Authorship representation in global emergency medicine: a bibliometric analysis from 2016 to 2020.

INTRODUCTION: High-income country (HIC) authors are disproportionately represented in authorship bylines compared with those affiliated with low and middle-income countries (LMICs) in global health research. An assessment of authorship representation in the global emergency medicine (GEM) literature is lacking but may inform equitable academic collaborations in this relatively new field. METHODS: We conducted a bibliometric analysis of original research articles reporting studies conducted in LMICs from the annual GEM Literature Review from 2016 to 2020. Data extracted included study topic, journal, study country(s) and region, country income classification, author order, country(s) of authors' affiliations and funding sources. We compared the proportion of authors affiliated with each income bracket using Χ2 analysis. We conducted logistic regression to identify factors associated with first or last authorship affiliated with the study country. RESULTS: There were 14 113 authors in 1751 articles. Nearly half (45.5%) of the articles reported work conducted in lower middle-income countries (MICs), 23.6% in upper MICs, 22.5% in low-income countries (LICs). Authors affiliated with HICs were most represented (40.7%); 26.4% were affiliated with lower MICs, 17.4% with upper MICs, 10.3% with LICs and 5.1% with mixed affiliations. Among single-country studies, those without any local authors (8.7%) were most common among those conducted in LICs (14.4%). Only 31.0% of first authors and 21.3% of last authors were affiliated with LIC study countries. Studies in upper MICs (adjusted OR (aOR) 3.6, 95% CI 2.46 to 5.26) and those funded by the study country (aOR 2.94, 95% CI 2.05 to 4.20) had greater odds of having a local first author. CONCLUSIONS: There were significant disparities in authorship representation. Authors affiliated with HICs more commonly occupied the most prominent authorship positions. Recognising and addressing power imbalances in international, collaborative emergency medicine (EM) research is warranted. Innovative methods are needed to increase funding opportunities and other support for EM researchers in LMICs, particularly in LICs.

Interleukin-2 Transiently Inhibits Pulsatile Growth Hormone Secretion in Young but not Older Healthy Men.

CONTEXT: Interleukin-2 (IL-2), a proinflammatory cytokine, has been used to treat malignancies. Increased cortisol and adrenocorticotropin (ACTH) were noted, but growth hormone (GH) secretion was not investigated in detail. OBJECTIVE: We quantified GH secretion after a single subcutaneous injection of IL-2 in 17 young and 18 older healthy men in relation to dose, age, and body composition. METHODS: This was a placebo-controlled, blinded, prospectively randomized, crossover study. At 20:00 hours IL-2 (3 or 6 million units/m2) or saline was injected subcutaneously. Lights were off between 23:00 and 07:00 hours. Blood was sampled at 10-minute intervals for 24 hours. Outcome measures included convolution analysis of GH secretion. RESULTS: GH profiles were pulsatile under both experimental conditions and lower in older than young volunteers. Since the effect of IL-2 might be time limited, GH analyses were performed on the complete 24-hour series and the 6 hours after IL-2 administration. Total and pulsatile 24-hour GH secretion decreased nonsignificantly. Pulsatile secretion fell over the first 6 hours after IL-2 (P = .03), with visceral fat as a covariate (P = .003), but not age (P = .10). Plots of cumulative 2-hour bins of GH pulse mass showed a distinction by treatment and age groups: A temporary GH decrease of 32% and 28% occurred in the first 2-hour bins after midnight (P = .02 and .04) in young participants, whereas in older individuals no differences were present at any time point. CONCLUSION: This study demonstrates that IL-2 temporarily diminishes GH secretion in young, but not older, men.

Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men.

BACKGROUND: Many hormones display distinct circadian rhythms, driven by central regulators, hormonal bioavailability, and half-life. A set of 11-oxygenated C19 steroids (11-oxyandrogens) and pregnenolone sulfate (PregS) are elevated in congenital adrenal hyperplasia and other disorders, but their circadian patterns have not been characterized. PARTICIPANTS AND METHODS: Peripheral blood was collected every 2 h over 24 h from healthy volunteer men (10 young, 18-30 years, and 10 older, 60-80 years). We used mass spectrometry to quantify 15 steroids, including androstenedione (A4), testosterone (T), 11ß-hydroxy- and 11-ketotestosterone (11OHT, 11KT),11ß-hydroxy- and 11-ketoandrostenedione (11OHA4, 11KA4), and 4 ∆5-steroid sulfates. Diurnal models including mesor (rhythm adjusted median), peak, and nadir concentrations, acrophase, and amplitude were computed. RESULTS: 11OHA4 followed a rhythm similar to cortisol: acrophase 8:00 h, nadir 21:00 h and were similar in young and old men. 11KT had similar diurnal patterns, but the peak was lower in older than in young men, as was the case for A4. All four steroid sulfates were higher in young vs older men. PregS and 17-hydroxypregnenolone sulfate (17OHPregS) showed sustained elevations between 8:00 and 18:00 h, and nadirs around midnight, while DHEAS and AdiolS displayed minimal diurnal variations. All 4 11-oxyandrogens correlated tightly with cortisol (r from 0.54 for 11OHT to 0.81 for 11OHA4, P < 0.0001 for all), but very weakly with T, supporting their adrenal origin and ACTH governance. CONCLUSIONS: 11-Oxyandrogens, PregS, and 17OHPregS display distinct circadian and age variations, which should be accounted for when used as clinical biomarkers.

