How Does Therapy Harm? A Model of Adverse Process Using Task Analysis in the Meta-Synthesis of Service Users' Experience.

Background: Despite repeated discussion of treatment safety, there remains little quantitative research directly addressing the potential of therapy to harm. In contrast, there are numerous sources of qualitative evidence on clients' negative experience of psychotherapy, which they report as harmful. Objective: To derive a model of process factors potentially leading to negative or harmful effects of therapy, from the clients' perspective, based on a systematic narrative synthesis of evidence on negative experiences and effects of psychotherapy from (a) qualitative research findings and (b) participants' testimony. Method: We adapted Greenberg (2007) task analysis as a discovery-oriented method for the systematic synthesis of qualitative research and service user testimony. A rational model of adverse processes in psychotherapy was empirically refined in two separate analyses, which were then compared and incorporated into a rational-empirical model. This was then validated against an independent qualitative study of negative effects. Results: Over 90% of the themes in the rational-empirical model were supported in the validation study. Contextual issues, such as lack of cultural validity and therapy options together with unmet client expectations fed into negative therapeutic processes (e.g., unresolved alliance ruptures). These involved a range of unhelpful therapist behaviors (e.g., rigidity, over-control, lack of knowledge) associated with clients feeling disempowered, silenced, or devalued. These were coupled with issues of power and blame. Conclusions: Task analysis can be adapted to extract meaning from large quantities of qualitative data, in different formats. The service user perspective reveals there are potentially harmful factors at each stage of the therapy journey which require remedial action. Implications of these findings for practice improvement are discussed.

A quantitative screening-level approach to incorporate chemical exposure and risk into alternative assessment evaluations.

As the general public and retailers ask for disclosure of chemical ingredients in the marketplace, a number of hazard screening tools were developed to evaluate the so-called "greenness" of individual chemical ingredients and/or formulations. The majority of these tools focus only on hazard, often using chemical lists, ignoring the other part of the risk equation: exposure. Using a hazard-only focus can result in regrettable substitutions, changing 1 chemical ingredient for another that turns out to be more hazardous or shifts the toxicity burden to others. To minimize the incidents of regrettable substitutions, BizNGO describes "Common Principles" to frame a process for informed substitution. Two of these 6 principles are: "reduce hazard" and "minimize exposure." A number of frameworks have emerged to evaluate and assess alternatives. One framework developed by leading experts under the auspices of the US National Academy of Sciences recommended that hazard and exposure be specifically addressed in the same step when assessing candidate alternatives. For the alternative assessment community, this article serves as an informational resource for considering exposure in an alternatives assessment using elements of problem formulation; product identity, use, and composition; hazard analysis; exposure analysis; and risk characterization. These conceptual elements build on practices from government, academia, and industry and are exemplified through 2 hypothetical case studies demonstrating the questions asked and decisions faced in new product development. These 2 case studies-inhalation exposure to a generic paint product and environmental exposure to a shampoo rinsed down the drain-demonstrate the criteria, considerations, and methods required to combine exposure models addressing human health and environmental impacts to provide a screening level hazard and exposure (risk) analysis. This article informs practices for these elements within a comparative risk context to improve alternatives assessment evaluation and decision making. Integr Environ Assess Manag 2017;13:1007-1022. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Outcome of Preterm Neonates with a Birth Weight <1,500 g with Severe Hypoxemic Respiratory Failure Rescued by Inhaled Nitric Oxide Therapy and High-Frequency Oscillatory Ventilation.

BACKGROUND: Despite being an experimental therapy in preterm neonates, inhaled nitric oxide (iNO) is used as a rescue therapy when high-frequency oscillatory ventilation (HFOV) and other conventional therapies fail. OBJECTIVE: We aimed to determine the outcomes of very-low-birth-weight (VLBW) neonates with hypoxemic respiratory failure (HRF) who had received iNO after maximal conventional therapies. METHODS: We retrospectively reviewed preterm neonates (<33 weeks of gestation with a birth weight <1,500 g) who had all received HFOV and then iNO from March 1, 2009 to April 1, 2014 at the Royal Alexandra Hospital. We collected demographic and clinical parameters, doses, duration and response to iNO, survival to neonatal intensive care unit (NICU) discharge, major complications, and neurodevelopmental outcome at 18-24 months of corrected age. RESULTS: During the study period, 1,168 eligible preterm neonates were admitted; 155 (13%) had HRF treated with HFOV, of whom 47 (30%) received iNO. The baseline characteristics between the 24 survivors and 23 nonsurvivors were not different. Survivors had a greater decrease in oxygenation index than nonsurvivors (61 vs. 33%) after 6 h of iNO (p = 0.003). The causes of death were refractory hypoxemia (8), multi-organ failure (7), treatment withdrawal (6), and others (2). During the NICU stay, 23 survivors (96%) developed complications. At 18-24 months, 7 (29%) had significant disabilities. CONCLUSIONS: Of the VLBW neonates with severe HRF rescued by HFOV and iNO, many survived without neurodevelopmental disability at early childhood, despite multiple short-term complications. Further research is necessary to understand the clinical course and risk factors of adverse outcomes and to improve the management care of these critically ill neonates.

