Transgender People's Experiences Sharing Information With Clinicians: A Focus Group-Based Qualitative Study.

PURPOSE: Investigating transgender people's experiences sharing health information in clinical encounters may yield insights for family medicine clinicians. METHODS: This was a qualitative study using a community-based participatory research approach and interpretive description methodology. Seven qualitative focus groups were conducted with 30 transgender adults living in North America. We used purposive sampling to ensure diversity. The focus groups were transcribed verbatim, and 2 investigators independently reviewed and coded each transcript, then they mutually reviewed the transcripts, reconciled their coding, and summarized the codes into themes. Themes were reviewed with community members, participants, and uninvolved clinically oriented investigators for member checking and peer debriefing. RESULTS: Four themes were noted: (1) transgender people often perceive clinicians' questions as voyeuristic, stigmatizing, or self-protective; (2) patients describe being pathologized, denied or given substandard care, or harmed when clinicians learned they are transgender; (3) transgender people frequently choose between risking stigma when sharing information and risking ineffective clinical problem solving if clinicians do not have all the information about their medical histories; (4) improving the safety of transgender people is difficult in the context of contemporary medical systems. CONCLUSIONS: Transgender people often must choose between stigma and potentially suboptimal care. Improvements in medical culture, policies, procedures, and data collection tools are necessary to improve the quality and safety of clinical care for transgender people. Institutional and systems changes may be required to safely and effectively implement sexual orientation and gender identity (SOGI) data collection in clinical settings.

FruitFire: a luciferase based on a fruit fly metabolic enzyme.

Firefly luciferase is homologous to fatty acyl-CoA synthetases from insects that are not bioluminescent. Here, we determined the crystal structure of the fruit fly fatty acyl-CoA synthetase CG6178 to 2.5 Å. Based on this structure, we mutated a steric protrusion in the active site to create the artificial luciferase FruitFire, which prefers the synthetic luciferin CycLuc2 to d-luciferin by >1000-fold. FruitFire enabled in vivo bioluminescence imaging in the brains of mice using the pro-luciferin CycLuc2-amide. The conversion of a fruit fly enzyme into a luciferase capable of in vivo imaging underscores the potential for bioluminescence with a range of adenylating enzymes from nonluminescent organisms, and the possibilities for application-focused design of enzyme-substrate pairs.

Experiences of Transgender People Reviewing Their Electronic Health Records, a Qualitative Study.

BACKGROUND: The 21st Century Cures Act and the OpenNotes movement have brought patients immediate access to their electronic health records (EHRs). The experiences of marginalized people, including transgender people, accessing and reviewing their EHRs could inform documentation guidelines to improve patient-clinician rapport and reduce harm. OBJECTIVE: To investigate the experiences of transgender people reviewing EHRs. DESIGN: Qualitative study using community-engaged research and an interpretive description methodology. Participants were recruited via social media, snowball sampling was employed, and purposive sampling was used to ensure diversity in terms of age, race/ethnicity, and other factors. In focus groups, participants were asked to discuss their experiences reviewing their EHRs and, for those participants who were clinicians, their experiences reviewing other clinicians' documentation. PARTICIPANTS: Thirty transgender adults aged 20 to 67 years, including 10 clinicians. APPROACH: Digital audio-recordings of focus groups were transcribed verbatim. Content was analyzed to identify emerging essential elements and analysis was continued until no new themes emerged (i.e., saturation). KEY RESULTS: Four themes were noted. (1) Using the wrong name, pronoun, or gender marker for patients is common in the EHR, erodes trust, and causes trauma. (2) Various aspects of clinicians' notes contradict, blame, or stigmatize patients, across multiple axes of oppression. (3) Limitations of EHR capabilities create barriers to quality care. (4) Certain medical customs set the stage for marginalizing, objectifying, and pathologizing transgender people. CONCLUSIONS: Transgender people experience harm via various aspects of EHR documentation, suggesting that changes must be made to improve patient-clinician relationships and reduce ill-effects for patients.

Gender- and Sexual Orientation- Based Inequities: Promoting Inclusion, Visibility, and Data Accuracy in Oncology.