Investigating the reaction and substrate preference of indole-3-acetaldehyde dehydrogenase from the plant pathogen Pseudomonas syringae PtoDC3000.

Aldehyde dehydrogenases (ALDHs) catalyze the conversion of various aliphatic and aromatic aldehydes into corresponding carboxylic acids. Traditionally considered as housekeeping enzymes, new biochemical roles are being identified for members of ALDH family. Recent work showed that AldA from the plant pathogen Pseudomonas syringae strain PtoDC3000 (PtoDC3000) functions as an indole-3-acetaldehyde dehydrogenase for the synthesis of indole-3-acetic acid (IAA). IAA produced by AldA allows the pathogen to suppress salicylic acid-mediated defenses in the model plant Arabidopsis thaliana. Here we present a biochemical and structural analysis of the AldA indole-3-acetaldehyde dehydrogenase from PtoDC3000. Site-directed mutants targeting the catalytic residues Cys302 and Glu267 resulted in a loss of enzymatic activity. The X-ray crystal structure of the catalytically inactive AldA C302A mutant in complex with IAA and NAD+ showed the cofactor adopting a conformation that differs from the previously reported structure of AldA. These structures suggest that NAD+ undergoes a conformational change during the AldA reaction mechanism similar to that reported for human ALDH. Site-directed mutagenesis of the IAA binding site indicates that changes in the active site surface reduces AldA activity; however, substitution of Phe169 with a tryptophan altered the substrate selectivity of the mutant to prefer octanal. The present study highlights the inherent biochemical versatility of members of the ALDH enzyme superfamily in P. syringae.

Evaluating the Implementation of a Remote-Monitoring Program for Chronic Obstructive Pulmonary Disease: Qualitative Methods from a Service Design Perspective.

BACKGROUND: Implementing digital health technologies is complex but can be facilitated by considering the features of the tool that is being implemented, the team that will use it, and the routines that will be affected. OBJECTIVE: The goal of this study was to assess the implementation of a remote-monitoring initiative for patients with chronic obstructive pulmonary disease in Ontario, Canada using the Tool+Team+Routine framework and to refine this approach to conceptualize the adoption of technologies in health care. METHODS: This study was a qualitative research project that took place alongside a randomized controlled trial comparing a technology-enabled self-monitoring program with a technology-enabled self- and remote-monitoring program in patients with chronic obstructive pulmonary disease and with standard care. This study included interviews with 5 remote-monitoring patients, 3 self-monitoring patients, 2 caregivers, 5 health care providers, and 3 hospital administrators. The interview questions were structured around the 3 main concepts of the Tool+Team+Routine framework. RESULTS: Findings emphasized that (1) technologies can alter relationships between providers and patients, and that these relationships drove the development of a new service arising from the technology, in our case, and (2) technologies can create additional work that is not visible to management as a result of not being considered within the scope of the service. CONCLUSIONS: Literature on the implementation of digital health technologies has still not reconciled the importance of interpersonal relationships to conventional implementation strategies. By acknowledging the centrality of such relationships, implementation teams can better plan for the adaptations required in order to make new technologies work for patients and health care providers. Further work will need to address how specific individuals administering a remote-monitoring program work to build relationships, and how these relationships and other sources of activity might lead to technological scope creep-an unanticipated expanding scope of work activities in relation to the function of the tool.

