CTLA-4 was capable of complete tumor eradication. Classical Ly6C+ monocytes differentiate into immunosuppressive cells, while blockade of classical monocytes drives dendritic cell differentiation/maturation to reinvigorate the anti-tumor T cell response. These findings support that immunotherapy resistance is associated with infiltrating monocytes and that controlling the differentiation process of monocytes can enhance the therapeutic potential of ICB.

Adaptación cultural al Quechua y análisis psicométrico del Patient Health Questionnaire (PHQ-9) en población peruana / Cultural adaptation to Quechua and psychometric analysis of the Patient Health Questionnaire PHQ-9 in a peruvian population

Objetivo . Traducir y adaptar culturalmente el Patient Health Questionnaire (PHQ-9) a tres variedades del quechua y analizar su validez, confiabilidad e invarianza. Materiales y métodos . 1) Fase de adaptación cultural: el PHQ-9 fue traducido del inglés a tres variantes del quechua (Central, Chanca, Cuzco-Collao) y traducido nuevamente al inglés, posteriormente expertos y grupos focales permitieron adaptar culturalmente las traducciones. 2) Fase psicométrica: se evaluó la uni-dimensionalidad del PHQ-9 adaptado mediante un Análisis Factorial Confirmatorio (CFA), la confiabilidad se evaluó mediante consistencia interna (Alpha y Omega), y la invarianza de medida según variedades del quechua y variables sociodemográficas se evaluó empleando CFA multigrupos y modelos MIMIC (Múltiples Indicadores y Múltiples Causas). Resultados . Cada una de las adaptaciones del PHQ-9 a las tres variedades de quechua reportaron ítems claros y culturalmente equivalentes. Posteriormente, con 970 datos de quechuahablantes adultos varones y mujeres, el modelo general unidimensional reportó un ajuste adecuado (índice de ajuste comparativo: 0,990, índice de Tucker-Lewis: 0,987, residuo estandarizado cuadrático medio: 0,048, raíz del error cuadrático medio de aproximación: 0,071), lo mismo ocurrió para cada variedad del quechua. La confiabilidad fue alta para todas las variedades (α = 0,865 - 0,915; ω = 0,833 - 0,881). Los resultados del CFA multigrupos y modelos MIMIC confirmaron invarianza de medida según variante del quechua, sexo, residencia, edad, estado civil y nivel educativo. Conclusiones . Las adaptaciones del PHQ-9 a Quechua Central, Chanca y Cuzco-Collao ofrecen una medición válida, confiable e invariante, confirmando que se pueden hacer comparaciones en los grupos evaluados. Su uso beneficiará a la investigación y a la atención en salud mental de poblaciones quechuahablantes.

Objective . To translate and culturally adapt the Patient Health Questionnaire (PHQ-9) to three varieties of Quechua and analyse their validity, reliability, and measurement invariance. Materials and methods . 1) Cultural adaptation phase: the PHQ-9 was translated from English into three variants of Quechua (Central, Chanca, Cuzco-Collao) and translated again into English. Then, experts and focus groups allowed the translations to be culturally adapted. 2) Psychometric phase: the unidimensionality of the adapted PHQ-9 was evaluated by using Confirmatory Factor Analysis (CFA), reliability was evaluated by internal consistency (Alpha and Omega), and measurement invariance according to Quechua varieties and sociodemographic variables was evaluated by using CFA, multigroups and MIMIC models (Multiple Indicator Multiple Cause). Results . Each of the adaptations of the PHQ-9 to the three Quechua varieties reported clear and culturally equivalent items. Subsequently, data from 970 Quechua-speaking adult men and women were analyzed. The general one-dimensional model reported an adequate fit (Comparative fit index = 0.990, Tucker-Lewis index = 0.987, Standardized root mean squared residual= 0.048, Root mean squared error of approximation=0.071); each of the Quechua varieties also showed an adequate fit. Reliability was high for all varieties (α = 0.865 - 0.915; ω = 0.833 - 0.881). The results of the multigroup CFA and MIMIC models confirmed measurement invariance according to Quechua variant, sex, residence, age, marital status and educational level. Conclusions . The PHQ-9 adaptations to Central Quechua, Chanca and Cuzco-Collao offer a valid, reliable and invariant measurement, confirming that comparisons can be made between the evaluated groups. Its use will benefit mental health research and care for Quechua-speaking populations.

Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial.

Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7-43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6-61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129 .).

Evolution of a structured cell population endowed with plasticity of traits under constraints on and between the traits.

Confronted with the biological problem of managing plasticity in cell populations, which is in particular responsible for transient and reversible drug resistance in cancer, we propose a rationale consisting of an integro-differential and a reaction-advection-diffusion equation, the properties of which are studied theoretically and numerically. By using a constructive finite volume method, we show the existence and uniqueness of a weak solution and illustrate by numerical approximations and their simulations the capacity of the model to exhibit divergence of traits. This feature may be theoretically interpreted as describing a physiological step towards multicellularity in animal evolution and, closer to present-day clinical challenges in oncology, as a possible representation of bet hedging in cancer cell populations.

Factors Influencing COVID-19 Vaccine Acceptance in the Workplace: Results From a Rapid Survey at 2 Corporations in Los Angeles County, California, 2021.

OBJECTIVES: Achieving widespread vaccine acceptance across various employment sectors is key to a successful public health response to COVID-19, but little is known about factors influencing vaccine acceptance among essential non-health care workers. We examined factors influencing vaccine acceptance among a sample of essential non-health care workers in California. METHODS: We conducted a survey in early spring 2021 at 2 corporations in Los Angeles County, California, to identify and describe factors influencing vaccine acceptance and the ability of incentives to increase this acceptance. We used modified Poisson regression analysis to estimate adjusted prevalence ratios and a best-subset selection algorithm to identify the strongest factors influencing vaccine acceptance. RESULTS: Of 678 workers who completed the survey, 450 were unvaccinated. Among unvaccinated participants, having trust in information about the vaccine from public health experts, having ≥1 chronic health condition related to COVID-19 severity, being Asian, and perceiving risk for COVID-19 were factors that most influenced vaccine acceptance. Most (271 of 296, 91.6%) participants who had trust in information from public health experts and 30.6% (30 of 98) of participants who did not have trust in information from public health experts said that they would accept the vaccine. Seventeen of 24 (70.8%) vaccine-hesitant workers who had trust in information from public health experts and 12 of 72 (16.7%) vaccine-hesitant workers who did not have trust in this information said that they would be more likely to accept the vaccine if an incentive were offered. CONCLUSIONS: Efforts to increase vaccine coverage at workplaces should focus on improving trust in the vaccine and increasing public awareness that the vaccine is free.

The microRNA-183/96/182 cluster inhibits lung cancer progression and metastasis by inducing an interleukin-2-mediated antitumor CD8+ cytotoxic T-cell response.

One of the mechanisms by which cancer cells acquire hyperinvasive and migratory properties with progressive loss of epithelial markers is the epithelial-to-mesenchymal transition (EMT). We have previously reported that in different cancer types, including nonsmall cell lung cancer (NSCLC), the microRNA-183/96/182 cluster (m96cl) is highly repressed in cells that have undergone EMT. In the present study, we used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of Kras mutant autochthonous lung adenocarcinomas. In contrast, ectopic expression of the m96cl in NSCLC cells results in a robust suppression of migration and invasion in vitro, and tumor growth and metastasis in vivo. Detailed immune profiling of the tumors revealed a significant enrichment of activated CD8+ cytotoxic T lymphocytes (CD8+ CTLs) in m96cl-expressing tumors, and m96cl-mediated suppression of tumor growth and metastasis was CD8+ CTL-dependent. Using coculture assays with naïve immune cells, we show that m96cl expression drives paracrine stimulation of CD8+ CTL proliferation and function. Using tumor microenvironment-associated gene expression profiling, we identified that m96cl elevates the interleukin-2 (IL2) signaling pathway and results in increased IL2-mediated paracrine stimulation of CD8+ CTLs. Furthermore, we identified that the m96cl modulates the expression of IL2 in cancer cells by regulating the expression of transcriptional repressors Foxf2 and Zeb1, and thereby alters the levels of secreted IL2 in the tumor microenvironment. Last, we show that in vivo depletion of IL2 abrogates m96cl-mediated activation of CD8+ CTLs and results in loss of metastatic suppression. Therefore, we have identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.

