Personalized cardiac resynchronization therapy guided by real-time electrocardiographic imaging for patients with non-left bundle branch block.

BACKGROUND: Patients with heart failure and a non-left bundle branch block (non-LBBB) QRS pattern have a limited response to biventricular pacing (BVP). OBJECTIVE: A personalized cardiac resynchronization therapy (CRT) implantation approach guided by real-time electrocardiographic imaging (ECGi) was studied. METHODS: Twenty patients with left ventricular ejection fraction (LVEF) ≤ 35%, QRS duration ≥ 120 ms, and non-LBBB [13 (65%) with right bundle branch block and 7 (35%) with intraventricular conduction delay] were recruited. During CRT implantation, right atrial, right ventricular, coronary sinus, His-bundle, and/or left bundle leads were inserted. The total activation time (TAT) with different pacing combinations were measured in real time during implantation by ECGi. The configuration producing the shortest TAT was chosen. Clinical response was defined as ≥1 New York Heart Association class improvement. Echocardiographic response was defined as left ventricular end-systolic volume reduction ≥ 15% and/or LVEF improvement ≥ 10% at 6 months. RESULTS: After ECGi-guided CRT implantation, LVEF improved from 26% ± 6% to 34% ± 11% (P < .01) and New York Heart Association class improved from 3.0 ± 0.5 to 2.0 ± 0.6 (P < .01). Both clinical and echocardiographic response rates were 70%. The ECGi approach resulted in better acute electrical resynchronization over BVP as measured by TAT reduction (40% vs 14%; P < .01). The percentage of TAT reduction was found to be a strong predictor for echocardiographic response (area under the curve for the receiver operating characteristic curve 0.91; 95% confidence interval 0.78-1.00). A strong positive correlation between percentage TAT reduction and percentage LVEF improvement (Pearson R = 0.70; P = .001) was found. CONCLUSION: ECGi-guided CRT implantation in patients with non-LBBB generates superior acute electrical resynchronization compared with BVP and is associated with favorable clinical and echocardiographic outcomes.

Male contraception development: monitoring effective spermatogenesis suppression utilizing a user-controlled sperm concentration test compared with standard semen analysis.

OBJECTIVE: To determine whether a user-controlled sperm concentration test compared with standard semen analysis can effectively monitor spermatogenesis suppression for male contraception. DESIGN: Single center, prospective sub study of the ongoing clinical trial: "Study of daily application of Nestorone and testosterone combination gel for male contraception." SETTING: Research institute at an academic medical center. PARTICIPANT(S): Couples participating in the male contraceptive clinical trial. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): The ability by participants to monitor sperm suppression to a threshold compatible with contraceptive efficacy utilizing a user-controlled test verified by sperm concentration determined by standard laboratory methods. RESULT(S): Thirty-eight men participating in a hormonal male contraceptive clinical trial provided multiple samples during spermatogenesis suppression for this substudy. Participants, employing a user-controlled test, correctly identified the absence of sperm (a negative test) in 100% of their laboratory-confirmed azoospermic samples (n = 122). Participants also identified 100% of samples (n = 73) with sperm >0.2 million/mL as positive. Sperm counts between 0.01 and 0.2 million/mL were identified as negative in 96% of samples. Trial participants noted the overall ease of using the test with respect to sample preparation, test timing, and result interpretation, and that they could accurately use this test at home without difficulty. CONCLUSION(S): Participants undergoing spermatogenesis suppression in a hormonal male contraceptive trial performed user-controlled test to determine whether their semen sperm concentration was ≤ or >0.2 million/mL. Compared with standard semen analyses, participants correctly identified 100% of samples with sperm counts >0.2 million/mL as positive (Sensitivity 100%). A positive result when the couple is using a male contraceptive method triggers the need for semen analysis by a laboratory while the couple uses another method of contraception. Participants correctly diagnosed samples ≤0.2 million sperm/mL as negative in 99% of samples (specificity 99%). A negative result indicates a sperm concentration ≤0.2 million/mL, well below the threshold of ≤1 million/mL offering contraceptive efficacy demonstrated by prior studies. At-home sperm concentration test would minimize the need for users to return to the clinic to monitor suppression of spermatogenesis, decreasing cost and burden of male contraception trials and increasing practicality of the method. CLINICAL TRIAL REGISTRATION NUMBER: NCT: 03452111.