Technology-Enabled Self-Management of Chronic Obstructive Pulmonary Disease With or Without Asynchronous Remote Monitoring: Randomized Controlled Trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and leads to frequent hospital admissions and emergency department (ED) visits. COPD exacerbations are an important patient outcome, and reducing their frequency would result in significant cost savings. Remote monitoring and self-monitoring could both help patients manage their symptoms and reduce the frequency of exacerbations, but they have different resource implications and have not been directly compared. OBJECTIVE: This study aims to compare the effectiveness of implementing a technology-enabled self-monitoring program versus a technology-enabled remote monitoring program in patients with COPD compared with a standard care group. METHODS: We conducted a 3-arm randomized controlled trial evaluating the effectiveness of a remote monitoring and a self-monitoring program relative to standard care. Patients with COPD were recruited from outpatient clinics and a pulmonary rehabilitation program. Patients in both interventions used a Bluetooth-enabled device kit to monitor oxygen saturation, blood pressure, temperature, weight, and symptoms, but only patients in the remote monitoring group were monitored by a respiratory therapist. All patients were assessed at baseline and at 3 and 6 months after program initiation. Outcomes included self-management skills, as measured by the Partners in Health (PIH) Scale; patient symptoms measured with the St George's Respiratory Questionnaire (SGRQ); and the Bristol COPD Knowledge Questionnaire (BCKQ). Patients were also asked to self-report on health system use, and data on health use were collected from the hospital. RESULTS: A total of 122 patients participated in the study: 40 in the standard care, 41 in the self-monitoring, and 41 in the remote monitoring groups. Although all 3 groups improved in PIH scores, BCKQ scores, and SGRQ impact scores, there were no significant differences among any of the groups. No effects were observed on the SGRQ activity or symptom scores or on hospitalizations, ED visits, or clinic visits. CONCLUSIONS: Despite regular use of the technology, patients with COPD assigned to remote monitoring or self-monitoring did not have any improvement in patient outcomes such as self-management skills, knowledge, or symptoms, or in health care use compared with each other or with a standard care group. This may be owing to low health care use at baseline, the lack of structured educational components in the intervention groups, and the lack of integration of the action plan with the technology. TRIAL REGISTRATION: ClinicalTrials.gov NCT03741855; https://clinicaltrials.gov/ct2/show/ NCT03741855.

Interleukin-2 drives cortisol secretion in an age-, dose-, and body composition-dependent way.

BACKGROUND: Interleukin-2 (IL-2), one of the proinflammatory cytokines, is used in the treatment of certain malignancies. In some studies, transient increases in cortisol and ACTH secretion occurred. Thus, this agent may be used as an experimental probe of adrenal cortisol secretion. OBJECTIVE: This study quantifies the effects of low and moderate doses of IL-2 on cortisol secretion and assesses the modulation by age, dose and body composition. SITE: Mayo Clinical Translational Research Unit. SUBJECTS: Study comprised 35 healthy men, 17 young and 18 older. METHODS: Randomized prospective double-blind saline-controlled study of IL-2 administration in two doses with concurrent 10-min blood sampling for 24 h. OUTCOME MEASURES: Deconvolution analysis and approximate entropy of cortisol secretion. RESULTS: Low-dose IL-2 administration increased nocturnal pulsatile cortisol secretion from 1460 ± 160 to 2120 ± 220 nmol/L/8 h in young subjects and from 1680 ± 105 to 1960 ± 125 nmol/L/8 h (treatment P < 0.0001, but more in young than older, P = 0.02). Comparable results were obtained for total cortisol secretion (P treatment <0.0001, age effect P = 0.005). The higher IL-2 dose caused a large increase in young (P < 0.0001), but not in older (P = 0.90) subjects. This dose also increased approximate entropy from 0.877 ± 0.041 to 1.024 ± 0.049 (P = 0.008), pointing to reduced secretory orderliness. Incremental cortisol (nocturnal) secretion correlated negatively with visceral fat mass (R = -0.41, P = 0.019). CONCLUSION: In healthy men, IL-2 injection drives pulsatile cortisol secretion in a dose-dependent way in young, but not older, individuals and erodes cortisol secretory orderliness at a higher dose in young subjects. Cortisol responses are diminished with increasing abdominal visceral fat mass.

Age and time-of-day differences in the hypothalamo-pituitary-testicular, and adrenal, response to total overnight sleep deprivation.

STUDY OBJECTIVES: In young men, sleep restriction decreases testosterone (Te) and increases afternoon cortisol (F), leading to anabolic-catabolic imbalance, insulin resistance, and other andrological health consequences. Age-related differences in the hypothalamo-pituitary-testicular/adrenal response to sleep restriction could expose older individuals to greater or lesser risk. We aimed to evaluate and compare the 24-h and time-of-day effect of sleep restriction on F, luteinizing hormone (LH), and Te in young and older men. METHODS: Thirty-five healthy men, aged 18-30 (n = 17) and 60-80 (n =18) years, underwent overnight sleep deprivation (complete nighttime wakefulness) or nighttime sleep (10 pm to 6 am) with concurrent 10-min blood sampling in a prospectively randomized crossover study. F, LH, and Te secretion were calculated by deconvolution analysis. RESULTS: Sleep deprivation had multiple effects on 24-h Te secretion with significant reductions in mean concentrations, basal, total and pulsatile secretion, and pulse frequency (each p < 0.05), in the absence of detectable changes in LH. These effects were most apparent in older men and differed according to age for some parameters: pulsatile Te secretion (p = 0.03) and Te pulse frequency (p = 0.02). Time-of-day analyses revealed that sleep restriction significantly reduced Te in the morning and afternoon, reduced LH in the morning in both age groups, and increased F in the afternoon in older men. CONCLUSIONS: These data suggest a time-of-day dependent uncoupling of the regulatory control of the testicular axis and of F secretion. Future studies will need to directly verify these regulatory possibilities specifically and separately in young and older men. CLINICAL TRIAL: Not applicable.