Sexual and gender minority (SGM) people, including agender, asexual, bisexual, gay, gender diverse, genderqueer, genderfluid, intersex, lesbian, nonbinary, pansexual, queer, and transgender people, comprise approximately 10% or more of the U.S. population. Thus, most oncologists see SGM patients whether they know it or not. SGM people experience stigma and structural discrimination that lead to cancer disparities. Because of the lack of systematic and comprehensive data collection, data regarding SGM cancer incidence, outcomes, and treatment responses are limited. Collection of data regarding sexual orientation, gender identity, transgender identity and/or experience, anatomy, and serum hormone concentrations in oncology settings would drastically increase collective knowledge about the impact of stigma and biologic markers on cancer outcomes. Increasing the safety of oncology settings for SGM people will require individual, institutional, and systems changes that will likely improve oncologic care for all patients.

Characteristics Associated With Nonreceipt of Surveillance Testing and the Relationship With Survival in Stage II and III Colon Cancer.

We investigated characteristics of patients with colon cancer that predicted nonreceipt of posttreatment surveillance testing and the subsequent associations between surveillance status and survival outcomes. This was a retrospective cohort study of the Surveillance, Epidemiology, and End Results database combined with Medicare claims. Patients diagnosed between 2002 and 2009 with disease stages II and III and who were between 66 and 84 years of age were eligible. A minimum of 3 years' follow-up was required, and patients were categorized as having received any surveillance testing (any testing) versus none (no testing). Poisson regression was used to obtain risk ratios with 95% confidence intervals for the relative likelihood of No Testing. Cox models were used to obtain subdistribution hazard ratios with 95% confidence intervals for 5- and 10-year cancer-specific and noncancer deaths. There were 16,009 colon cancer cases analyzed. Patient characteristics that predicted No Testing included older age, Black race, stage III disease, and chemotherapy. Patients in the No Testing group had an increased rate of 10-year cancer death that was greater for patients with stage III disease (subdistribution hazard ratio = 1.79, 95% confidence interval: 1.48, 2.17) than those with stage II disease (subdistribution hazard ratio = 1.41, 95% confidence interval: 1.19, 1.66). Greater efforts are needed to ensure all patients receive the highest quality medical care after diagnosis of colon cancer.

Bioluminescence imaging in mice with synthetic luciferin analogues.

Luciferase enzymes from bioluminescent organisms can be expressed in mice, enabling these rodents to glow when treated with a corresponding luciferin substrate. Light emission occurs where the expression of the genetically-encoded luciferase overlaps with the biodistribution of the administered small molecule luciferin. Here we discuss differences between firefly luciferin analogues for bioluminescence imaging, focusing on transgenic and adeno-associated virus (AAV)-transduced mice.

Enzymatic promiscuity and the evolution of bioluminescence.

Bioluminescence occurs when an enzyme, known as a luciferase, oxidizes a small-molecule substrate, known as a luciferin. Nature has evolved multiple distinct luciferases and luciferins independently, all of which accomplish the impressive feat of light emission. One of the best-known examples of bioluminescence is exhibited by fireflies, a class of beetles that use d-luciferin as their substrate. The evolution of bioluminescence in beetles is thought to have emerged from ancestral fatty acyl-CoA synthetase (ACS) enzymes present in all insects. This theory is supported by multiple lines of evidence: Beetle luciferases share high sequence identity with these enzymes, often retain ACS activity, and some ACS enzymes from nonluminous insects can catalyze bioluminescence from synthetic d-luciferin analogues. Recent sequencing of firefly genomes and transcriptomes further illuminates how the duplication of ACS enzymes and subsequent diversification drove the evolution of bioluminescence. These genetic analyses have also uncovered candidate enzymes that may participate in luciferin metabolism. With the publication of the genomes and transcriptomes of fireflies and related insects, we are now better positioned to dissect and learn from the evolution of bioluminescence in beetles.

Multisensory Integration Is Modulated by Auditory Sound Frequency and Visual Spatial Frequency.

