Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition.

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.

Stopping denosumab, a medication commonly used to improve bone mass by blocking formation of bone resorbing osteoclasts, leads to a rebound loss in the bone which was gained during treatment. Current strategies to prevent this bone loss fail in most cases as they are unable to prevent the rise and overshoot in bone resorption by osteoclasts. Thie stems from an incomplete understanding of how osteoclasts behave during denosumab treatment and after treatment is discontinued. We use a mouse model of this phenomenon to show how osteoclast formation and activity changes throughout this process. We show that increases in the processes that drive the formation of osteoclasts can be detected in the circulation before bone loss occurs. These findings could therefore provide insight into a targeted 'window of opportunity' to intervene and prevent the rebound bone loss following stopping denosumab in patients.

Fatty acid transport protein inhibition sensitizes breast and ovarian cancers to oncolytic virus therapy via lipid modulation of the tumor microenvironment.

Introduction: Adipocytes in the tumour microenvironment are highly dynamic cells that have an established role in tumour progression, but their impact on anti-cancer therapy resistance is becoming increasingly difficult to overlook. Methods: We investigated the role of adipose tissue and adipocytes in response to oncolytic virus (OV) therapy in adipose-rich tumours such as breast and ovarian neoplasms. Results: We show that secreted products in adipocyte-conditioned medium significantly impairs productive virus infection and OV-driven cell death. This effect was not due to the direct neutralization of virions or inhibition of OV entry into host cells. Instead, further investigation of adipocyte secreted factors demonstrated that adipocyte-mediated OV resistance is primarily a lipid-driven phenomenon. When lipid moieties are depleted from the adipocyte-conditioned medium, cancer cells are re-sensitized to OV-mediated destruction. We further demonstrated that blocking fatty acid uptake by cancer cells, in a combinatorial strategy with virotherapy, has clinical translational potential to overcome adipocyte-mediated OV resistance. Discussion: Our findings indicate that while adipocyte secreted factors can impede OV infection, the impairment of OV treatment efficacy can be overcome by modulating lipid flux in the tumour milieu.

Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma.

An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-low-density lipoprotein receptor-related protein 6 (LRP6) antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. Micro-computed tomography (µCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti-LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti-LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Effectiveness and feasibility of three types of parent reminders to increase adolescent human papillomavirus (HPV) vaccination.

Parent reminders have produced modest improvements in human papillomavirus (HPV) vaccination among adolescents. However, little prior research has compared the effectiveness and feasibility of different HPV reminder types in resource-limited settings. We conducted a quasi-experimental study (2016-2017) to evaluate the effectiveness of three parent reminder types (mailed letters, robocalls, text messages) on next-dose HPV vaccine receipt among 12-year-olds in a large Federally Qualified Health Center in Los Angeles County. Six clinics were matched into three pairs: randomly assigning one clinic within each pair to intervention and control. Intervention clinics were randomly assigned to deliver one of the three parent reminder types. We calculated rates of next-dose vaccine receipt and assessed intervention effects using logistic regression models. We calculated the proportion of each type of reminder successfully delivered as a feasibility measure. The study sample comprised 877 12-year-olds due for an HPV vaccine dose (47% female, >85% Latino). At 4-month follow-up, 23% of intervention patients received an HPV vaccine dose compared to only 12% of control patients. Overall, receipt of any reminder increased rates of the next-needed HPV vaccine compared to usual care (p = 0.046). Significant improvements were observed for text reminders (p = 0.036) and boys (p = 0.006). Robocalls were the least feasible reminder type. Text message reminders are feasible and effective for promoting HPV vaccination. Future research is needed to assess the effectiveness and feasibility of reminders compared to other vaccine promotion strategies.

Direct Observation of Ultrafast Lattice Distortions during Exciton-Polaron Formation in Lead Halide Perovskite Nanocrystals.