Dynamic Interactions Between LH and Testosterone in Healthy Community-Dwelling Men: Impact of Age and Body Composition.

BACKGROUND: Aging is associated with diminished testosterone (Te) secretion, which may be attributed to Leydig cell dysfunction, decreased pituitary stimulation, and altered Te feedback. OBJECTIVE: To study all regulatory nodes-gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and Leydig cell-in the same cohort of healthy men. STUDY DESIGN: This was a placebo-controlled, blinded, prospectively randomized cross-over study in 40 men, age range 19 to 73 years, and body mass index (BMI) range 20 to 34.3 kg/m2. A submaximal dose of the GnRH antagonist ganirelix was used to assess outflow of GnRH, by calculating the difference between LH output during the control arm and ganirelix arm. Ketoconazole (a steroidogenic inhibitor) was used to estimate feedback, by the difference in LH output during the ketoconazole and control arm. High-dose ganirelix and repeated LH infusions were used to measure testicular responsivity. Blood sampling was performed at 10-minute intervals. RESULTS: There were age-related, but not body composition-related decreases in estimated GnRH secretion, the feedback strength of Te on LH, and Leydig cell responsivity to LH, accompanied by changes in approximate entropy. Bioavailable Te levels were negatively related to both age and computed tomography (CT)-estimated abdominal visceral mass (AVF), without interaction between these variables. The LH response to a submaximal dose of GnRH was independent of age and AVF. CONCLUSION: Advancing age is associated with (1) attenuated bioavailable Te secretion caused by diminished GnRH outflow and not by decreased GnRH responsivity of the gonadotrope, (2) diminished testicular responsivity to infused LH pulses, and (3) partial compensation by diminished Te feedback on central gonadotropic regulation.

Technology-Enabled Self-Monitoring of Chronic Obstructive Pulmonary Disease With or Without Asynchronous Remote Monitoring: Protocol for a Randomized Controlled Trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality worldwide. Reducing the number of COPD exacerbations is an important patient outcome and a major cost-saving approach. Both technology-enabled self-monitoring (SM) and remote monitoring (RM) programs have the potential to reduce exacerbations, but they have not been directly compared with each other. As RM is a more resource-intensive strategy, it is important to understand whether it is more effective than SM. OBJECTIVE: The objective of this study is to evaluate the impact of SM and RM on self-management behaviors, COPD disease knowledge, and respiratory status relative to standard care (SC). METHODS: This was a 3-arm open-label randomized controlled trial comparing SM, RM, and SC completed in an outpatient COPD clinic in a community hospital. Patients in the SM and RM groups recorded their vital signs (oxygen, blood pressure, temperature, and weight) and symptoms with the Cloud DX platform every day and were provided with a COPD action plan. Patients in the RM group also received access to a respiratory therapist (RT). The RT monitored their vital signs intermittently and contacted them when their vitals varied outside of predetermined thresholds. The RT also contacted patients once a week irrespective of their vital signs or symptoms. All patients were randomized to 1 of the 3 groups and assessed at baseline and 3 and 6 months after program initiation. The primary outcome was the Partners in Health scale, which measures self-management skills. Secondary outcomes included the St. George's Respiratory Questionnaire, Bristol COPD Knowledge Questionnaire, COPD Assessment Test, and modified-Medical Research Council Breathlessness Scale. Patients were also asked to self-report on health system usage. RESULTS: A total of 122 patients participated in the study, 40 in the SC, 41 in the SM, and 41 in the RM groups. Out of those patients, 7 in the SC, 5 in the SM, and 6 in the RM groups did not complete the study. There were no significant differences in the rates of study completion among the groups (P=.80). CONCLUSIONS: Both SM and RM have shown promise in reducing acute care utilization and exacerbation frequencies. As far as we are aware, no studies to date have directly compared technology-enabled self-management with RM programs in COPD patients. We believe that this study will be an important contribution to the literature. TRIAL REGISTRATION: ClinicalTrials.gov NCT03741855; https://clinicaltrials.gov/ct2/show/NCT03741855. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13920.

A Web-Based Mental Health Platform for Individuals Seeking Specialized Mental Health Care Services: Multicenter Pragmatic Randomized Controlled Trial.

