Sexual identity formation or “coming out” as lesbian, gay, or bisexual (LGB) involves a complex process including both private realization and public disclosure. Private realization refers to the process through which an individual becomes aware of their LGB identity, whereas public disclosure reflects when an individual discloses their identity to another person. Sex, race, and class affect the timing of these processes across the life course. While extant research has identified the bivariate nature of these processes, we took a multivariate approach to understand the timing of these sexual identity milestones from a life-course perspective. Using data from the Pew Research Center’s 2013 Survey of LGBT Adults (n?=?1136), we considered how the timing of private realization and public disclosure of LGB identity is a sexed, racialized, and classed experience. The sample consisted of lesbians (n?=?270), gay males (n?=?396), bisexual females (n?=?342), and bisexual males (n?=?127). Results indicated that females uniformly realized and disclosed their identities at later stages in the life course, whereas individuals with at least some college education came out during their prime college-age years. We also found variation in timing between private realization and public disclosure for Black respondents, but not other racial groups. These findings provide insight into how organizations can develop specific programs that allow LGB individuals to safely explore their sexuality and provide support over the life course.
BACKGROUND: Few epidemiological studies have examined the temporal relationship between chronic pain and depression using longitudinal data. In the present study, we examined major depression as both an antecedent risk factor and consequence of chronic back pain (CBP) in the general population. METHOD: Data on 9909 pain-free individuals 15 years and older with no history of back problems were drawn from cycle 1 of the National Population Health Survey and followed up 24 months later. Major depression was assessed using a structured diagnostic interview. RESULTS: At cycle 2, the rate of new cases of CBP in persons who were depressed at cycle 1 was 3.6% compared to 1.1% in non-depressed persons. Compared to pain-free individuals, new cases of CBP were more likely to perceive their health status as poor or fair at cycle 1, were less likely to be working, reported more chronic health problems, and sustained a back or neck injury in the preceding 12 months. After controlling for other factors, pain-free individuals diagnosed as major depressed at cycle 1 were almost three times more likely (OR 2.9, 95% CI 1.2-7.0) to develop CBP at cycle 2. CONCLUSIONS: Consistent with other longitudinal studies major depression increases the risk of developing future chronic pain. The causal mechanism linking these conditions is unknown however depression may represent a modifiable risk factor in the development of CBP. 相似文献
Introduction: Improved prostate localization techniques should allow the reduction of margins around the target to facilitate dose escalation in high-risk patients while minimizing the risk of normal tissue morbidity. A daily CT simulation technique is presented to assess setup variations in portal placement and organ motion for the treatment of localized prostate cancer.
Methods and Materials: Six patients who consented to this study underwent supine position CT simulation with an alpha cradle cast, intravenous contrast, and urethrogram. Patients received 46 Gy to the initial Planning Treatment Volume (PTV1) in a four-field conformal technique that included the prostate, seminal vesicles, and lymph nodes as the Gross Tumor Volume (GTV1). The prostate or prostate and seminal vesicles (GTV2) then received 56 Gy to PTV2. All doses were delivered in 2-Gy fractions.
After 5 weeks of treatment (50 Gy), a second CT simulation was performed. The alpha cradle was secured to a specially designed rigid sliding board. The prostate was contoured and a new isocenter was generated with appropriate surface markers. Prostate-only treatment portals for the final conedown (GTV3) were created with a 0.25-cm margin from the GTV to PTV. On each subsequent treatment day, the patient was placed in his cast on the sliding board for a repeat CT simulation. The daily isocenter was recalculated in the anterior/posterior (A/P) and lateral dimension and compared to the 50-Gy CT simulation isocenter. Couch and surface marker shifts were calculated to produce portal alignment. To maintain proper positioning, the patients were transferred to a stretcher while on the sliding board in the cast and transported to the treatment room where they were then transferred to the treatment couch. The patients were then treated to the corrected isocenter. Portal films and electronic portal images were obtained for each field.