Endogenous Diurnal Patterns of Adrenal and Gonadal Hormones During a 24-Hour Constant Routine After Simulated Shift Work.

Context: Night-shift work causes circadian misalignment, predicts the development of metabolic diseases, and complicates the interpretation of hormone measurements. Objective: To investigate endogenous circadian rhythms, dissociated from behavioral and environmental confounds, in adrenal and gonadal steroids after simulated shift work. Methods: Fourteen healthy adults (ages 25.8 ± 3.2 years) were randomized to 3 days of night or day (control) shift work followed by a constant routine protocol designed to experimentally unveil rhythms driven endogenously by the central circadian pacemaker. Blood was sampled every 3 hours for 24 hours during the constant routine to concurrently obtain 16 Δ4 steroid profiles by mass spectrometry. Cosinor analyses of these profiles provided mesor (mean abundance), amplitude (oscillation magnitude), and acrophase (peak timing). Results: Night-shift work marginally increased cortisol by 1 µg/dL (P = 0.039), and inactive/weak derivatives cortisone (P = 0.003) and 18-hydroxycortisol (P < 0.001), but did not alter the mesor of potent androgens testosterone and 11-ketotestosterone. Adrenal-derived steroids, including 11-ketotestosterone (P < 0.01), showed robust circadian rhythmicity after either day- or night-shift work. In contrast, testosterone and progesterone showed no circadian pattern after both shift work conditions. Night-shift work did not alter the amplitude or acrophase of any of the steroid profiles. Conclusion: Experimental circadian misalignment had minimal effects on steroidogenesis. Adrenal steroids, but not gonadal hormones, showed endogenous circadian regulation robust to prior shift schedule. This dichotomy may predispose night-shift workers to metabolic ill health. Furthermore, adrenal steroids, including cortisol and the main adrenal androgen 11-ketostosterone, should always be evaluated during the biological morning whereas assessment of gonadal steroids, particularly testosterone, is dependent on the shift-work schedule.

Acceptability of the oral hormonal male contraceptive prototype, 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC), in a 28-day placebo-controlled trial.

OBJECTIVE: To determine men's satisfaction with and the potential acceptability of 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC) when used for 28 days as an experimental, once-daily, oral hormonal male contraceptive (HMC). STUDY DESIGN: We surveyed participants from a double-blind, randomized, placebo-controlled, phase 1 clinical trial, examining their experience with and willingness to use daily oral 11ß-MNTDC for male contraception. RESULTS: Of 42 trial participants, 40 (30 11ß-MNTDC, 10 placebo) completed baseline and end-of-treatment surveys. Based on a 28-day experience, few cited any baseline concerns about safety and drug adherence. Following treatment, nearly three-quarters (72.5%) of participants reported satisfaction with the study drug and nearly all (92.5%) would recommend the method to others. More than half of participants would be willing to pay for the study drug (62.5%) and indicated that the method exceeded initial expectations (53.9%). Nearly 90% reported that taking the pill was easy to remember and did not interfere with their daily routines. Approximately one-third of participants reported bothersome side effects (37% 11ß-MNTDC vs. 20% placebo, p = 0.45). Given the option, 42% of participants would prefer a daily HMC pill over injectable regimens or a daily topical gel. CONCLUSION: A majority of participants in this short-term trial of daily oral 11ß-MNTDC reported satisfaction with the regimen, would recommend it to others, and would pay to use the drug as HMC despite some bothersome side effects. IMPLICATIONS: Oral 11ß-MNTDC would be an acceptable and preferable method among men desiring reversible hormonal male contraception (HMC). These data support further trials of novel oral HMCs such as 11ß-MNTDC.

Sleep and the Testis.

