SummaryBackgroundDespite its diagnostic accuracy, the clinical impact of the use of Point-of-care Ultrasound (POCUS) in the emergency department (ED) is not well described, especially when performed by junior in-training residents.Aim of the studyto assess the effect of a short, structured POCUS training program on the management of ED patients by in-training residents.MethodIMPULSE is a before-and-after implementation study, evaluating the impact of a structured POCUS training program for ED in-training residents on the management of patients admitted for acute respiratory and/or circulatory failure in a Swiss regional hospital. The training curriculum was organized in three stages and combined an on-line training course, an 8-hour practical hands-on session, and 10 supervised POCUS exams. The ED residents who successfully completed the curriculum participated in the study. Observed outcomes were time to ED diagnosis, rate of correct diagnosis made during the ED stay and time needed to reach it, time to prescribe an appropriate treatment, and hospital mortality. Standard statistical analyses were performed with the use of Chi-square and Mann-Whitney U tests as appropriate, completed by a Bayesian analysis, with a Bayes Factor (BF) > 3 considered as significant.ResultsSixty-nine patients were included before the training program implementation and 54 after. After implementation, the median time to ED diagnosis was 25 minutes (IQR 44) vs 30 minutes (IQR 56) before implementation, a difference that was significant (BF 9.6). The rate of correct diagnosis was higher (95 vs 52 %) (p<0.001) and the time to make this correct diagnosis was significantly shorter after implementation (25 minutes, IQR 45, vs 43, IQR 60) (BF 5.0). This had an impact on the median time to prescribe the appropriate therapy, with a trend toward a shorter delay (47 minutes, IQR 76, vs 70, IQR 100) (BF 2.0). Eventually, there was a significant difference in hospital mortality (13 % vs 5.5 %, BF 15.7).Conclusionthe IMPULSE study shows that the implementation of a short, structured POCUS training program for ED residents to use ultrasound for the initial evaluation of acute respiratory and circulatory failure patients has an impact on diagnostic accuracy, on time to make a correct diagnosis and to prescribe an appropriate therapy, and eventually possibly on hospital mortality. If these results are reproduced in other settings, POCUS use by ED residents after short, structured training curriculum could become the standard of care for these patients.

Abstract Introduction A novel oral testosterone replacement therapy (TRT), testosterone undecanoate (TU, JATENZO) has been shown in 1- and 2-year studies to have durable efficacy and safety. Hypogonadal men are heterogeneous with respect to age, body mass index (BMI), and diabetic status. These factors have been shown to affect the hypothalamic-pituitary-gonadal axis. Objective The purpose of this study is to investigate the role of baseline age, BMI, and diabetic status on change in T levels, final TU dose, and safety. Methods Hypogonadal men, ages 18 – 65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. 222 subjects were randomized to BID TU (n = 166) or testosterone gel (n = 56). Subjects had dose adjustments based on plasma T levels (Cavg). Safety was assessed by standard clinical measures. Post hoc safety, efficacy, and dosing analyses were conducted on subjects who were stratified by age, BMI, and diabetes status. The age groups were <= 44 y/o, 45 – 54 y/o, and => 55 y/o; the BMI groups were < 30 kg/m^2, 30 – 35 kg/m^2, and > 35 kg/m^2; and the subjects were grouped as non-diabetic, pre-diabetic, or diabetic. Results Overall, serum total T Cavg for the oral TU group was 489 ± 12.6 ng/dL (mean ± SE). For all groups, the mean total T was in the eugonadal range. Age, BMI, or diabetes status did not affect key efficacy variables, such as total T or calculated free T, nor key safety variables, such as hematocrit, PSA, liver transaminases, systolic BP, diastolic BP, HDL-C, or LDL-C. There were no differences in the final TU dose among the age categories. In contrast, the final TU dose was significantly different among BMI categories (p=0.0003), and the diabetic status (p < 0.0001). The higher BMI groups need a significantly higher oral TU dose. Those in the pre-diabetic or diabetic groups needed a significantly higher dose than the non-diabetic group. Because the pre-diabetic and diabetic groups had significantly higher BMI, it is difficult to determine if it was diabetes status or BMI that influenced the final dose [baseline BMI: non-diabetic 30.5 ± 0.52 (mean ± SEM), pre-diabetic 32.7 ± 0.54 (p = 0.003 vs the non-diabetic group), diabetic 32.5 ± 0.56 (p = 0.0175 vs the non-diabetic group)]. BMI had a greater effect on the final dose in the non-diabetic group, and its effect appeared to decrease in the pre-diabetic and diabetic groups. See figure for the final mean doses. Although the final total T values were in the eugonadal range, there was also a significantly smaller change from baseline in total T comparing non-diabetics to diabetics (p=0.0042). Conclusions Regardless of age, BMI, or diabetes status, eugonadal total T levels were achieved in men administered oral TU. Age did not influence the final dose. In contrast, BMI and diabetes status influenced the final dose. Patient characteristics (BMI and diabetic status) may guide dosing of testosterone replacement with oral testosterone undecanoate to optimize T levels. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics.