The microscopic origin of slow hot-carrier cooling in lead halide perovskites remains debated and has direct implications for applications. Slow hot-carrier cooling of several picoseconds has been attributed to either polaron formation or a hot-phonon bottleneck effect at high excited carrier densities (>1018 cm-3). These effects cannot be unambiguously disentangled with optical experiments alone. However, they can be distinguished by direct observations of ultrafast lattice dynamics, as these effects are expected to create qualitatively distinct fingerprints. To this end, we employ femtosecond electron diffraction and directly measure the sub-picosecond lattice dynamics of weakly confined CsPbBr3 nanocrystals following above-gap photoexcitation. While we do not observe signatures of a hot-phonon bottleneck lasting several picoseconds, the data reveal a light-induced structural distortion appearing on a time scale varying between 380 and 1200 fs depending on the excitation fluence. We attribute these dynamics to the effect of exciton-polarons on the lattice and the slower dynamics at high fluences to slower sub-picosecond hot-carrier cooling, which slows down the establishment of the exciton-polaron population. Further analysis and simulations show that the distortion is consistent with motions of the [PbBr3]- octahedral ionic cage, and closest agreement with the data is obtained for Pb-Br bond lengthening. Our work demonstrates how direct studies of lattice dynamics on the sub-picosecond time scale can discriminate between competing scenarios proposed in the literature to explain the origin of slow hot-carrier cooling in lead halide perovskites.

Effect of stimulant medication on loss of control eating in youth with attention deficit/hyperactivity disorder: a prospective, observational case series study protocol.

BACKGROUND: Loss of control eating (LOC-E) in youth predicts the later development of full-syndrome binge-eating disorder (BED), and therefore, could be a relevant target for prevention treatments. To develop these treatments, it is important to understand the underlying disease processes and mechanisms. Based on the putative role of neurocognitive impairments in the pathogenesis of LOC-E, treatments that modulate these neurocognitive factors warrant further exploration. For instance, stimulants are an effective treatment for impulsivity in youth with attention deficit/hyperactivity disorder (ADHD) and have been shown to improve symptoms of BED in adults. Notably, stimulants have not been examined as a treatment for LOC-E in youth. To explore this gap, we aim to measure change in LOC-E episodes and secondary outcomes in youth with comorbid ADHD and LOC-E who are being started on stimulants. METHODS: We will collect prospective observational data on forty 8-to-13-year-old youth diagnosed with comorbid ADHD and LOC-E who are initiating a stimulant for ADHD. Prior to stimulant initiation, participants will complete baseline measures including LOC-E episode frequency in the last 3 months (primary outcome), and secondary outcomes including disordered eating cognitions, emotions and behaviors, ADHD symptom severity, parental LOC-E, impulsivity and reward sensitivity, and anxiety/mood severity. Outcome measurements will be gathered again at 3-months after initiating the stimulant. Within-patient standardized effect sizes with 95% confidence intervals will be calculated from baseline to 3-month follow-up for all outcomes. DISCUSSION: Many individuals with LOC-E or binge eating do not fully remit over the course of psychotherapy. Whereas psychotherapy may address psychological and sociocultural domains associated with LOC-E, some individuals with neurocognitive impairments (e.g., ADHD) and neurobiological deficits (e.g., low intrasynaptic dopamine or norepinephrine) may benefit from adjunctive treatment that targets those factors. This will be the first study to provide pilot data for future studies that could examine both the effect of stimulants on LOC-E in youth and underlying mechanisms. TRIAL REGISTRATION: Trial registration number: NCT05592119.

Impact of a Multi-Level, Multi-Component, System Intervention on HPV Vaccination in a Federally Qualified Health Center.