BACKGROUND: Web-based self-directed mental health applications are rapidly emerging to address health service gaps and unmet needs for information and support. OBJECTIVE: The aim of this study was to determine if a multicomponent, moderated Web-based mental health application could benefit individuals with mental health symptoms severe enough to warrant specialized mental health care. METHODS: A multicenter, pragmatic randomized controlled trial was conducted across several outpatient mental health programs affiliated with 3 hospital programs in Ontario, Canada. Individuals referred to or receiving treatment, aged 16 years or older, with access to the internet and an email address, and having the ability to navigate a Web-based mental health application were eligible. A total of 812 participants were randomized 2:1 to receive immediate (immediate treatment group, ITG) or delayed (delayed treatment group, DTG) access for 3 months to the Big White Wall (BWW), a multicomponent Web-based mental health intervention based in the United Kingdom and New Zealand. The primary outcome was the total score on the Recovery Assessment Scale, revised (RAS-r) which measures mental health recovery. Secondary outcomes were total scores on the Patient Health Questionnaire-9 item (PHQ-9), the Generalized Anxiety Disorder Questionnaire-7 item (GAD-7), the EuroQOL 5-dimension quality of life questionnaire (EQ-5D-5L), and the Community Integration Questionnaire. An exploratory analysis examined the association between actual BWW use (categorized into quartiles) and outcomes among study completers. RESULTS: Intervention participants achieved small, statistically significant increases in adjusted RAS-r score (4.97 points, 95% CI 2.90 to 7.05), and decreases in PHQ-9 score (-1.83 points, 95% CI -2.85 to -0.82) and GAD-7 score (-1.55 points, 95% CI -2.42 to -0.70). Follow-up was achieved for 55% (446/812) at 3 months, 48% (260/542) of ITG participants and 69% (186/270) of DTG participants. Only 58% (312/542) of ITG participants logged on more than once. Some higher BWW user groups had significantly greater improvements in PHQ-9 and GAD-7 relative to the lowest use group. CONCLUSIONS: The Web-based application may be beneficial; however, many participants did not engage in an ongoing way. This has implications for patient selection and engagement as well as delivery and funding structures for similar Web-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02896894; https://clinicaltrials.gov/ct2/show/NCT02896894 (Archived by WebCite at http://www.webcitation.org/78LIpnuRO).

Optional Web-Based Videoconferencing Added to Office-Based Care for Women Receiving Psychotherapy During the Postpartum Period: Pilot Randomized Controlled Trial.

BACKGROUND: Depression and anxiety during the postpartum period are common, with psychotherapy often being the preferred method of treatment. However, psychological, physical, and social barriers prevent women from receiving appropriate and timely psychotherapy. The option of receiving psychotherapy through videoconferencing (VC) during the postpartum period presents an opportunity for more accessible and flexible care. OBJECTIVE: The aim of this study was to assess the feasibility, acceptability, and preliminary effectiveness of optional VC added to usual office-based psychotherapy, with a psychotherapist during the postpartum period. METHODS: We conducted a pilot randomized controlled trial with 1:1 randomization to office-based care (treatment as usual; TAU) or office-based care with the option of VC (treatment as usual plus videoconferencing; TAU-VC) for psychotherapy during the postpartum period. We assessed the ability to recruit and retain postpartum women into the study from an urban perinatal mental health program offering postpartum psychotherapy, and we evaluated the uptake, acceptability, and satisfaction with VC as an addition to in-person psychotherapy. We also compared therapy attendance using therapist logs and symptoms between treatment groups. Symptoms were assessed at baseline and 3 months postrandomization with the Edinburgh Postnatal Depression Scale, Generalized Anxiety Disorder 7-item, and Parental Stress Scale. Furthermore, 3-month scores were compared between groups with intention-to-treat linear mixed-effects models controlling for baseline score. RESULTS: We enrolled 38 participants into the study, with 19 participants in each treatment group. Attendance data were available for all participants, with follow-up symptom measures available for 25 out of 38 participants (66%). Among the 19 TAU-VC participants, 14 participants (74%) utilized VC at least once. Most participants were highly satisfied with the VC option, and they reported average savings of Can $26 and 2.5 hours in travel and childcare expenses and time per appointment. There were no significant differences between the 2 groups for psychotherapy attendance or symptoms. CONCLUSIONS: The option of VC appears to be an acceptable method of receiving psychotherapy for postpartum women, with benefits described in costs and time savings. On the basis of this small pilot sample, there were no significant differences in outcomes between office-based care with or without the option of VC. This study has demonstrated the feasibility of such a program in an urban center, which suggests that a larger study would be beneficial to provide evidence that is more conclusive.

Modulating Effects of Progesterone on Spontaneous Nocturnal and Ghrelin-Induced GH Secretion in Postmenopausal Women.