Disordered sleep impairs neurocognitive performance, and is now recognized to cause metabolic ill-health. This review assesses the nascent relationship between insufficient, misaligned, and disrupted sleep with andrological health. High-quality cohort studies show a reduced sperm count in men with sleep disturbances. Well-designed interventional studies show a reduction in testosterone with sleep restriction. Studies of long-term shift workers show no effect of misaligned sleep on mean testosterone concentrations. Men with obstructive sleep apnea (OSA) and more severe hypoxemia have lower testosterone levels, although it is unknown if this relationship is entirely explained by concomitant obesity, or is reversible. Nevertheless, erectile dysfunction, which is common in men with OSA, is clinically improved when OSA is properly treated. Few studies manipulating sleep have been performed in older men, in whom the accumulation of sleep disturbances over decades of life may contribute to age-related illnesses. Improving sleep could ameliorate the development of these disorders.

Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11ß-MNTDC in healthy men.

BACKGROUND: Dimethandrolone (DMA) and 11ß-methyl-19-nortestosterone (11ß-MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men. OBJECTIVE: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. MATERIALS/METHODS: In two clinical trials of DMA undecanoate (DMAU) and 11ß-MNT dodecylcarbonate (11ß-MNTDC), oral prodrugs of DMA and 11ß-MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non-parametric Kruskal-Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo. RESULTS: Class effects were seen, with decrease in HDL-C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA-IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11ß-MNTDC. An increase in LDL-C was seen with 11ß-MNTDC but not with DMAU. DISCUSSION: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. CONCLUSION: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds.

Online community queries on hormonal male contraception: An analysis of the Reddit "Ask Me Anything" experience.

OBJECTIVE: Reddit is one of the most popular websites in the United States because of its user-driven aggregation and community-based curation of online content. We describe the use and impact of Reddit's Ask Me Anything platform, for public engagement and education about developments in hormonal male contraception (HMC). METHODS: We analyzed the content from and user engagement with 2 Reddit Ask Me Anything events that answered user queries about HMC in June 2018 and March 2019. Clinical trial investigators provided real-time responses throughout the events. We examined the 25 most popular posts from each event, analyzing content for salient themes via an inductive approach. To quantify event impact, we examined Google Trends data and subsequent traffic to the investigator website. RESULTS: Over 18,000 registered Reddit users interacted with each of the 2 Ask Me Anything events, with each generating over 1600 comments. The most popular posts of each Ask Me Anything event expressed interest in off-target effects associated with the use of HMCs. Additional themes included queries about previous and ongoing clinical trials, HMC physiology, and market analyses and projections of public willingness to use HMCs. The events coincided with a spike in both Google searches for "male birth control" and first-time visits to the study's website where users could express interest in participating in clinical trials. CONCLUSION: Reddit Ask Me Anything events conducted by HMC investigators revealed wide public interest in HMCs. The events prompted further searches for more information on male contraception, while driving traffic to the investigator website for trial recruitment purposes. IMPLICATIONS: Reddit Ask Me Anything events are a popular, cost-free online platform for publicly responding to a range of HMC-related queries, while providing investigators with insight into stakeholder priorities and preoccupations.

Sleep and Circadian Regulation of Cortisol: A Short Review.

The central circadian pacemaker (CCP) located in the suprachiasmatic nucleus (SCN) of the hypothalamus drives the 24-hour pattern in cortisol, which functions as the main central synchronizing signal that coordinates peripheral clocks in organs that control whole body metabolism. A superimposed pulsatile pattern of cortisol allows rapid responses that fine tune the body's reaction to changes in the environment. In addition to coordinating metabolic processes to predictable environmental events, cortisol is the main catabolic signal which acts with testosterone, the quintessential male anabolic hormone, to maintain catabolic-anabolic homeostasis in men. Sleep restriction, when sufficiently substantial, increases late afternoon/early evening cortisol, but does not alter 24-hour cortisol; whereas even maximal acute circadian misalignment only slightly delays the cortisol rhythm. Prolonged circadian misalignment decreases overall cortisol exposure. The implications of these regulatory changes on health and disease requires further evaluation.

Dimethandrolone Undecanoate, a Novel, Nonaromatizable Androgen, Increases P1NP in Healthy Men Over 28 Days.