Assessing the Policy Landscape for Salt Reduction in South-East Asian and Latin American Countries - An Initiative Towards Developing an Easily Accessible, Integrated, Searchable Online Repository.

Background: High dietary salt intake is an avoidable cause of hypertension and associated cardiovascular diseases (CVDs). Thus, salt reduction is recommended as one of the most cost-effective interventions for CVD prevention and for achieving the World Health Organization's (WHO) 25% reduction in premature non-communicable disease (NCD) mortality by 2025. However, current and comprehensive information about national salt reduction policies and related actions across different regions are difficult to access and impede progress and monitoring. Objectives: As an initial step to developing an online repository of salt reduction policies and related actions, and to track nation-wise progress towards the WHO's 25 by 25 goal, we aimed to identify and assess salt reduction policies and actions in select countries from two of the top five most populous regions of the world- the South-East Asia and Latin America. Methods: We conducted a literature review to identify national and regional salt reduction policies in the selected South-East Asian and Latin American countries, from January 1990-August 2020, available in English and Spanish. We also contacted selected WHO country offices (South-East Asian region) or relevant national authorities (Latin America) to gain access to unpublished documents. Results: In both regions, we found only a few dedicated stand-alone salt reduction policies: Bhutan, Sri-Lanka and Thailand from South East Asia and Costa Rica from Latin America. Available polices were either embedded in other national health/nutritional policy documents/overall NCD policies or were unpublished and had to be accessed via personal communication. Conclusions: Salt reduction policies are limited and often embedded with other policies which may impede their implementation and utility for tracking national and international progress towards the global salt reduction target associated with the 25 by 25 goal. Developing an online repository could help countries address this gap and assist researchers/policymakers to monitor national progress towards achieving the salt reduction target.

Tobacco consumption and positive mental health: an epidemiological study from a positive psychology perspective.

BACKGROUND: Positive mental health (PMH) is much more than the absence of mental illnesses. For example, PMH explains that to be happy or resilient can drive us to live a full life, giving us a perception of well-being and robustness against everyday problems. Moreover, PMH can help people to avoid risky behaviours like tobacco consumption (TC). Our hypothesis was that PMH is negatively associated with TC, and this association differs across rural, urban and migrant populations. METHODS: A cross-sectional study was conducted using the PERU MIGRANT Study's dataset, including rural population from the Peruvian highlands (n = 201), urban population from the capital city Lima (n = 199) and migrants who were born in highlands but had to migrated because of terrorism (n = 589). We used an adapted version of the 12-item Global Health Questionnaire to measure PMH. The outcome was TC, measured as lifetime and recent TC. Log-Poisson robust regression, performed with a Maximum Likelihood method, was used to estimate crude prevalence ratios (PR) and 95 % confidence intervals (95%CI), adjusted by sex, age, family income and education which were the confounders. The modelling procedure included the use of LR Test, Akaike information criteria (AIC) and Bayesian information criteria (BIC). RESULTS: Cumulative occurrence of tobacco use (lifetime TC) was 61.7 % in the rural group, 78 % in the urban group and 76.2 % in rural-to-urban migrants. Recent TC was 35.3 % in the rural group, 30.7 % in the urban group and 20.5 % in rural-to-urban migrants. After adjusting for confounders, there was evidence of a negative association between PMH and lifetime TC in the rural group (PR = 0.93; 95%CI: 0.87-0.99), and a positive association between PMH and recent TC in migrants (PR = 1.1; 95%CI: 1.0-1.3). CONCLUSIONS: PMH was negatively associated with TC in rural participants only. Urbans exhibited just a similar trend, while migrants exhibited the opposite one. This evidence represents the first step in the route of knowing the potential of PMH for fighting against TC. For rural populations, this study supplies new information that could support decisions about prevention programmes and psychotherapy for smoking cessation. However, more research in the topic is needed.

Regionally nested patterns of fish assemblages in floodplain lakes of the Magdalena river (Colombia).