Using exhaled CO2 to guide initial respiratory support at birth: a randomised controlled trial.

IMPORTANCE: A sustained inflation (SI) provided at birth might reduce bronchopulmonary dysplasia (BPD). OBJECTIVE: This study aims to examine whether an SI-guided exhaled carbon dioxide (ECO2) compared with positive pressure ventilation (PPV) alone at birth decreases BPD. DESIGN: Randomised controlled trial. Infants were randomly allocated to either SI (SI group) or PPV (PPV group). PARTICIPANTS: Participants of this study include infants between 23+0 and 32+6 weeks gestation with a need for PPV at birth. INTERVENTION: Infants randomised into the SI group received an initial SI with a peak inflation pressure (PIP) of 24 cmH2O over 20 s. The second SI was guided by the amount of ECO2. If ECO2 was ≤20 mm Hg, a further SI of 20 s was delivered. If ECO2 was >20 mm Hg the second SI was 10 s. Infants randomised into the PPV group received mask PPV with an initial PIP of 24 cmH2O. PRIMARY OUTCOMES: Reduction in BPD defined as the need for respiratory support or supplemental oxygen at corrected gestational age of 36 weeks. RESULTS: SI (n=76) and PPV (n=86) group had similar rates of BPD (23% vs 33%, p=0.090, not statistically significant). The duration of mechanical ventilation was significantly reduced with SI versus PPV (63 (10-246) hours versus 204 (17-562) hours, respectively (p=0.045)). No short-term harmful effects were identified from two SI lasting up to 40 s (eg, pneumothorax, intraventricular haemorrhage or patent ductus arteriosus). CONCLUSION: Preterm infants <33 weeks gestation receiving SI at birth had lower duration of mechanical ventilation and similar incidence of BPD compared with PPV. Using ECO2 to guide length of SI is feasible. TRIAL REGISTRATION NUMBER: NCT01739114; Results.

Hershey Medical Center Technical Workshop Report: optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure.

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings.

Use of a physiologically based pharmacokinetic model to identify exposures consistent with human biomonitoring data for chloroform.

Biomonitoring data provide evidence of human exposure to environmental chemicals by quantifying the chemical or its metabolite in a biological matrix. To better understand the correlation between biomonitoring data and environmental exposure, physiologically based pharmacokinetic (PBPK) modeling can be of use. The objective of this study was to use a combined PBPK model with an exposure model for showering to estimate the intake concentrations of chloroform based on measured blood and exhaled breath concentrations of chloroform. First, the predictive ability of the combined model was evaluated with three published studies describing exhaled breath and blood concentrations in people exposed to chloroform under controlled showering events. Following that, a plausible exposure regimen was defined combining inhalation, ingestion, and dermal exposures associated with residential use of water containing typical concentrations of chloroform to simulate blood and exhaled breath concentrations of chloroform. Simulation results showed that inhalation and dermal exposure could contribute substantially to total chloroform exposure. Next, sensitivity analysis and Monte Carlo analysis were performed to investigate the sources of variability in model output. The variability in exposure conditions (e.g., shower duration) was shown to contribute more than the variability in pharmacokinetics (e.g., body weight) to the predicted variability in blood and exhaled breath concentrations of chloroform. Lastly, the model was used in a reverse dosimetry approach to estimate distributions of exposure consistent with concentrations of chloroform measured in human blood and exhaled breath.

Collection and use of exposure data from human milk biomonitoring in the United States.

Human milk is a unique biological matrix that can be used to estimate exposures in both the mother and the breastfed infant. In addition, the presence of environmental chemicals in human milk may act as a sentinel for exposures to a broader population. Several factors play a role in determining the quantity of chemicals transferred to milk and, subsequently, to the breastfeeding infant, including maternal, infant, and chemical characteristics. Exposure to certain environmental chemicals during critical periods can disrupt normal infant development, yet few data exist to quantify the hazards posed by environmental chemicals in human milk. Chemicals measured in human milk may also provide insights to agents suspect in altering breast development and breast-related disease risk. Carefully designed exposure assessment and toxicokinetic studies are needed to elucidate mechanisms and establish relationships between human milk and other biologic matrices. Data from human milk biomonitoring studies can be used to inform and validate models that integrate information about chemical properties, human metabolism, and biomarker concentrations. Additional research is needed to determine the degree to which environmental chemicals enter, are present in, and are excreted from human milk, their impact on the host (mother), and the extent of their bioavailability to breastfeeding infants. This article describes how the collection and use of exposure data from human milk biomonitoring in the United States can be designed to inform future research and policy.