BACKGROUND: Human papillomavirus (HPV) vaccines can significantly reduce the burden of HPV-associated cancers, but remain underutilized. We evaluated a multi-component, system-level intervention to improve HPV vaccination in a large Federally Qualified Health Center (FQHC) that serves a primarily low income Latino population. METHODS: From January 2015 through March 2017, we evaluated the effectiveness of a multi-component, system-level intervention to improve HPV vaccination rates in eight clinics randomly assigned to study condition (four intervention, four usual care). The intervention included parent reminders for HPV vaccine series completion, provider training, clinic-level audit and feedback, and workflow modifications to reduce missed opportunities for vaccination. Using a difference-in-differences approach, we compared HPV vaccination rates among patients, ages 11 to 17 during a 12-month preintervention period and a 15-month intervention period. Linear mixed models were used to estimate intervention effects on vaccine initiation and completion. RESULTS: The sample included approximately 15,000 adolescents each quarter (range 14,773-15,571; mean age 14 years; 51% female, 88% Latino). A significantly greater quarterly increase in HPV vaccine initiation was observed for intervention compared with usual care clinics (0.75 percentage point greater increase, P < 0.001), corresponding to 114 additional adolescents vaccinated per quarter. The intervention led to a greater increase in HPV vaccine completion rates among boys (0.65 percentage point greater increase, P < 0.001), but not girls. CONCLUSIONS: Our system-level intervention was associated with modest improvements in HPV vaccine initiation overall and completion among boys. IMPACT: Study findings have implications for reducing HPV-related cancers in safety net populations.

The Impact of a Comic Book Intervention on East African-American Adolescents' HPV Vaccine-Related Knowledge, Beliefs and Intentions.

HPV vaccine uptake is low among East African-American (EAA) adolescents. We developed a comic book and evaluated the impact on HPV/HPV-vaccine knowledge, beliefs and vaccine intentions. The intervention was delivered to HPV-unvaccinated EAA adolescents attending educational dinners with their mothers. Adolescents aged 14-17 were sequentially assigned alternately to a pre- or post-test. Results were compared with chi-squared tests and generalized estimating equation models adjusted for age, gender, and mother's language. Among 136 (pre-test = 64, post-test = 72) participants (90% Somali), pre/post differences were observed for proportions of correct responses to questions on HPV (44.0% vs. 82.9%, RR:1.87[95%CI 1.54-2.27]), HPV-vaccine knowledge (42.8% vs. 75.4%, RR:1.74[95%CI 1.46-2.07]), comfort discussing HPV/HPV vaccine with parents (57.8% vs. 90.3% somewhat/very comfortable, RR:1.55[95%CI 1.24-1.94]), and willingness (37.5% vs. 83.3% probably/definitely willing, RR:2.16[95%CI 1.55-3.01]) and intention (34.4% vs. 86.1% somewhat/very likely, RR:2.38[95%CI:1.69-3.37]) to get vaccinated. The intervention improved participants' HPV/HPV-vaccine knowledge, beliefs and vaccine intentions. Similar interventions could be adapted for other racial/ethnic minorities.

Effect of a media intervention on hepatitis B screening among Vietnamese Americans.

Objective: There is a lack of controlled studies of community-wide interventions to increase screening for hepatitis B (HBV) among Asian Americans, particularly Vietnamese Americans, who disproportionately suffer from HBV-related illnesses. The objective of our study was to develop, implement, and evaluate the effectiveness of a media campaign to promote HBV screening among Vietnamese Americans.Design: We designed and implemented a three-year media campaign promoting HBV screening among Vietnamese Americans. Evaluation consisted of cross-sectional pre- and post-intervention population-based telephone surveys of Vietnamese Americans adults age 18-64 who spoke English or Vietnamese and lived in the Northern California (intervention) or Greater Washington, D.C. (comparison) communities in 2007 or 2011. Statistical analysis was completed in 2012. The main outcome was self-report of HBV testing, defined as participants answering 'Yes' to the question: 'Have you ever had a blood test to check for hepatitis B?'Results: The sample sizes at pre- and post-intervention were 1,704 and 1,666, respectively. Both communities reported increased exposure to HBV-related booklets, radio and television advertisements, and websites. Only the intervention community reported increased exposure to newspaper elements. HBV screening increased in both communities (intervention: 65.3% to 73.1%, p < 0.01, comparison: 57.7% to 66.0%, p < 0.01). In multivariable analyses, there was no intervention effect. In both communities, exposure to media elements (Odds Ratio 1.26 [95% Confidence Interval: 1.21, 1.31] for each additional element) was significantly associated with screening.Conclusions: Among Vietnamese Americans in 2 large communities, HBV screening rates were sub-optimal. Screening increased in both the intensive media intervention and comparison communities, and exposure to HBV-related media messages was associated with increased screening. Efforts to address HBV screening among Vietnamese Americans should include mass media messaging.