Accurate integration of auditory and visual information is essential for our ability to communicate with others. Previous studies have shown that the temporal discrepancies over which audiovisual speech stimuli will be integrated into a coherent percept are much wider than those typically observed for simple stimuli like beeps and flashes of light. However, our sensitivity to the low-level features of simple stimuli is not constant. We hypothesized that part of the enhanced integration of audiovisual speech may be due to it consisting predominantly of the sound frequencies and visual spatial frequencies that humans are most sensitive to. Here, we examined integration behaviors for pure tones across the sound frequency spectrum and visual gratings across the spatial frequency spectrum to examine how these low-level features modulate integration. The temporal window of integration was modulated by both sound frequency and visual spatial frequency, with the widest integration window occurring when both stimuli fell within their respective peak sensitivity ranges. These results suggest that part of the increased tolerance for temporal asynchrony typically observed for audiovisual speech may be due to the differential integration of low-level stimulus features that are dominant within complex audiovisual speech.

Sulfonamides Are an Overlooked Class of Electron Donors in Luminogenic Luciferins and Fluorescent Dyes.

Many fluorophores, and all bright light-emitting substrates for firefly luciferase, contain hydroxyl or amine electron donors. Sulfonamides were found to be capable of serving as replacements for these canonical groups. Unlike "caged" carboxamides, sulfonamide donors enable bioluminescence, and sulfonamidyl luciferins, coumarins, rhodols, and rhodamines are fluorescent in water.

Lessons Learned from Luminous Luciferins and Latent Luciferases.

Compared to the broad palette of fluorescent molecules, there are relatively few structures that are competent to support bioluminescence. Here, we focus on recent advances in the development of luminogenic substrates for firefly luciferase. The scope of this light-emitting chemistry has been found to extend well beyond the natural substrate and to include enzymes incapable of luciferase activity with d-luciferin. The broadening range of luciferin analogues and evolving insight into the bioluminescent reaction offer new opportunities for the construction of powerful optical reporters of use in live cells and animals.

Rapid Access to a Broad Range of 6'-Substituted Firefly Luciferin Analogues Reveals Surprising Emitters and Inhibitors.

Light-emitting firefly luciferin analogues contain electron-donating groups in the 6'-position, but the scope of known 6'-substitution remains narrow. A two-step route to a broad range of 6'-substituted luciferin analogues was developed to fill this void and enable more extensive study of the 6'-functionality. This chemistry allowed direct access to "caged" amide and bright azetidine analogues, but also revealed thioether inhibitors and unexpectedly luminogenic aryl amine derivatives.

Firefly Luciferase Mutants Allow Substrate-Selective Bioluminescence Imaging in the Mouse Brain.

Bioluminescence imaging is a powerful approach for visualizing specific events occurring inside live mice. Animals can be made to glow in response to the expression of a gene, the activity of an enzyme, or the growth of a tumor. But bioluminescence requires the interaction of a luciferase enzyme with a small-molecule luciferin, and its scope has been limited by the mere handful of natural combinations. Herein, we show that mutants of firefly luciferase can discriminate between natural and synthetic substrates in the brains of live mice. When using adeno-associated viral (AAV) vectors to express luciferases in the brain, we found that mutant luciferases that are inactive or weakly active with d-luciferin can light up brightly when treated with the aminoluciferins CycLuc1 and CycLuc2 or their respective FAAH-sensitive luciferin amides. Further development of selective luciferases promises to expand the power of bioluminescence and allow multiple events to be imaged in the same live animal.

Ultraviolet Radiation Exposure and the Incidence of Oral, Pharyngeal and Cervical Cancer and Melanoma: An Analysis of the SEER Data.