CONTEXT: Dimethandrolone undecanoate (DMAU) is being developed as a male contraceptive. Daily oral administration of DMAU, a potent androgen that is not aromatized, markedly suppresses serum testosterone (T) and estradiol (E2) in healthy men. E2 deficiency can increase bone resorption in men. OBJECTIVE: This work aimed to assess changes in bone turnover markers with DMAU administration in a 28-day study. DESIGN: A randomized, double-blind, placebo-controlled study was conducted. SETTING: This study took place at 2 academic medical centers. PARTICIPANTS: Healthy men, age 18 to50 years (n = 81), participated. INTERVENTION: Men received 0, 100, 200, or 400 mg of oral DMAU for 28 days. Serum C-terminal telopeptide of type I collagen (CTX; bone resorption marker) and procollagen type I amino-terminal propeptide (P1NP; bone formation marker) were measured on days 1 and 28. MAIN OUTCOME MEASURES: Changes in bone turnover markers and serum hormones over the treatment period were measured. RESULTS: On day 28, median serum T and E2 were markedly suppressed in all treatment groups vs placebo (P < .001 for both). Percentage change (%) in serum P1NP significantly differed across treatment groups (P = .007): Serum P1NP significantly increased in the 200 mg (5%, interquartile range [IQR] -7% to 27%) and 400 mg (22%, IQR -1% to 40%) groups relative to placebo (-8%, IQR -20% to 0%). Change (%) in serum CTX did not differ between groups (P = .09). CONCLUSIONS: DMAU administration for 28 days to healthy men leads to marked suppression of serum T and E2, yet increases P1NP, a serum marker of bone formation. Longer-term studies of the potent androgen DMAU are warranted to determine its impact on bone health in men.

Acceptability of oral dimethandrolone undecanoate in a 28-day placebo-controlled trial of a hormonal male contraceptive prototype.

OBJECTIVE: To determine men's satisfaction with and acceptability of a once-daily, oral regimen of dimethandrolone undecanoate (DMAU) versus placebo when used for 28 days. STUDY DESIGN: After a Phase I double-blind, randomized, placebo-controlled, dose-escalating trial of oral DMAU for 28-days, 57 healthy male volunteers completed a survey assessing their experience and satisfaction with the regimen. In the trial, participants were randomized to receive up to 4 DMAU capsules daily versus placebo and instructed to ingest them within 30 min of consuming a high fat meal. Pharmacokinetic and pharmacodynamic profiles were performed, followed by a 6-week recovery phase. Participants were counseled that they could not rely on the drug for contraception. RESULTS: Fifty-seven participants were offered acceptability surveys (39 DMAU, 18 placebo). Most respondents, 80% (45/56), reported satisfaction with the method; 77% (44/57) would recommend it. 54% (31/57), reported that, if available, they would use the method as their primary contraceptive. More respondents reported satisfaction with active DMAU than placebo (87% vs. 67%; p = 0.05). Most respondents, 91% (52/57), reported no difficulty with having to take up to 4 pills within 30 min of ingesting a high-fat meal. CONCLUSION: Most participants reported that the study method, daily oral DMAU or placebo, was satisfactory and acceptable. Having to take the drug after a high-fat meal did not detract from acceptability. IMPLICATIONS: Most participants in a 4-week trial of daily DMAU capsules would recommend and use the method. High satisfaction among DMAU and placebo groups affirms acceptability of a daily male contraceptive pill, warranting further study of oral DMAU.

Continuing the search for a hormonal male contraceptive.

This chapter discusses the mechanisms of action of hormonal male contraception, which suppresses the hypothalamic-pituitary-testis axis. When the intratesticular concentration of testosterone is subsequently suppressed to adequately low concentrations, spermatogenesis is arrested. Androgens are a necessary hormonal male contraceptive component because they not only suppress the hypothalamic-pituitary-testis axis, but also provide the male hormone necessary to maintain peripheral androgen functions. Past studies using testosterone alone and testosterone combined with progestins demonstrated contraceptive efficacy in the female partner at rates similar to combined hormonal female methods. Newer hormonal male contraceptive formulations and the alternative routes of administration are discussed, along with potential barriers, challenges, and opportunities for hormonal male contraceptive development. Novel methods that are safe, effective, reversible, user-friendly, and coitus-independent are intrinsic to equitably meet the various needs and limitations of an increasingly diverse population.