We investigated if fish assemblages in neotropical floodplain lakes (cienagas) exhibit nestedness, and thus offer support to the managers of natural resources of the area for their decision making. The location was floodplain lakes of the middle section of the Magdalena river, Colombia. We applied the nested subset analysis for the series of 30 cienagas (27 connected to the main river and three isolated). All fish were identified taxonomically in the field and the matrix for presence-absence in all the lakes was used for the study of the pattern of nestedness. The most diverse order was Characiformes (20 species), followed by Siluriformes (19 species). Characidae and Loricaridae were the richest families. The species found in all the lakes studied were migratory species (17), and sedentary species (33). Two species (Caquetaia kraussii and Cyphocharax magdalenae) were widespread across the cienagas archipelago (100% of incidence). Nestedness analysis showed that the distribution of species over the spatial gradient studied (840 km) is significantly nested. The cienagas deemed the most hospitable were Simiti, El Llanito, and Canaletal. Roughly, 13 out of the 50 species caught show markedly idiosyncratic distributions. The resulting dataset showed a strong pattern of nestedness in the distribution of Magdalenese fishes, and differed significantly from random species assemblages. Out of all the measurements taken in the cienagas, only the size (area) and local richness are significantly related to the range of order of nested subset patterns (r=-0.59 and -0.90, respectively, at p < 0.01). Differential species extinction is suggested as the cause of a nested species assemblage, when the reorganized matrix of species occurring in habitat islands is correlated with the island area. Our results are consistent with this hypothesis.

Emergency contraception under attack in Latin America: response of the medical establishment and civil society.

The concept that it is possible to prevent a pregnancy after coitus is not new, but has gained prominence over the last 10-15 years. It provides a second chance to women who do not want to get pregnant and who, voluntarily or not, have had unprotected intercourse. Emergency contraception has been under strong attack by the Catholic church and anti-choice organisations in Latin America, who claim that the interference with implantation of the fertilised ovum is equivalent to an early abortion. The accumulation of evidence, however, is that the mechanism of action of emergency contraception is to prevent ovulation and that it does not interfere with implantation. This has been ignored by the anti-choice movement. The pattern of opposition to emergency contraception has been the same all over the Latin America region. The medical establishment and civil society, including the International Consortium for Emergency Contraception, have played a key role in defending access to emergency contraception throughout the region. A positive consequence of the public opposition of the Catholic church is that the concept and the method have become better known, and emergency contraception has become widely used. The cases of Peru, Brazil and Chile are described as examples.

Ototoxic occupational exposures for a stock car racing team: I. Noise surveys.

The National Institute for Occupational Safety and Health (NIOSH) surveyed noise exposure for a professional stock car team at their race shop and during two races at one racetrack. At the team's shop, area sound pressure levels (SPLs) were measured for various work tasks. Equivalent levels (Leqs) ranged from 58 to 104 decibels, A-weighted (dBA). Personal noise dosimetry was conducted for at least one employee for each job description in race car assembly (n = 9). The Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 90 dBA for an 8-hour, 5-dB exchange rate time-weighted average (TWA) was never exceeded, but in two instances values exceeded OSHA's action level of 85 dBA for hearing conservation implementation. The NIOSH recommended exposure limit (REL) of 85 dBA for a 3-dB exchange rate Leq was exceeded for five of the measured jobs. During the races, SPLs averaged above 100 dBA in the pit area where cars undergo adjustments/refueling, both before and during the race. Peak levels reached 140 dB SPL. NIOSH REL was exceeded for every personal noise dosimetry measurement. Recommendations for hearing protection and communication are presented.

Ototoxic occupational exposures for a stock car racing team: II. chemical surveys.

The National Institute for Occupational Safety and Health (NIOSH) conducted a series of surveys to evaluate occupational exposure to noise and potentially ototoxic chemical agents among members of a professional stock car racing team. Exposure assessments included site visits to the team's race shop and a worst-case scenario racetrack. During site visits to the race team's shop, area samples were collected to measure exposures to potentially ototoxic chemicals, including, organic compounds (typical of solvents), metals, and carbon monoxide (CO). Exposures to these chemicals were all below their corresponding Occupational Safety and Health Administration (OSHA) permissible exposure limits (PELs), NIOSH recommended exposure limits (RELs), and American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit values (TLVs). During site visits to the racetrack, area and personal samples were collected for organic compounds, lead, and CO in and around the "pit" area where the cars undergo race preparation and service during the race. Exposures to organic compounds and lead were either nondetectable or too low to quantify. Twenty-five percent of the CO time-weighted average concentrations exceeded the OSHA PEL, NIOSH REL, and ACGIH TLV after being adjusted for a 10-hour workday. Peak CO measurements exceeded the NIOSH recommended ceiling limit of 200 ppm. Based on these data, exposures to potentially ototoxic chemicals are probably not high enough to produce an adverse effect greater than that produced by the high sound pressure levels alone. However, carbon monoxide levels occasionally exceeded all evaluation criteria at the racetrack.