Increasing HPV Vaccination among Low-Income, Ethnic Minority Adolescents: Effects of a Multicomponent System Intervention through a County Health Department Hotline.

BACKGROUND: Introduction of the human papillomavirus (HPV) vaccine in 2006 was a game-changing advance in cancer control. Despite the vaccine's potential cancer prevention benefits, uptake remains low. We utilized a randomized design to evaluate a multicomponent intervention to improve HPV vaccine uptake among low-income, ethnic minority adolescents seeking services through a county health department telephone hotline. METHODS: Hotline callers who were caregivers of never-vaccinated adolescents (11-17 years) were randomized by call-week to intervention or control conditions. The intervention included brief telephone and print education, delivered in multiple languages, and personalized referral to a low-cost/free vaccine provider. Participants completed baseline (n = 238), 3-month (n = 215), and 9-month (n = 204) telephone follow-up surveys. RESULTS: HPV vaccine initiation rates increased substantially by 9-month follow-up overall, although no differences were observed between intervention and control groups (45% vs. 42%, respectively, P > 0.05). We also observed significant improvements in perceived HPV risk, barriers to vaccination, and perceived knowledge in both study conditions (P < 0.05). CONCLUSIONS: A low-intensity county hotline intervention did not produce a greater increase in HPV vaccination rates than routine practice. However, 44% of unvaccinated adolescents in both conditions received at least one dose of the vaccine, which can be viewed as a successful public health outcome. Future studies should evaluate more intensive interventions that address accessing and utilizing services in complex safety net settings. IMPACT: Study results suggest the need for investigators to be aware of the potential priming effects of study participation, which may obscure the effect of low-intensity interventions.

Functional and Oncologic Outcomes of Octogenarians Undergoing Transoral Laser Microsurgery for Laryngeal Cancer.

OBJECTIVE: To evaluate the oncologic and functional outcomes of transoral laser microsurgery (TLM) for glottic cancers in patients ≥80 years. STUDY DESIGN: Prospectively collected case series. SETTING: QEII Health Sciences Centre, Halifax, Canada. METHODS: This case series used a prospectively collected glottic cancer database to examine consecutive elderly patients (≥80 years old) undergoing TLM. Kaplan-Meier analysis was used to evaluate rates of disease-free, disease-specific, and overall survival as the primary end points of oncologic control. Secondary functional outcomes included voice function, length of hospital stay, and time to readmission. RESULTS: From 2005 to 2017, 17 octogenarian patients underwent TLM for glottic cancer. Median follow-up was 4.19 years (interquartile range, 0.71-6.95). Kaplan-Meier estimates of 5-year survival were 78.4% (disease free), 92.9% (disease specific), and 81.9% (overall). The median length of hospital stay was 1 day (range, 0-8). There was only 1 readmission within 30 days of surgery. No patients in this study developed significant surgical or postoperative complications requiring unplanned readmissions. Patient-perceived voice function improved to normal after treatment in 62.5% of patients. CONCLUSION: The results of this study suggest that TLM is a safe and effective treatment modality for glottic cancer in patients aged ≥80 years, providing good oncologic control and satisfactory functional outcomes.

Development of a theory-based HPV vaccine promotion comic book for East African adolescents in the US.

BACKGROUND: Human Papillomavirus (HPV) vaccine uptake is low among East African adolescents in the US. Adolescents' preferences influence HPV vaccine decisions, yet few interventions exist that address East African adolescents' beliefs about HPV vaccines. We describe a multi-step process on how to create a theory-based comic book by integrating empirical findings, theory and focus group data from East African parents in the US. METHODS: Our multi-methods process included conducting focus groups with Somali, Ethiopian, and Eritrean mothers (n = 30) to understand mothers and adolescents socio-cultural beliefs and information needs about the HPV vaccine, creating comic book messages integrating the focus group findings, and assessing the acceptability of the finalized comic book among Somali, Ethiopian, and Eritrean adolescents (n = 134). RESULTS: We identified categories around socio-cultural beliefs (such ethnic representation and concerns about pork gelatin in vaccines), HPV vaccine information needs, and diffusion of information. We then mapped the categories to theoretical constructs and operationalized them into the comic book. Finally, we describe the overall acceptability of the comic book and specifics on comic book structure, appeal of characters, and message relevance. CONCLUSIONS: A rigorous multi-step process that integrates theory and focus group data can help create culturally appropriate health messages that can educate and appeal to the community.