Results: Utilizing CT–CT image registration (fusion) of the daily and 50-Gy baseline CT scans, the isocenter changes were quantified to reflect the contribution of positional (surface marker shifts) error and absolute prostate motion relative to the bony pelvis. The maximum daily A/P shift was 7.3 mm. Motion was less than 5 mm in the remaining patients and the overall mean magnitude change was 2.9 mm. The overall variability was quantified by a pooled standard deviation of 1.7 mm. The maximum lateral shifts were less than 3 mm for all patients. With careful attention to patient positioning, maximal portal placement error was reduced to 3 mm.
Conclusion: In our experience, prostate motion after 50 Gy was significantly less than previously reported. This may reflect early physiologic changes due to radiation, which restrict prostate motion. This observation is being tested in a separate study. Intrapatient and overall population variance was minimal. With daily isocenter correction of setup and organ motion errors by CT imaging, PTV margins can be significantly reduced or eliminated. We believe this will facilitate further dose escalation in high-risk patients with minimal risk of increased morbidity. This technique may also be beneficial in low-risk patients by sparing more normal surrounding tissue. 相似文献
There is a growing body of research focused on developing and evaluating behavioral training paradigms meant to induce enhancements in cognitive function. It has recently been proposed that one mechanism through which such performance gains could be induced involves participants’ expectations of improvement. However, no work to date has evaluated whether it is possible to cause changes in cognitive function in a long-term behavioral training study by manipulating expectations. In this study, positive or negative expectations about cognitive training were both explicitly and associatively induced before either a working memory training intervention or a control intervention. Consistent with previous work, a main effect of the training condition was found, with individuals trained on the working memory task showing larger gains in cognitive function than those trained on the control task. Interestingly, a main effect of expectation was also found, with individuals given positive expectations showing larger cognitive gains than those who were given negative expectations (regardless of training condition). No interaction effect between training and expectations was found. Exploratory analyses suggest that certain individual characteristics (e.g., personality, motivation) moderate the size of the expectation effect. These results highlight aspects of methodology that can inform future behavioral interventions and suggest that participant expectations could be capitalized on to maximize training outcomes.There is a great deal of current scientific interest as to whether and/or how basic cognitive skills can be improved via dedicated behavioral training (1–3). This potential, if realized, could lead to substantial real-world impact. Indeed, effective training paradigms would have significant value not only for populations that show deficits in cognitive skills (e.g., individuals diagnosed with Attention Deficit Hyperactivity Disorder [ADHD] or Alzheimer’s disease and related dementias) but also, for the general public, where core cognitive capacities underpin success in both academic and professional contexts (4–6). These possible translational applications, paired with an emerging understanding of how to best unlock neuroplastic change across the life span (7, 8), have spurred hundreds of behavioral intervention studies over the past few decades. While the results have not been uniformly positive (perhaps not surprising given the massive heterogeneity in theoretical approach, methods, etc.), multiple meta-analyses suggest that it is possible for cognitive functions to be improved via some forms of dedicated behavioral training (9–11). However, while these basic science results provide optimism that real-world gains could be realized [and in fact, real-world gain is already being realized in some spheres, such as a Food and Drug Administration (FDA)–cleared video game–based treatment supplement for ADHD (12, 13)], concerns have been raised as to whether those interventions that have produced positive outcomes are truly working via the proposed mechanisms or through other nonspecific third-variable mechanisms. Several factors have been proposed to explain improvements in behavioral interventions, including selective attrition, contextual factors, regression to the mean, and practice effects to name a few (14). Here, we focus on whether expectation-based (i.e., placebo) mechanisms can explain improvements in cognitive training (15–17).In other domains, such as in clinical trials in the pharmaceutical domain for instance, expectation-based mechanisms are typically controlled for by making the experimental treatment and the control treatment perceptually indistinguishable (e.g., both might be clear fluids in an intravenous bag or a white unmarked pill). Because perceptual characteristics cannot be used to infer condition, this methodology is meant to ensure that expectations are matched between the experimental and control groups (both in terms of the expectations that the participants have and in terms of the expectations