BACKGROUND: Oral administration of estradiol (E2) generally increases GH secretion in postmenopausal women. Oral administration of E2 is associated with a decrease in IGF-1, whereas parenteral or transdermally administered E2 may have no effect on GH. The effect of progesterone (P4) on GH secretion has rarely been studied. We hypothesized that moderately increased serum E2 levels stimulate GH and that P4 modulates E2-stimulated GH secretion. STUDY DESIGN: Four parallel groups of randomly assigned postmenopausal women (n = 40). Treatments were saline placebo and oral placebo, saline placebo and oral micronized P4 (3 × 200 mg/d IM), E2 (5 mg IM) and oral placebo, and E2 IM and oral micronized P4. Outcome measures were overnight GH secretion (10 hours), stimulated (ghrelin, 0.3 µg/kg IV bolus) GH secretion, and CT-estimated visceral fat. RESULTS: Intramuscular E2 administration did not alter nocturnal and ghrelin-stimulated GH secretion. Nocturnal GH secretion was not changed by P4 administration. However, P4 diminished ghrelin-stimulated pulsatile GH release with or without E2 (average, 7.20 ± 2.14 and 9.58 ± 1.97 µg/L/2 h, respectively; P = 0.045). Respective outcomes for mean GH concentrations and GH peak amplitudes were 0.97 ± 0.31 and 1.52 µg/L ± 0.29 (P = 0.025) and 2.76 ± 1.04 and 3.95 µg/L ± 0.90 (P = 0.031). Ghrelin-stimulated GH secretion correlated negatively with P4 concentration with or without correction for visceral fat area in the regression equation (R = 0.49, P = 0.04, ß = -0.040 ± 0.016). CONCLUSIONS: Low-range physiological E2 concentrations do not affect spontaneous or ghrelin-stimulated pulsatile GH secretion. Conversely, P4 inhibits ghrelin-stimulated GH secretion in a concentration-dependent fashion. The mechanistic aspects and physiological significance of natural P4's regulation of ghrelin-evoked GH secretion require further study.

Extending access to a web-based mental health intervention: who wants more, what happens to use over time, and is it helpful? Results of a concealed, randomized controlled extension study.

BACKGROUND: Web-based mental health applications may be beneficial, but adoption is often low leaving optimal implementation and payment models unclear. This study examined which users were interested in extended access to a web-based application beyond an initial 3-month trial period and evaluated if an additional 3 months of access was beneficial. METHODS: This study was a concealed extension of a multi-center, pragmatic randomized controlled trial that assessed the benefit of 3 months of access to the Big White Wall (BWW), an anonymous web-based moderated, multi-component mental health application offering self-directed activities and peer support. Trial participants were 16 years of age or older, recruited from hospital-affiliated mental health programs. Participants who received access to the intervention in the main trial and completed 3-month outcome assessments were offered participation. We compared those who were and were not interested in an extension of the intervention, and re-randomized consenting participants 1:1 to receive extended access or not over the subsequent 3 months. Use of the intervention was monitored in the extension group and outcomes were measured at 3 months after re-randomization in both groups. The primary outcome was mental health recovery as assessed by total score on the Recovery Assessment Scale (RAS-r), as in the main trial. Linear mixed models were used to examine the time by group interaction to assess for differences in responses over the 3-month extension study. RESULTS: Of 233 main trial participants who responded, 119 (51.1%) indicated an interest in receiving extended BWW access. Those who were interested had significantly higher baseline anxiety symptoms compared to those who were not interested. Of the 119, 112 were re-randomized (55 to extended access, 57 to discontinuation). Only 21 of the 55 extended access participants (38.2%) used the intervention during the extension period. Change in RAS-r scores over time was not significantly different between groups (time by group, F(1,77) = 1.02; P = .31). CONCLUSIONS: Only half of eligible participants were interested in extended access to the intervention with decreasing use over time, and no evidence of added benefit. These findings have implications for implementation and payment models for this type of web-based mental health intervention. TRIAL REGISTRATION: Clinicaltrials.gov NCT02896894 . Registered retrospectively on September 12, 2016.

Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition.

CONTEXT: Quantitative studies of the short-term feedback of testosterone (T) on luteinizing hormone (LH) secretion in healthy men are relatively rare. Such studies require the shutting down of endogenous T secretion and the imposition of experimentally controlled IV T addback. OBJECTIVE: To evaluate whether pulsatile and continuous T delivery confers equivalent negative feedback on LH secretion. DESIGN: This was a placebo-controlled, blinded, and prospectively randomized crossover study comprising 16 healthy men [age range 23 to 54 years and a body mass index (BMI) between 22.3 and 34.2 kg/m2]. Subjects received ketoconazole to block endogenous T secretion and received continuous or 90-minute pulses of IV T addback. SETTING: The study was performed in a Clinical Translational Research Unit. INTERVENTIONS: Subjects underwent 14 hours of blood sampling at 10-minute intervals, with a bolus IV injection of 33 ng/kg gonadotropin-releasing hormone (GnRH). MAIN OUTCOME MEASURES: Log-transformed LH and T concentration ratios before and after GnRH administration. RESULTS: Despite higher T concentrations during pulsatile T feedback, LH concentrations and secretion rates, whether driven by endogenous or exogenous GnRH, were similar to those during continuous T infusion, indicating diminished pulsatile T feedback. Feedback correlated negatively with BMI. Under controlled T feedback, basal but not pulsatile LH secretion correlated negatively with CT-estimated visceral fat mass. CONCLUSION: Feedback by pulsatile T delivery has diminished inhibitory strength compared with continuous infusion. Feedback is negatively correlated with BMI.

Differential Effects of Estradiol and Progesterone on Cardiovascular Risk Factors in Postmenopausal Women.