Psychosocial Distress in Adult Patients Awaiting Cancer Surgery during the COVID-19 Pandemic.

Cancer causes substantial emotional and psychosocial distress, which may be exacerbated by delays in treatment. The COVID-19 pandemic has resulted in increased wait times for many patients with cancer. In this study, the psychosocial distress associated with waiting for cancer surgery during the pandemic was investigated. This cross-sectional, convergent mixed-methods study included patients with lower priority disease during the first wave of COVID-19 at an academic, tertiary care hospital in eastern Canada. Participants underwent semi-structured interviews and completed two questionnaires: Hospital Anxiety and Depression Scale (HADS) and Perceived Stress Scale (PSS). Qualitative analysis was completed through a thematic analysis approach, with integration achieved through triangulation. Fourteen participants were recruited, with cancer sites including thyroid, kidney, breast, prostate, and a gynecological disorder. Increased anxiety symptoms were found in 36% of patients and depressive symptoms in 14%. Similarly, 64% of patients experienced moderate or high stress. Six key themes were identified, including uncertainty, life changes, coping strategies, communication, experience, and health services. Participants discussed substantial distress associated with lifestyle changes and uncertain treatment timelines. Participants identified quality communication with their healthcare team and individualized coping strategies as being partially protective against such symptoms. Delays in surgery for patients with cancer during the COVID-19 pandemic resulted in extensive psychosocial distress. Patients may be able to mitigate these symptoms partially through various coping mechanisms and improved communication with their healthcare teams.

The impact of an educational forum intervention on East African mothers' HPV vaccine-related knowledge, attitudes, and intentions to vaccinate their adolescent children.

OBJECTIVE: HPV vaccine uptake in U.S. East African adolescents is low. We developed and evaluated a culturally-targeted interactive educational intervention for East African immigrant mothers to increase HPV-vaccine-related knowledge, attitudes, and intentions to vaccinate adolescent children. METHODS: Eligible mothers had ≥ 1 11-17-year-old child and reported all children's HPV vaccination status as unvaccinated or unknown. The intervention was delivered via 10 dinners in the Seattle metropolitan area (8 with the Somali community, 2 with the Ethiopian community). Educational presentations and pre/post-tests on knowledge, attitudes, and intentions were conducted in the participants' native language by a co-ethnic physician. Pre/post differences in responses were evaluated with McNemar's tests and GEE models. HPV vaccination uptake 6-months post-intervention was evaluated using state immunization registry data. RESULTS: Of 115 participating mothers, most (84%) were Somali and < 40 years of age (60%). Median years of formal education was 8 (range 0-16), and 61% reported a household income <$25,000. Knowledge of HPV/HPV-vaccines was low pre-intervention, with correct responses ranging from 4% to 39% (61%-91% of responses were "not sure"); correct post-intervention responses ranged from 29% to 97%. Pre-intervention, only 12% of mothers thought they had enough information to make a decision about vaccination, compared to 90% post-intervention. Pre-intervention, only 16% of mothers reported that they were somewhat or very likely to vaccinate their child, compared to 83% post-intervention. All pre/post comparisons were statistically significantly different (p < 0.0001). Although mothers were more likely to report correct HPV-related knowledge and positive vaccine attitudes and intentions post-intervention, only two mothers' children initiated HPV vaccination within 6 months after the intervention. CONCLUSIONS: Results illustrate that a culturally targeted educational intervention effectively increased East African mothers' HPV vaccine-related knowledge, attitudes, and intentions to vaccinate their adolescent children. Future research should identify additional intervention components that can bridge the gap between intention and behavior to facilitate HPV vaccine uptake.