that the research team members who interact with the participants have). Under ideal circumstances, the use of such a “double-unaware” design ensures that expectations cannot be an explanatory mechanism underlying any differences between the groups’ outcomes [note that we use the double-unaware terminology in lieu of the more common “double-blind” terminology, which can be seen as ableist (18)].It is unclear whether most pharmaceutical trials do, in fact, truly meet the double-unaware standard (e.g., despite being perceptually identical, active and control treatments nonetheless often produce different patterns of side effects that could be used to infer condition) (19, 20). Yet, meeting the double-unaware standard is particularly difficult in the case of cognitive training interventions (16). Here, there is simply no way to make the experimental and control interventions perceptually indistinguishable while at the same time, ensuring that the experimental condition contains an “active ingredient” that the control condition lacks. In behavioral interventions, no matter what the active ingredient may be, it will necessarily produce a difference in look and feel as compared with a training condition that lacks the ingredient.Researchers designing cognitive training trials, therefore, typically attempt to utilize experimental and control conditions that, while differing in the proposed active ingredient, will nonetheless produce similar expectations about the likely outcomes (16, 21–24). This type of matching process, however, is inherently difficult as it is not always clear what expectations will be induced by a given type of experience. Consistent with this, there is reason to believe that expectations have not always been successfully matched. In multiple cases, despite attempts to match expectations across conditions, participants in behavioral intervention studies have nonetheless indicated the belief that the true active training task will produce more cognitive gains than the control task (25–27). Critically, the data as to whether differential expectations in these cases actually, in turn, influence the observed outcomes are decidedly mixed. In some cases, participant expectations differed between training and control conditions, and these expectations were at least partially related to differences in behavior (25). In other cases, participants expected to improve but did not show any actual improvements in cognitive skill (28), or the degree to which they improved was unrelated to their stated expectations (29).Regardless of the mixed nature of the data thus far, there is increasing consensus that training studies should 1) attempt to match the expectations generated by their experimental and control treatment conditions, 2) measure the extent to which this matching is successful and if the matching was not successful, and 3) evaluate the extent to which differential expectations explain differences in outcome (16, 30). Yet, such methods are not ideal with respect to getting to the core question of whether expectation-based mechanisms can, in fact, alter performance on cognitive tasks in the context of cognitive intervention studies in the first place. Indeed, there is a growing body of work suggesting that self-reported expectations do not necessarily fully reflect the types of predictions being generated by the brain (e.g., it is possible to produce placebo analgesia effects even in the absence of self-reported expectation of pain relief) (31, 32). Instead, addressing this question would entail purposefully maximizing the differences in expectations between groups (i.e., rather than attempting to minimize differential expectations and then, measuring the possible impact if the differences were not eliminated, as is done in most cognitive training studies).One key question then is how to maximize such expectations. In general, in those domains that have closely examined placebo effects, expectations are typically induced through two broad routes: an explicit route and an associative route. In the explicit route, as given by the name, participants are explicitly told what behavioral changes they should expect (e.g., “this pill will improve your symptoms” or “this cognitive training will improve your cognition”) (33). In the associative learning route, participants are made to experience a behavioral change associated with expected outcomes (e.g., feeling improvements of symptoms or gains in cognition) through some form of deception (34). For example, in an explicit expectation induction study, participants may first have a hot temperature probe applied to their skin, after which they are asked to rate their pain level. An inert cream is then applied that is explicitly described as an analgesic before the hot temperature probe is reapplied. If participants indicate less pain after the cream is applied, this is taken as evidence of an explicit expectation effect. In the associative expectation version, the study progresses identically as above except that when the hot temperature probe is applied the second time, it is at a physically lower temperature than it was initially (participants are not made aware of this fact). This is meant to create an associative pairing between the cream and a reduction in experienced pain (i.e., not only are they told that the cream will reduce their pain, they are