Daily Oral Administration of the Novel Androgen 11ß-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men.

BACKGROUND: 11ß-methyl-19-nortestosterone (11ß-MNT) is a modified testosterone (T) with androgenic and progestational activity. A single oral dose of the prodrug, 11ß-MNT dodecylcarbonate (11ß-MNTDC), was well tolerated in healthy men. METHODS: We conducted a randomized, double-blind study at 2 academic medical centers. 42 healthy men (18-50 years) were randomized to receive oral placebo or 11ß-MNTDC, 200 or 400 mg daily, for 28 consecutive days. Primary outcome (safety and tolerability) measures were assessed twice per week. Subjects underwent serial blood sampling over 24 hours on days 1 and 28 to assess secondary outcomes: pharmacokinetics (serum drug concentrations); pharmacodynamics of 11ß-MNTDC (serum sex steroids and gonadotropins); and mood and sexual function (via validated questionnaires). RESULTS: There were no serious adverse events. No participants discontinued because of an adverse event or laboratory test abnormality. 11ß-MNTDC resulted in a dose-related increase in serum 11ß-MNTDC and 11ß-MNT concentrations sustained over 24 hours. Administration of 11ß-MNTDC resulted in a marked suppression of serum gonadotropins, T, calculated free T, estradiol, and SHBG over the treatment period (P < 0.01). Adverse effects that may be related to 11ß-MNTDC included weight gain, acne, headaches, fatigue, and mild mood changes, with 5 men reporting decreased libido and 3 decreased erectile/ejaculatory function. Serum low-density lipoprotein cholesterol, weight (~2 kg), hematocrit, and hemoglobin increased and serum high-density lipoprotein cholesterol decreased in both 11ß-MNTDC groups. CONCLUSION: Daily oral 11ß-MNTDC for 28 days in healthy men markedly suppressed serum gonadotropin and T concentrations without serious adverse effects. These results warrant further evaluation of 11ß-MNTDC as a potential male oral contraceptive.

Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11ß-Methyl-19-Nortestosterone-17ß-Dodecylcarbonate in Men.

Context: 11ß-Methyl-19-nortestosterone-17ß-dodecylcarbonate (11ß-MNTDC) is an orally bioavailable prodrug of 11ß-methyl-19-nortestosterone (11ß-MNT) with androgenic and progestational activity. Objectives: (i) Quantify 11ß-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11ß-MNTDC in men. Design and Setting: (i) In vitro receptor binding and transactivation studies and (ii) randomized, double-blind, placebo-controlled single-dose, dose-escalating phase I study at two academic medical centers. Participants and Intervention: Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11ß-MNTDC or placebo given with or without food. Main Outcome Measures: (i) In vitro 11ß-MNT/11ß-MNTDC human receptor binding and transactivation and (ii) safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24 hours following dosing. Results: 11ß-MNT avidly binds and activates human androgen and progesterone receptors, but 11ß-MNTDC has minimal activity. Single oral doses of 11ß-MNTDC were well tolerated without serious adverse events. Administration of 11ß-MNTDC with food markedly increased average 11ß-MNTDC and 11ß-MNT serum concentrations (P < 0.001 for all doses) compared with fasting with a significant dose-related effect on average serum drug concentrations (P < 0.0001). The 200-, 400-, and 800-mg doses significantly suppressed average serum testosterone concentrations (P < 0.05). Conclusions: A single, oral dose of 11ß-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11ß-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive.

Spatiotemporal clustering and temporal order in the excitable BZ reaction.

The prototype experimental example of "spontaneous" pattern formation in an unstirred chemical medium is the oscillatory Belousov-Zhabotinsky (BZ) reaction: target patterns of outward-moving concentric rings are readily observed when the reaction is run in a thin layer in a Petri dish. In many experimental runs, new target centers appeared to form closer to pre-existing target centers than expected in a randomized model. Here we describe a simple direct test for the presence of temporal order in the spatiotemporal dynamics of target nucleation, and apply this test to detect significant temporal order in target formation in the ferroin-catalyzed BZ reaction. We also describe how mixing heterogeneity can generate temporal order, even in the absence of heterogeneous physical nucleating centers.