We demonstrate large single-phonon optomechanical coupling rates, g0= 1.2 MHz, between InAs quantum dots and surface-acoustic-wave microcavity resonators. We show that these systems can be used for microwave-to-optical quantum transduction at mK temperatures.

Since the identification of its role as the functional receptor for SARS-CoV in 2003 and for SARS-CoV-2 in 2020, ACE2 has been studied in depth to understand COVID-19 susceptibility and severity. ACE2 is a widely expressed protein, and it plays a major regulatory role in the renin-angiotensin-aldosterone System (RAAS). The key to understanding susceptibility and severity may be found in ACE2 variants. Some variants have been shown to affect binding affinity with SARS-CoV-2. In this review, we discuss the role of ACE2 in COVID-19 infection, highlighting the importance of ACE2 isoforms (soluble and membrane-bound) and explore how ACE2 variants may influence an individual's susceptibility to SARS-CoV-2 infection and disease outcome.

BackgroundLong-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). AimTo determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. MethodsHypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. OutcomesThe efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. ResultsOver 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300–1,000 ng/dL [10–35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3–6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests. Clinical ImplicationsOver 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. Strengths & LimitationsThese are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. ConclusionOral TU offers a safe and effective long-term treatment option for men with hypogonadism.Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750–1758.

Abstract A closed-loop geothermal well design is presented which incorporates both wellbore configuration and completions components as well as a strategy for well operations which together achieve meaningful production of thermal energy. Planning and optimization of intermittent circulation enable "thermal soak" periods to thermally charge the working fluid while mitigating thermal depletion in the reservoir. Technical challenges of a viable closed-loop downhole heat exchanger scheme are discussed. Advantages of Closed-loop Geothermal Systems (CLGS) compared to Enhanced Geothermal System (EGS) designs are also considered. Fully transient and closely coupled thermal-hydraulic simulations using an industry standard software model were performed on a representative well design and schedule of well circulation operations. The simulation model accounts for detailed conduction, forced and natural convection and radiative heat transfer modes in both the wellbore and the formation as appropriate. Detailed thermophysical characteristics are incorporated into the model for all wellbore completion components which include industry available OCTG grades and sizes, specialized variations such as Vacuum-Insulated-Tubing (VIT), insulating fluids including nitrogen, conventional and foamed cements and syntactic foam as well as the variation in the earth formation. Water is used as a demonstration working fluid and the full spectrum of fluid behavior for all potential phase and quality regimes are accounted for throughout the circulation flow path and at the surface wellhead. Resultant transient temperatures over an extended sequence of flow and shut-in periods are reported inclusive of near-by earth formation temperatures out to the far-field boundary. Comparisons with analytical reference models are also considered. Well simulations presented herein achieve repeatable and extended return fluid temperatures in the range of 200°F to over 400°F. In combination with a pad well concept, this allows for long-term steady energy generation. Clearly the generation of useful temperatures and ultimately justifiable enthalpy delivery with closed-loop configurations is a challenge. Further work on innovative design concepts, refinements such as integration with surface plant processes to optimize surface pressures and pump requirements as well as the recycling of heated water, and identification of optimal locations for deployment will progress this work. Advantages of fully closed-loop well systems include avoidance of potential problems associated with traditional geothermal and EGS wells such as induced seismicity and bedding plane slippage, formation interface skin quality, reservoir degradation over time and introduction of corrosive formation species into the wellbore, and disposal thereof. Combined optimization of both wellbore configuration components and staged circulation and thermal soak periods is shown here to provide a realistic option for significant steady heat generation. Impact of various completion components on operational efficiency can be quantified. In particular, the optimal staging of intermittent circulation operations and their associated thermal soak periods is a featured design option which has not received wide consideration in the literature.

The objective of the investigation was to determine the ocular biodistribution of cysteamine, a reducing agent used for treatment of cystine crystals in cystinosis, following topical administration of a sustained release formulation and traditional eyedrop formulation. To the right eye only, rabbits received a 50 µL drop of 0.44% cysteamine eyedrops at one drop per waking hour for 2, 6, 12, and 24 h. A second group received one 100 µL drop of a sustained release formulation containing encapsulated cysteamine microspheres suspended in a thermoresponsive gel. Upon serial sacrifice, ocular tissues from both eyes and plasma were obtained and quantified for cysteamine using LC-MS/MS. Cysteamine was detected in the cornea, aqueous humor and vitreous humor. Systemic plasma concentrations of cysteamine from treatment groups were below the limit of detection. As expected, 0.44% cysteamine eyedrops when administered hourly maintained drug concentrations within the cornea at a magnitude 5 times higher than a single dose of the sustained release formulation over 12 h. The sustained release formulation maintained cysteamine presentation across 12 h from a single drop. These studies demonstrate distribution of cysteamine to the eye following topical administration, including high drug uptake to the cornea and low systemic distribution.