Tuberculosis exposure of patients and staff in an outpatient hemodialysis unit.

BACKGROUND: Patients receiving hemodialysis are generally considered to be at increased risk of developing tuberculosis (TB). We evaluated a 13-station chronic outpatient hemodialysis unit associated with a community hospital in northern California. Within 6 months, there were 2 incident source cases in the unit of active smear positive pulmonary tuberculosis; the first in a health care worker (HCW), diagnosed April 3, 1998, and the second in a patient undergoing dialysis treatment in October 1998. We describe the cases; the evaluation of exposures; and the institution of an intentional prospective TB control plan, designed specifically for the unique hemodialysis setting. METHODS: We evaluated 23 HCWs twice and 89 patients undergoing hemodialysis treatment who were exposed to case 1 and 38 patients who were exposed to case 2. All 23 HCWs had documented prior negative Sierbert purified protein derivative of tuberculin (PPD) status and were retested at 12 weeks after exposure. None of the patients had documentation of PPD status. All of the patients were skin-tested initially with use of the 2-step method, and those with positive test results were offered isoniazid (INH). RESULTS: One of the 23 HCWs' negative baseline PPD skin test status converted after exposure to case 1, and none of the remaining 22 converted after exposure to case 2. Twelve of 89 exposed patients with no prior skin test record had positive results for PPD after initial testing with the 2-step method. Three of the 12 (25%) patients were treated with INH at the discretion of their attending nephrologist. The 77 patients with negative results for PPD still had negative test results when retested at 3 months. None of 38 patients who underwent dialysis on the same schedule as source case 2 had a converted PPD test. Restriction fragment length polymorphism on TB isolates from both source cases ultimately showed them to be unrelated strains. CONCLUSION: Our experience with these exposures suggests that TB screening of patient populations undergoing renal dialysis-though they have intrinsic high anergy rates-is advisable with a designed prospective plan before any inadvertent and/or repetitive exposure of that population to active TB. A planned intentional TB control program increases HCW awareness of TB, establishes baselines for evaluation, decreases "panic" in the event of subsequent exposures, and emphasizes the rationale for preventive therapy.

Pharmacokinetic study of different dosing regimens of levonorgestrel for emergency contraception in healthy women.

BACKGROUND: Levonorgestrel (LNG) is a commonly used progestin for emergency contraception; however, little is known about its pharmacokinetics and optimal dose for use. METHODS: Serum levels of LNG and sex hormone-binding globulin (SHBG) were measured in five women who received three different regimens: A: 0.75 mg LNG twice with a 12 h interval; B: 0.75 mg twice with a 24 h interval; and C: 1.50 mg in a single dose, with a washout period of 28 days between each treatment. Blood samples were taken before pill intake and at 1, 2, 4, 8 and 12 h after each dose, every 12 h up to day 4 and every 24 h until day 10. LNG and SHBG were measured in all samples. RESULTS: Maximum LNG concentrations were of approximately 27 nmol/l for treatments A and B, and close to 40 nmol/l for treatment C. The area under the curve was significantly higher for treatment C during the first 12 h, and significantly lower for treatment B during the first 24 h. After 48 h and up to 9 days from onset of treatment, serum LNG levels were similar in all three regimens. SHBG levels remained stable for 24 h, decreasing to 60% of the initial value from day 5 until day 10, with no difference between regimens. CONCLUSIONS: The similarity of LNG serum levels obtained with one single dose of 1.5 mg or two doses of 0.75 mg with a 12 h interval justify a clinical comparison of these two regimes.