Carbon footprint reduction associated with a surgical outreach clinic.

BACKGROUND: Healthcare systems generate substantial carbon footprints that may be targeted to decrease greenhouse gas emissions. Outreach clinics may represent tools to assist in this reduction by optimizing patient related travel. Therefore, we sought to estimate the carbon footprint savings associated with a head and neck surgery outreach clinic. METHODS: This study was a cross-sectional survey of patient travel patterns to a surgical outreach clinic compared to a regional cancer treatment centre from December 2019 to February 2020. Participants completed a self-administered survey of 12 items eliciting travel distance, vehicle details, and ability to combine medical appointments. Canadian datasets of manufacturer provided vehicular efficiency were used to estimate carbon emissions for each participant. Geographic information systems were used for analyses. RESULTS: One hundred thirteen patients were included for analysis. The majority of patients (85.8%) used their own personal vehicle to travel to the outreach clinic. The median distance to the clinic and regional centre were 29.0 km (IQR 6.0-51.9) and 327.0 km (IQR 309.0-337.0) respectively. The mean carbon emission reduction per person was therefore 117,495.4 g (SD: 29,040.0) to 143,570.9 g (SD: 40,236.0). This represents up to 2.5% of an average individual's yearly carbon footprint. Fewer than 10% of patients indicated they were able to carpool or group their appointments. CONCLUSION: Surgical outreach clinics decrease carbon footprints associated with patient travel compared to continued care at a regional centre. Further research is needed to determine possible interventions to further reduce carbon emissions associated with the surgical care of patients.

Pharmacological Comparison of Mitragynine and 7-Hydroxymitragynine: In Vitro Affinity and Efficacy for µ-Opioid Receptor and Opioid-Like Behavioral Effects in Rats.

Relationships between µ-opioid receptor (MOR) efficacy and effects of mitragynine and 7-hydroxymitragynine are not fully established. We assessed in vitro binding affinity and efficacy and discriminative stimulus effects together with antinociception in rats. The binding affinities of mitragynine and 7-hydroxymitragynine at MOR (Ki values 77.9 and 709 nM, respectively) were higher than their binding affinities at κ-opioid receptor (KOR) or δ-opioid receptor (DOR). [35S]guanosine 5'-O-[γ-thio]triphosphate stimulation at MOR demonstrated that mitragynine was an antagonist, whereas 7-hydroxymitragynine was a partial agonist (Emax = 41.3%). In separate groups of rats discriminating either morphine (3.2 mg/kg) or mitragynine (32 mg/kg), mitragynine produced a maximum of 72.3% morphine-lever responding, and morphine produced a maximum of 65.4% mitragynine-lever responding. Other MOR agonists produced high percentages of drug-lever responding in the morphine and mitragynine discrimination assays: 7-hydroxymitragynine (99.7% and 98.1%, respectively), fentanyl (99.7% and 80.1%, respectively), buprenorphine (99.8% and 79.4%, respectively), and nalbuphine (99.4% and 98.3%, respectively). In the morphine and mitragynine discrimination assays, the KOR agonist U69,593 produced maximums of 72.3% and 22.3%, respectively, and the DOR agonist SNC 80 produced maximums of 34.3% and 23.0%, respectively. 7-Hydroxymitragynine produced antinociception; mitragynine did not. Naltrexone antagonized all of the effects of morphine and 7-hydroxymitragynine; naltrexone antagonized the discriminative stimulus effects of mitragynine but not its rate-decreasing effects. Mitragynine increased the potency of the morphine discrimination yet decreased morphine antinociception. Here we illustrate striking differences in MOR efficacy, with mitragynine having less than 7-hydroxymitragynine. SIGNIFICANCE STATEMENT: At human µ-opioid receptor (MOR) in vitro, mitragynine has low affinity and is an antagonist, whereas 7-hydroxymitragynine has 9-fold higher affinity than mitragynine and is an MOR partial agonist. In rats, intraperitoneal mitragynine exhibits a complex pharmacology including MOR agonism; 7-hydroxymitragynine has higher MOR potency and efficacy than mitragynine. These results are consistent with 7-hydroxymitragynine being a highly selective MOR agonist and with mitragynine having a complex pharmacology that combines low efficacy MOR agonism with activity at nonopioid receptors.