provided “evidence” that the cream works as described). If then, after reapplying the cream and applying the hot temperature probe a third time (this time at the same temperature setting as the first application), if participants indicate even less pain than in the explicit condition, this is taken as evidence of an associative expectation effect. It remains to be clarified how associative learning approaches may be best applied to cognitive training; however, we suggest here that a reasonable approach to this would be to provide test sessions where test items are manipulated to provide participants with an experience where they perceive that they are performing better, or worse in the case of a nocebo, than they did at the initial test session. Notably, while there are cases where strong placebo effects have been induced via only explicit (35) or only associative methods (36), in general, the most consistent and robust effects have been induced when a combination of these methods has been utilized (37–39).Within the cognitive training field, the corresponding literature is quite sparse. Few studies have deliberately attempted to create differences in participant expectations, and of those, all have used the explicit expectation route alone, have implemented the manipulation in the context of rather short interventions (e.g., utilizing 20 min of “training” within a single session rather than the multiple hours that are typically implemented in actual training studies), or both. Of these, the results are again at best mixed, with one study suggesting that expectations alone can result in a positive impact on cognitive measures (40), while others have found no such effects (33, 41, 42). Given this critical gap in knowledge, here we examined the impact of manipulations deliberately designed to maximize the presence of differential expectations in the context of a long-term cognitive training study. 相似文献
Attributing individual deaths to extreme heat events (EHE) in Canada and elsewhere is important for understanding the risk factors, protective interventions, and burden of mortality associated with climate change. However, there is currently no single mechanism for identifying individual deaths due to EHE and different agencies have taken different approaches, including (1) vital statistics coding based on medical certificates of death, (2) probabilistic methods, and (3) enhanced surveillance. The 2018 EHE in Montréal provides an excellent case study to compare EHE deaths identified by these different approaches. There were 353 deaths recorded in the vital statistics data over an 8-day period, of which 102 were potentially attributed to the EHE by at least one approach and 251 were not attributed by any approach. Only nine of the 102 deaths were attributed to the EHE by all three approaches, 23 were attributed by two approaches, and 70 were attributed by only one approach. Given that there were approximately 50 excess deaths during the EHE, it remains unclear exactly which of the total 353 deaths should be attributed to the extreme temperatures. These results highlight the need for a more systematic and cooperative approach to EHE mortality in Canada, which will continue to increase as the climate changes. 相似文献
Considerable attention is given to absolute nutrient levels in lakes, rivers, and oceans, but less is paid to their relative concentrations, their nitrogen:phosphorus (N:P) stoichiometry, and the consequences of imbalanced stoichiometry. Here, we report 38 y of nutrient dynamics in Flathead Lake, a large oligotrophic lake in Montana, and its inflows. While nutrient levels were low, the lake had sustained high total N: total P ratios (TN:TP: 60 to 90:1 molar) throughout the observation period. N and P loading to the lake as well as loading N:P ratios varied considerably among years but showed no systematic long-term trend. Surprisingly, TN:TP ratios in river inflows were consistently lower than in the lake, suggesting that forms of P in riverine loading are removed preferentially to N. In-lake processes, such as differential sedimentation of P relative to N or accumulation of fixed N in excess of denitrification, likely also operate to maintain the lake’s high TN:TP ratios. Regardless of causes, the lake’s stoichiometric imbalance is manifested in P limitation of phytoplankton growth during early and midsummer, resulting in high C:P and N:P ratios in suspended particulate matter that propagate P limitation to zooplankton. Finally, the lake’s imbalanced N:P stoichiometry appears to raise the potential for aerobic methane production via metabolism of phosphonate compounds by P-limited microbes. These data highlight the importance of not only absolute N and P levels in aquatic ecosystems, but also their stoichiometric balance, and they call attention to potential management implications of high N:P ratios.The emergence of the Anthropocene era has been marked by major changes in all of Earth’s major biogeochemical cycles (1). For example, fluxes of carbon (C) (as CO2) to the atmosphere have increased by ∼14% during the last 120 y largely due to fossil fuel combustion. Fluxes of nitrogen (N) into the biosphere have increased by at least 100% due to application of the Haber-Bosch reaction for fertilizer production, land use change favoring N-fixing legumes, and conversion of atmospheric N2 to available forms (NOx) by