ABSTRACT Introduction An oral testosterone (T) replacement therapy (TRT) would be the preferred administration route for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men with two-year follow up. Methods Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results Overall, 86 subjects participated in both studies. T concentration increased from 193.75 ± 9.44 ng/dL (Mean ± SEM) at baseline (BL) to 475.5 ± 49.7 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests – ALP (64.05 ± 1.95 to 53.74 U/L ± 1.86 U/L), ALT (27.8 ± 1.40 to 26.7 ± 1.6 U/L), AST (21.6 ± 0.76 to 22.0 ± 1.0 U/L), and bilirubin (0.58 ± 0.03 to 0.52 ± 0.03 mg/dL) throughout the two studies. At d270, one subject had an ALT level of 227 U/L, which was &amp;gt; 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on d290, and the level dropped to 87 U/L, &amp;lt; 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. Although there was a slight increase in prostate-growth related endpoints, there were no significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (44.3 ± 0.3 to 46.6 ± 0.5%, p &amp;lt; 0.001) and cuff systolic BP (127.1 ± 1.2 to 131.8 ± 1.67 mmHg vs BL, p = 0.006). The change in CV endpoints, including HDL-C, hematocrit, and BP, changed initially and stabilized throughout the 2 trials. For example, systolic BP varied 3 – 6 mm Hg from BL throughout the study. Conclusion This oral TU formulation is an option for hypogonadal men and has a safety profile consistent with other approved T products, such as a rise in hematocrit and a decrease in HDL-C. Notably, no evidence of liver toxicity was observed over 2 years. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children. Disclosure Work supported by industry: yes, by Clarus Therapeutics. A consultant, employee (part time or full time) or shareholder is among the authors (Clarus Therapeutics).

ABSTRACT Introduction The diagnosis of hypogonadism (HG) in men requires both consistently low testosterone (T) levels and signs and symptoms of T deficiency. Management of HG with T replacement therapy (TRT) aims to improve both low serum T levels and patients’ symptomatic complaints. The first oral softgel formulation of testosterone undecanoate (TU) was recently approved by FDA (JATENZO®) for TRT in men with specific hypogonadal conditions and is available in 3 capsule strengths and 5 dosage combinations for necessary dose adjustments. However, dose titration may not be necessary in many patients treated with this new oral TU formulation given the wide eugonadal range. Objective Assess the ability of any given daily dosage of oral TU to restore T to eugonadal levels without dose adjustment at steady state (Css); and determine real-world dose titration experience of patients treated with oral TU. Methods Pharmacokinetic (PK) simulations were performed using a robust population PK model developed for T in 474 hypogonadal men who were treated with oral TU in prior PK studies. The model consisted of a 1-compartment model with absorption lag time and an allometric function on key allometric parameters to account for differences in body weight. This final population PK model was coded in Trial Simulator v2.3.0.6 software. T levels were simulated following oral TU BID dosing on Day 55 (i.e., at steady state) with no dose adjustments. Average T concentrations (Cavg) were derived from multiple serial blood samples collected over 24 hrs for oral TU doses of 237, 316, and 396 mg TU, BID (without dose modification). The percent of subjects with T levels within the eugonadal range (serum Cavg between 304 ng/dL-1030 ng/dL) at each of these TU dose levels was calculated. Prescription data was also accessed in the Symphony PatientSource Patient Transactional Dataset to evaluate the frequency of real-world dose titration. Results The percentage of subjects with Css T Cavg within the eugonadal range for 237, 316, and 396 mg TU, BID were 61%, 74% and 74%, respectively. These corresponded to mean [5%, 95% CI] serum T levels (ng/dL) of 398 [389, 406], 560 [549, 572] and 728 [715, 741] ng/dL, respectively. Early assessment of real-world prescribing data for JATENZO indicated 35% of patients underwent dose titration by month 5. Conclusions Simulated daily BID dosing of oral TU without dose adjustment yielded eugonadal T levels in most subjects at all 3 dose levels examined. These data are consistent with initial early real-world experience with oral TU that indicates dose titration has not been required in most patients. However, because the desired outcome of TRT therapy focuses on both T Cavg and symptomatic response, this oral TU formulation enables necessary dose adjustment when needed. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics, Inc. Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics, Inc.