BACKGROUND: Based on the hypothesis that ultraviolet radiation (UVR) exposure can cause DNA damage that may activate dormant viruses such as human papilloma virus, a recent ecological study, which estimated state-level UVR exposure, reported positive correlations between annual UVR exposure and the incidence of oral, pharyngeal, and cervical cancer in 16 U.S. states using the International Agency for Research on Cancer (IARC) data. The purpose of the current study was to further investigate whether the annual UVR level, estimated on a county level, is associated with incidence rates of such cancers using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 data. If UVR exposure is associated with incidence of these cancer types, we would expect to see a similar or stronger association with melanoma because UVR exposure is a well-demonstrated risk factor for this disease. Thus, we also included melanoma in the study. MATERIALS AND METHODS: The study subjects were White and Black individuals with oral, pharyngeal, cervical cancer or melanoma diagnosed between 1973 and 2011 from the SEER 18 data. UVR was estimated at the county level and grouped into high-, medium- and low-exposure levels. Age-adjusted incidence rates of cancer were calculated and compared among the UVR exposure groups. The comparisons were also stratified by sex and race. RESULTS: There was an inverse association between UVR exposure and incidence of oral, pharyngeal, and cervical cancer. The inverse association was also observed for melanoma. When stratified by race and sex, the inverse associations remained except for melanoma among Blacks. CONCLUSION: In contrast to a previous study, our study found that there were inverse associations between UVR exposure and the incidence of oral, pharyngeal, and cervical cancer, as well as of melanoma. Our findings are in agreement with several other published studies reporting no positive correlation between UVR exposure and the incidence rates of oral, pharyngeal, and cervical cancer and melanoma.

Luciferin Amides Enable in Vivo Bioluminescence Detection of Endogenous Fatty Acid Amide Hydrolase Activity.

Firefly luciferase is homologous to fatty acyl-CoA synthetases. We hypothesized that the firefly luciferase substrate d-luciferin and its analogs are fatty acid mimics that are ideally suited to probe the chemistry of enzymes that release fatty acid products. Here, we synthesized luciferin amides and found that these molecules are hydrolyzed to substrates for firefly luciferase by the enzyme fatty acid amide hydrolase (FAAH). In the presence of luciferase, these molecules enable highly sensitive and selective bioluminescent detection of FAAH activity in vitro, in live cells, and in vivo. The potency and tissue distribution of FAAH inhibitors can be imaged in live mice, and luciferin amides serve as exemplary reagents for greatly improved bioluminescence imaging in FAAH-expressing tissues such as the brain.

Beyond D-luciferin: expanding the scope of bioluminescence imaging in vivo.

The light-emitting chemical reaction catalyzed by the enzyme firefly luciferase is widely used for noninvasive imaging in live mice. However, photon emission from the luciferase is crucially dependent on the chemical properties of its substrate, D-luciferin. In this review, we describe recent work to replace the natural luciferase substrate with synthetic analogs that extend the scope of bioluminescence imaging.

A synthetic luciferin improves bioluminescence imaging in live mice.

Firefly luciferase is the most widely used optical reporter for noninvasive bioluminescence imaging (BLI) in rodents. BLI relies on the ability of the injected luciferase substrate D-luciferin to access luciferase-expressing cells and tissues within the animal. Here we show that injection of mice with a synthetic luciferin, CycLuc1, improves BLI with existing luciferase reporters and enables imaging in the brain that could not be achieved with D-luciferin.

Escherichia coli antimicrobial resistance increased faster among geriatric outpatients compared with adult outpatients in the USA, 2000-10.

OBJECTIVES: Few studies have examined Escherichia coli antimicrobial resistance across age groups over time. The objective of this study was to compare urinary E. coli antimicrobial resistance trends among adult and geriatric outpatients from 2000 to 2010. METHODS: Antimicrobial susceptibility results for E. coli urine isolates from adult (aged 16-64 years) and geriatric (aged ≥65 years) outpatients were analysed using data from The Surveillance Network Database-USA. RESULTS: Susceptibility test results from adult (n = 6 412 025) and geriatric (n = 3 395 297) outpatients showed that E. coli antimicrobial resistance increased faster among geriatric outpatients for all agents studied. The greatest increases in resistance over the study time period were for ciprofloxacin (9.4% and 23.5% increases among adult and geriatric individuals, respectively), trimethoprim/sulfamethoxazole (4.3% and 10.5%) and ampicillin (2.0% and 13.6%). CONCLUSIONS: Urinary E. coli antimicrobial resistance increased faster among geriatric outpatients than adult outpatients in the USA. Rising antimicrobial resistance disproportionately affects geriatric populations and presents a threat to public health.