high temperature combustion of petroleum and fossil gas (2). Finally, large-scale mining of phosphorus (P)-rich geological deposits for production of fertilizers has amplified rates of P cycling in the biosphere by ∼400% (1). Each of these perturbations has biophysical and ecological impacts at differing time and space scales. For C, its accumulation in the atmosphere has altered Earth’s radiative balance, warming the planet and perturbing precipitation patterns globally. Amplified inputs of reactive N to the Earth system enter the hydrosphere and, thus, potentially lead to overenrichment of lakes, rivers, and coastal oceans across broad regions. Amplifications of P inputs often impair water quality at watershed and local scales (3), stimulating phytoplankton production and contributing, along with N, to harmful algal blooms, fish kills, and “dead zones” (4, 5). These differential amplifications and their contrasting spatial scales indicate that ecosystems are experiencing not only absolute changes in biogeochemical cycling, but also perturbations in the relative inputs and outputs of biologically important elements (6). Studies of elemental coupling and uncoupling in ecosystems are not yet widespread, but emerging work has shown how C, N, and P are differentially processed as they pass through watersheds (7).The potential for differential alteration in supplies of N and P to aquatic ecosystems suggests that understanding the nutrient status of a water body requires knowledge of not only absolute supplies of limiting nutrients, but also their relative proportions (i.e., their N:P stoichiometry). This work has been facilitated in recent years by the emergence of the theory of ecological stoichiometry (8). For example, seminal work by Redfield (9) found that N:P ratios in marine organic matter were tightly constrained around 16:1 (molar, here and throughout), a value that may represent the central tendency for the N:P ratio of phytoplankton undergoing balanced growth in which major pools of N (protein) and P (RNA) are produced at the same rate (10). In lakes, N:P ratios show much wider variation—around a value of ∼30—perhaps reflecting the biogeochemical connections of lakes to terrestrial systems where N:P ratios have a similar value and range of variation (11). Nevertheless, this classic “Redfield ratio” of 16:1 can be thought of as representing a balanced nutrient supply for primary producers in pelagic ecosystems. When the ratios of N and P supplied deviate from this balanced ratio, primary limitation of growth by N (when N:P is low) or by P (when N:P is high) can occur. For example, phytoplankton growth in lakes with imbalanced total N: total P (TN:TP) ratios that exceed 30:1 is generally P limited (12). Disproportionate inputs of N relative to P from atmospheric deposition can increase lake TN:TP ratios and shift lake phytoplankton from N to P limitation (13), inducing P limitation in zooplankton (14). Imbalanced N:P ratios in nutrient supplies can also shift the competitive advantage among phytoplankton and enhance production of potentially toxic compounds during harmful algal blooms. For example, skewed supplies of N relative to P can increase production of N-rich secondary compounds by phytoplankton, while disproportionate inputs of P relative to N can induce production of C-based toxins (15). High N:P ratios can also enhance proliferation of fungal parasites of phytoplankton (16).Imbalanced N:P ratios can impact aquatic ecosystems in other ways. For example, they can alter the functioning of food webs. In particular, shifts in nutrient supply regimes that enhance P limitation can impede energy flow in trophic interactions because biomass of P-limited primary producers is of low quality for animals due to its low P content (8). Ecosystem shifts to high N:P ratios and more prevalent P limitation can also impact the cycling of the greenhouse-active gas methane (CH4) because phosphate limitation can result in production of methane under aerobic conditions in both marine and freshwater phytoplankton and bacteria (17, 18). Both chemoheterotrophic and photoautotrophic bacteria (e.g., Pseudomonas, SAR11, Trichodesmium, Synechococcus) can metabolize organic P compounds, called phosphonates, to acquire P. Microbial cleavage of one type of phosphonate, methylphosphonic acid (MPn), to acquire P results in formation of methane (17). While it is likely that anaerobic methane production due to oxygen depletion in response to P-driven eutrophication is the dominant process connecting P to methane dynamics, the significance of aerobic phosphonate metabolism to global methane cycles remains to be assessed. However, contributions are potentially large, given the prevalence of P limitation in both freshwater and marine ecosystems. In light of emerging trends that suggest overall increases in ecosystem N:P ratios due to human impacts (6), these trophic and biogeochemical impacts of stoichiometric imbalance show that it is critical to consider not only absolute levels of nutrients, but also their stoichiometry. In particular, high N:P ratios can accentuate P limitation, causing a suite of ecological impacts that, currently, are poorly described.In this paper, we illustrate the utility of stoichiometric approaches by combining analyses of long-term records of nutrient supply and dynamics, together with contemporary