Discrepancies between arterial oxygen saturation and functional oxygen saturation measured with pulse oximetry in very preterm infants.

BACKGROUND: Discrepancies between pulse oximetry saturation (SpO(2)) and arterial saturation (SaO(2)) at low blood oxygenation values have been previously reported with significant variations among instruments and studies. Whether pulse oximeters that attenuate motion artifact are less prone to such discrepancies is not well known. OBJECTIVE: To prospectively assess the agreement of the Masimo V4 pulse oximeter within the critical 85-95% SpO(2) target range. PATIENTS AND METHODS: For all consecutive babies with gestational age <33 weeks, postnatal age <7 days, and an umbilical arterial line, SpO(2) was measured continuously and SaO(2) analyzed on an as-needed basis. Bland-Altman techniques provided estimates of the difference (D = SaO(2) - SpO(2)), standard deviation (SD), and 95% limits of agreement (D ± 2*SD). RESULTS: There were 1,032 measurements (114 babies) with SpO(2) between 85 and 95%. The 95% limits of agreement were -2.0 ± 5.8, -2.4 ± 9.2, and -1.9 ± 5.3 in the SpO(2) categories 85-95, 85-89, and 91-95%, respectively. For the SpO(2) categories 85-89% and 91-95%, only 52% (53/101) and 59% (523/886) of SpO(2) values, respectively, corresponded to the analogous SaO(2) categories. In the 85-89% SpO(2) category, SaO(2) was lower than 85% in 39 of the 101 (39%) measurements. CONCLUSION: SaO(2) was lower on average than SpO(2) with an increased bias at lower saturation. The -2.4 ± 9.2 95% limits of agreement for SaO(2) - SpO(2) in the 85-89% SpO(2) category suggest that SpO(2) and SaO(2) are not interchangeable and intermittent SaO(2) assessments are warranted when the targeted SpO(2) is within this range.

Improving the scientific foundation for mixtures joint toxicity and risk assessment: contributions from the SOT mixtures project--introduction.

Risk assessments are enhanced when policy and other decision-makers have access to experimental science designed to specifically inform key policy questions. Currently, our scientific understanding and science policy for environmental mixtures are based largely on extrapolating from and combining data in the observable range of single chemical toxicity to lower environmental concentrations and composition, i.e., using higher dose data to extrapolate and predict lower dose toxicity. There is a growing consensus that the default assumptions underlying those mixtures risk assessments that are conducted in the absence of actual mixtures data rest on an inadequate scientific database. Future scientific research should both build upon the current science and advance toxicology into largely uncharted territory. More precise approaches to better characterize toxicity of mixtures are needed. The Society of Toxicology (SOT) sponsored a series of panels, seminars, and workshops to help catalyze and improve the design and conduct of experimental toxicological research to better inform risk assessors and decision makers. This paper summarizes the activities of the SOT Mixtures Program and serves as the introductory paper to a series of articles in this issue, which hope to inspire innovative research and challenge the status quo.

Can mode of action predict mixture toxicity for risk assessment?

Recent regulatory guidance for mixture risk assessments and for regulating pesticide chemicals recommends using information about the "mode" or "mechanism" of action of individual chemicals to predict dose response characteristics of mixtures. Dose addition is assumed for mixtures of chemicals that have similar mechanisms and response addition for those with dissimilar mechanisms. Three different sets of criteria have been formulated to guide the selection of an appropriate data set for characterizing a chemical's mode of action, but the sufficiency of those criteria to predict dose addition for a mixture has not been validated experimentally. Several examples from the pharmacological and toxicological literature challenge the premise that dose response characteristics of a mixture can be predicted from the modes of action of its components. Detoxification pathways may need to be understood before dose addition in the observable effect range can be extrapolated to mixture concentrations below the no observable effect levels of the mixture components. Because elucidating discreet mechanisms of action may be possible only for chemicals that exhibit a high degree of biological specificity and dose sensitivity, practical limitations on the approach must be defined. To reduce the large uncertainties inherent in the recommended approach, future research should be focused on defining the mechanistic features that predict dose additive toxicity in mixtures. A detailed characterization of pharmacodynamics, pharmacokinetics, and slope of dose response curves may be necessary to evaluate whether the toxicity of a mixture can be predicted by the mode of action of its component chemicals.