CONTEXT: Controlled, blinded studies of sex-hormone replacement in postmenopausal women using natural estradiol (E2) and native progesterone (P) are few. OBJECTIVE: To delineate the effect of E2 alone or with P on lipids and inflammatory markers. DESIGN: A placebo-controlled, double-masked, prospectively randomized study of 40 healthy, postmenopausal volunteers assigned to four treatment groups: placebo, intramuscular E2, and/or micronized oral P for 23 (±2) days. RESULTS: Treatment with E2 alone compared with placebo lowered total cholesterol (TC; P = 0.006), non-high-density lipoprotein cholesterol (nonHDL-C; P = 0.004), low-density lipoprotein cholesterol (LDL-C; P = 0.012), and apolipoprotein B (Apo B; P = 0.02) levels, and raised HDL-C levels (P = 0.03 vs the 3 other groups). Conversely, addition of P to E2 reduced HDL-C levels (P = 0.015). Triglyceride concentrations manifested no effect on E2 or P. High-sensitivity C-reactive protein (hsCRP) level was highest in women with E2 and P replacement (P = 0.018 vs placebo). Leptin and IL-6 concentrations did not vary. P treatment decreased adiponectin levels (P = 0.019). Serum E2 levels correlated linearly with TC, LDL-C, nonHDL-C, Apo B (all negatively), and SHBG (positively) concentrations. P level correlated negatively with TC (P = 0.029), HDL-C (P = 0.002), and adiponectin (P = 0.002) levels. CONCLUSION: In this study, there were individual and interactive effects of E2 and P on key lipids in postmenopausal individuals.

Estradiol Does Not Influence Lipid Measures and Inflammatory Markers in Testosterone-Clamped Healthy Men.

CONTEXT: Experimentally controlled studies of estrogenic regulation of lipid measures and inflammatory cytokines in men are rare. OBJECTIVE: To delineate the effect of estradiol (E2) on lipids and inflammatory markers. DESIGN: This was a placebo-controlled, single-masked, prospectively randomized study comprising experimentally degarelix-downregulated healthy men [n = 74; age 65 years (range, 57 to 77)] assigned to four treatment groups: (1) IM saline and oral placebo; (2) IM testosterone and oral placebo; (3) IM testosterone and oral anastrozole (aromatase inhibitor); and (4) IM testosterone, oral anastrozole, and transdermal E2 for 22 (±1) days. RESULTS: Mean mass spectrometry-quantified serum E2 concentrations ranged from 1.2 to 82 pg/mL in the four treatment groups. E2 extremes did not alter total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol (HDL-C) , non-HDL-C, apolipoprotein B, lipoprotein (a), IL-6, or high-sensitivity C-reactive protein (hsCRP) concentrations. Higher E2 concentrations elevated both sex hormone-binding globulin and prolactin as positive controls. LDL cholesterol, adiponectin, and leptin were higher in hypogonadal subjects without testosterone or E2 addback (P = 0.018, 0.039, and 0.023, respectively). Abdominal visceral fat area by CT (independent variable) correlated negatively with HDL-C (P = 0.017), and positively with triglycerides (P = 0.004), hsCRP (P = 0.005), and leptin (P < 0.0001). CONCLUSION: In this placebo-controlled prospectively randomized study, wide variations in circulating E2 did not influence lipid measures and inflammatory markers when testosterone concentrations were controlled experimentally. However, medically induced central hypogonadism in older men was accompanied by increased LDL cholesterol and metabolic cytokines, adiponectin and leptin. Abdominal visceral fat correlated strongly and positively with triglycerides, hsCRP, and leptin, but negatively with HDL.

Aromatized Estrogens Amplify Nocturnal Growth Hormone Secretion in Testosterone-Replaced Older Hypogonadal Men.

Context: Testosterone (T) increases GH secretion in older men with a relative lack of T, in hypogonadal men of all ages, and in patients undergoing sex reassignment. The role of estradiol (E2) in men is less well defined. Objective: To assess the contribution of aromatization of T to spontaneous nocturnal and stimulated GH secretion. Participants: Four groups of healthy older men (N = 74, age range 57 to 77 years) were studied. The gonadotropic axis was clamped with the gonadotropin-releasing hormone antagonist degarelix. Three groups received T and one group placebo addback. Two T-replaced groups were treated with anastrozole (an aromatase inhibitor) and either placebo or E2 addback. Main Outcome Measures: Ten-minute GH concentration profiles were quantified by deconvolution analysis, after overnight (2200 to 0800 hours) sampling, and after combined IV injection of GHRH (0.3 µg/kg) and GHRH-2 (0.3 µg/kg) and withdrawal of a 2-hour somatostatin infusion (1 µg/kg/h). Results: E2 addback during aromatase inhibition increased basal (P = 0.046), pulsatile (P = 0.020), and total (P = 0.018) GH secretion by 60% to 70%. E2 did not potentiate GH secretory stimuli. Logarithmically transformed pulsatile GH secretion correlated strongly and positively with concurrent E2 concentrations overall (P = 0.028) and under anastrozole treatment (P = 0.005). Conclusion: E2 administration in older men transdermally stimulates overnight pulsatile GH secretion. The exact site of E2 action cannot be ascertained from these experiments but may include hypothalamic loci involved in GH regulation, especially because GH secretagogue effects on somatotrope pituitary cells were not affected.