experiments, to examine how imbalances in N:P stoichiometry (e.g., strong divergence from classic Redfield proportions) influence plankton ecology and biogeochemistry across multiple scales in Flathead Lake, a large lake in western Montana. The lake is itself relatively unperturbed by human impacts and, thus, maintains low overall nutrient levels. However, the strong stoichiometric imbalance that we describe makes Flathead Lake appropriate for assessing ecosystem consequences of what appear to be general trends of increasing N:P ratios in global ecosystems (6). Numerous limnological properties of the lake and its inflow rivers have been monitored continuously for several decades, including concentrations of various forms of N and P. Thus, these time-series data allow us not only to assess long-term variability or stability in the stoichiometry of N and P in the lake and its river inflows over decadal time scales, but also to connect its stoichiometry with potential consequences for nutrient limitation, food web dynamics, and biogeochemical cycling under low-nutrient conditions. 相似文献
Rezafungin is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections. The objectives of this randomized, double‐blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics of rezafungin after subcutaneous (s.c.) administration. The study design consisted of six sequential cohorts of eight subjects, except for the first cohort with four subjects. The subjects were randomized in a 3:1 ratio of rezafungin to placebo and were to receive a single dose of 1, 10, 30, 60, 100, or 200 mg. The most common adverse events (AEs) were increased alanine aminotransferase and sinus bradycardia (unsolicited) and erythema at the injection site (solicited). Unsolicited AEs were generally mild to moderate and not rezafungin‐related. Although the study was terminated after the 10 mg dose cohort due to concerns of potential increased severity of injection site reactions, no predetermined dose escalation halting criteria were met. Following the 10 mg single s.c. dose of rezafungin (n = 6), the geometric mean (GM) maximum concentration (Cmax) was 105.0 ng/ml and the median time to Cmax was 144 h. The GM area under the concentration‐time curve was 32,770 ng*h/ml. The median estimated terminal half‐life was 193 h. The GM apparent oral clearance was 0.255 L/h and the GM apparent volume of distribution was 68.5 L. This study demonstrates that a single s.c. dose of rezafungin in healthy adult subjects: (1) did not result in serious AEs, death, or withdrawal from the study due to an AE; and (2) produced a pharmacokinetic profile with long exposure period postadministration. In an effort to reduce the occurrence of injection site reactions, a re‐evaluation of the rezafungin s.c. formulation could be considered in the future. Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Currently marketed antifungal agents of the echinocandin class are dosed by i.v. once daily and are therefore not practical for prolonged or outpatient prophylaxis. Rezafungin is an investigational echinocandin (currently in phase III trials studying once‐weekly i.v. administration) that has excellent activity against clinically relevant Candida and Aspergillus spp. and Pneumocystis jirovecii, a prolonged half‐life allowing for longer dosing intervals, and a stability/solubility profile that allows for the possibility of subcutaneous (s.c.) dosing.
WHAT QUESTION DID THE STUDY ADDRESS?
The objectives of this randomized, double‐blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics (PKs) of rezafungin after s.c. administration.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
This study provided safety data regarding s.c. administration of rezafungin. Despite common solicited injection site reactions, s.c. administration of 10 mg of rezafungin did not result in serious adverse event (AEs), death, or withdrawals due to an AE in healthy adult subjects. The study also showed that rezafungin had a PK profile with a long exposure period.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
In an effort to reduce the occurrence of injection site reactions, these findings may lead to a future re‐evaluation of the s.c. formulation of rezafungin. 相似文献
We have developed a specialized microfluidic electrochemical cell that enables in situ investigation of the electrochemical corrosion of microgram quantities of redox active solids. The advantage of downscaling is the reduction of hazards, waste, expense, and greatly expanding data collection for hazardous materials, including radioactive samples. Cyclic voltammetry was used to monitor the oxidation–reduction cycle of minute quantities of micron-size uraninite (UO2) particles, from the formation of hexavalent uranium (U(vi)), U3O7 and reduction to UO2+x. Reaction progress was also studied in situ with scanning electron microscopy. The electrochemical measurements matched those obtained at the bulk-scale and were consistent with ex situ characterization of the run products by X-ray photoelectron spectroscopy, scanning transmission electron microscopy, and atomic force microscopy; thus, demonstrating the utility of the microfluidic approach for studying radioactive materials.Highlight of the multimodal characterization of corrosion behaviour of microgram quantities of UO2, enabled by a novel particle-attached microfluidic electrochemical cell.相似文献