"A slow and unrewarding and miserable pause in your life": Waiting in medicalized gender transition.

Waiting is a common experience in medicalized gender transition. In this article, I address subjective experiences of medicalized gender transition through a temporal lens, focusing on personal narratives of wait lists, setbacks, and other delays experienced by trans patients. I consider administered waiting as a biopolitical practice of governance, one that has subjectifying and somatic effects on individuals and that speaks to the role of time in the administration of bodies, sex/gender, and biomedical citizenship. I ground my discussion in narratives created by trans people that chronicle their gender transitions; I analyze a set of gender transition vlogs appearing on YouTube, focusing on temporal aspects of medicalized transition and experiences of waiting. My discussion recognizes that the temporal modes of gender transition are multivalent, but these social media narratives also suggest being made to wait is an experience of power relations, one that is capable of producing submission, weariness, and precarity.

Can mammogram readers swiftly and effectively learn to interpret first post-contrast acquisition subtracted (FAST) MRI, a type of abbreviated breast MRI?: a single centre data-interpretation study.

OBJECTIVES: To assess whether NHS breast screening programme (NHSBSP) mammogram readers could effectively interpret first post-contrast acquisition subtracted (FAST) MRI, for intended use in screening for breast cancer. METHODS: Eight NHSBSP mammogram readers from a single centre (four who also read breast MRI (Group 1) and four who do not (Group 2)) were given structured FAST MRI reader training (median 4 h: 32 min). They then prospectively interpreted 125 FAST MRIs (250 breasts: 194 normal and 56 cancer) comprising a consecutive series of screening MRIs enriched with additional cancer cases from 2015, providing 2000 interpretations. Readers were blinded to other readers' opinions and to clinical information. Categorisation followed the NHSBSP MRI reporting categorisation, with categories 4 and 5 considered indicative of cancer. Diagnostic accuracy (reference standard: histology or 2 years' follow-up) and agreement between readers were determined. RESULTS: The accuracy achieved by Group 2 (847/1000 (85%; 95% confidence interval (CI) 82-87%)) was 5% less than that of Group 1 (898/1000 (90%; 95% CI 88-92)). Good inter-reader agreement was seen between both Group 1 readers (κ = 0.66; 95% CI 0.61-0.71) and Group 2 readers (κ = 0.63; 95% CI 0.58-0.68). The median time taken to interpret each FAST MRI was Group 1: 34 s (range 3-351) and Group 2: 77 s (range 11-321). CONCLUSION: Brief structured training enabled multiprofessional mammogram readers to achieve similar accuracy at FAST MRI interpretation to consultant radiologists experienced at breast MRI interpretation. ADVANCES IN KNOWLEDGE: FAST MRI could be feasible from a training-the-workforce perspective for screening within NHSBSP.

A multi-site case study of community-clinical linkages for promoting HPV vaccination.

Human papillomavirus (HPV) vaccination rates in the U.S. are suboptimal, requiring innovative partnerships between community and clinical entities to remedy this issue. A rigorous evaluation of HPV-related community-clinical linkages (CCLs) was conducted to understand their components, processes, and outcomes to increase HPV vaccination. Cancer Prevention and Control Research Network (CPCRN) investigators explored CCLs in their communities employing an iterative, case study approach. Information describing nine CCLs on HPV vaccination was collected from representatives from the community organization and clinical setting. Thematic content analysis was used to analyze and interpret data. Five CCLs included a federally qualified health center as the clinical partner, and five included a non-profit organization as the community partner. Five reflected clinically focused integration wherein engagement occurs in the community but vaccine delivery and follow-up occur in the clinical setting. The main impetus was the need to improve HPV vaccination and a community's strong interest in preventing cancer. Noted critical components were a designated person to support the CCL and funding. Results will guide HPV vaccination promotion, education, and intervention efforts. CCLs provide an opportunity to study the adaption, integration, and enhancement of evidence-based approaches to increase HPV vaccination.