Optimizing Electronic Consultation Between Primary Care Providers and Psychiatrists: Mixed-Methods Study.

BACKGROUND: The use of electronic consultation (e-consult) between primary care providers (PCPs) and psychiatrists has potential, given the high prevalence of mental health issues in primary care and problematic access to specialist care. Utilization and uptake, however, appears to be lower than would be expected. OBJECTIVE: This study aimed to examine actual utilization of e-consult between PCPs and psychiatrists and investigate the perceptions of PCPs about this form of psychiatric advice to inform how to optimize the utility and thereby the uptake of this service. METHODS: In this mixed-methods study, we conducted a chart review of psychiatry e-consults (N=37) over 2 platforms during early implementation in Ontario, Canada, as well as 3 group interviews and 1 individual interview with PCPs (N=10) with variable experience levels and from a range of practice settings. The chart review assessed response times and referral content including the type of request, referral attachments, and consultant responses. Interviews explored the perceptions of the PCPs about the uses and barriers of psychiatry e-consult. Thematic content analysis of interview data identified common themes as well as themes unique to different provider profiles (eg, experienced PCPs vs new PCPs and rural vs urban practice). On the basis of interpretation of the quantitative and qualitative findings, we developed recommendations for the optimization of psychiatry e-consultation services. RESULTS: During the study period, psychiatry e-consults comprised 3.66% (49/1339) of all e-consults submitted on the studied platforms. Among the e-consults reviewed, different psychiatric diagnoses were represented: 70% of requests (26/37) queried about medication safety or side effects, whereas 59% (22/37) asked about psychiatric symptom management. Moreover, 81% (30/37) of e-consults were answered within 24 hours, and 65% (24/37) were addressed in a single exchange. Themes from the interview data included psychiatry having a complexity that differentiates it from other specialties and may limit the utility of e-consult, other than for psychopharmacology advice. Variability in awareness exists in the way e-consultation could be used in psychiatry, with new PCPs feeling unsure about the appropriateness of a question. In general, new PCPs and PCPs practicing in rural areas were more receptive to psychiatry e-consult. PCPs viewed e-consult as an opportunity to collaborate and desired that it be integrated with other available services. Recommendations include the need for appropriate specialist staffing to address a wide range of requests, adequate education to referrers regarding the use of psychiatry e-consult, and the need to integrate psychiatry e-consult with other geographically relevant services, given the complexity of psychiatric issues. CONCLUSIONS: E-consult is a viable and timely way for PCPs to get much-needed psychiatric advice. For optimizing its utility and uptake, e-consult needs to be integrated into reliable care pathways with adequate referrer and consultant preparation.

Effects of Toremifene, a Selective Estrogen Receptor Modulator, on Spontaneous and Stimulated GH Secretion, IGF-I, and IGF-Binding Proteins in Healthy Elderly Subjects.

CONTEXT: Estrogens amplify spontaneous and stimulated growth hormone (GH) secretion, whereas they diminish GH-dependent insulin-like growth factor (IGF)-I in a dose-dependent manner. Selective estrogen receptor modulators (SERMs), including tamoxifen and toremifene, are widely adjunctively used in breast and prostate cancer. Although some endocrine effects of tamoxifen are known, few data are available for toremifene. OBJECTIVE: To explore sex-dependent effects of toremifene on spontaneous 10-hour overnight GH secretion, followed by GH-releasing hormone-ghrelin stimulation. Additionally, effects on IGF-I, its binding proteins, and sex hormone-binding globulin (SHBG) were quantified. PARTICIPANTS AND DESIGN: Twenty men and 20 women, within an allowable age range of 50 to 80 years, volunteered for this double-blind, placebo-controlled prospective crossover study. Ten-minute blood sampling was done for 10 hours overnight and then for 2 hours after combined GH-releasing hormone-ghrelin injection. MAIN OUTCOME MEASURES: Pulsatile GH and stimulated GH secretion, and fasting levels of IGF-I, IGF-binding protein (IGFBP)1, IGFBP3, and SHBG. RESULTS: Toremifene did not enhance pulsatile or stimulated GH secretion, but decreased IGF-I by 20% in men and women. IGFBP3 was unchanged, whereas while IGFBP1 and SHBG increased in both sexes to a similar extent. CONCLUSIONS: The expected rise in spontaneous and stimulated GH secretion under the diminished negative feedback restraint of powered IGF-I favors a central inhibitory antiestrogenic effect of toremifene. Estrogenic effects of toremifene on the liver were present, as evidenced by increased IGFBP1 and SHBG levels. Men and women responded to this SERM comparably.