Pharmacokinetics of N,N-dimethyltryptamine in Humans.

BACKGROUND AND OBJECTIVE: N,N-dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the preclinical and clinical pharmacokinetics and metabolism of DMT in healthy subjects. METHODS: The physiochemical properties of DMT were determined using a series of in vitro experiments and its metabolic profile was assessed using monoamine oxidase (MAO) and cytochrome P450 (CYP) inhibitors in hepatocyte and mitochondrial fractions. Clinical pharmacokinetics results are from the phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial (NCT04673383). Healthy adults received single escalating doses of DMT fumarate (SPL026) via a two-phase intravenous (IV) infusion. Dosing regimens were calculated based on pharmacokinetic modelling and predictions with progression to each subsequent dose level contingent upon safety and tolerability. RESULTS: In vitro clearance of DMT was reduced through the inhibition of MAO-A, CYP2D6 and to a lesser extent CYP2C19. Determination of lipophilicity and plasma protein binding was low, indicating that a high proportion of DMT is available for distribution and metabolism, consistent with the very rapid clinical pharmacokinetics. Twenty-four healthy subjects received escalating doses of DMT administered as a 10-min infusion over the dose range of 9-21.5 mg (DMT freebase). DMT was rapidly cleared for all doses: mean elimination half-life was 9-12 min. All doses were safe and well tolerated and there was no relationship between peak DMT plasma concentrations and body mass index (BMI) or weight. CONCLUSION: This is the first study to determine, in detail, the full pharmacokinetics profile of DMT following a slow IV infusion in humans, confirming rapid attainment of peak plasma concentrations followed by rapid clearance. These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of MDD. CLINICAL TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT04673383).

Electronic health records and online medical records: an asset or a liability under current conditions?

Objective The aim of the present study was to audit the current use of medical records to determine completeness and concordance with other sources of medical information. Methods Medical records for 40 patients from each of five Melbourne major metropolitan hospitals were randomly selected (n=200). A quantitative audit was performed for detailed patient information and medical record keeping, as well as data collection, storage and utilisation. Using each hospital's current online clinical database, scanned files and paperwork available for each patient audited, the reviewers sourced as much relevant information as possible within a 30-min time allocation from both the record and the discharge summary. Results Of all medical records audited, 82% contained medical and surgical history, allergy information and patient demographics. All audited discharge summaries lacked at least one of the following: demographics, medication allergies, medical and surgical history, medications and adverse drug event information. Only 49% of records audited showed evidence the discharge summary was sent outside the institution. Conclusions The quality of medical data captured and information management is variable across hospitals. It is recommended that medical history documentation guidelines and standardised discharge summaries be implemented in Australian healthcare services. What is known about this topic? Australia has a complex health system, the government has approved funding to develop a universal online electronic medical record system and is currently trialling this in an opt-out style in the Napean Blue Mountains (NSW) and in Northern Queensland. The system was originally named the personally controlled electronic health record but has since been changed to MyHealth Record (2016). In Victoria, there exists a wide range of electronic health records used to varying degrees, with some hospitals still relying on paper-based records and many using scanned medical records. This causes inefficiencies in the recall of patient information and can potentially lead to incidences of adverse drug events. What does this paper add? This paper supports the concept of a shared medical record system using 200 audited patient records across five Victorian metropolitan hospitals, comparing the current information systems in place for healthcare practitioners to retrieve data. This research identifies the degree of concordance between these sources of information and in doing so, areas for improvement. What are the implications for practitioners? Implications of this research are the improvements in the quality, storage and accessibility of medical data in Australian healthcare systems. This is a relevant issue in the current Australian environment where no guidelines exist across the board in medical history documentation or in the distribution of discharge summaries to other healthcare providers (general practitioners, etc).

E-band Nd3+ amplifier based on wavelength selection in an all-solid micro-structured fiber.

A Nd3+ fiber amplifier with gain from 1376 nm to 1466 nm is demonstrated. This is enabled by a wavelength selective waveguide that suppresses amplified spontaneous emission between 850 nm and 1150 nm. It is shown that while excited state absorption (ESA) precludes net gain below 1375 nm with the exception of a small band from 1333 nm to 1350 nm, ESA diminishes steadily beyond 1375 nm allowing for the construction of an efficient fiber amplifier with a gain peak at 1400 nm and the potential for gain from 1375 nm to 1500 nm. A peak small signal gain of 13.3 dB is measured at 1402 nm with a noise figure of 7.6 dB. Detailed measurements of the Nd3+ emission and excited state absorption cross sections suggest the potential for better performance in improved fibers. Specifically, reduction of the fiber mode field diameter from 10.5 µm to 5.25 µm and reduction of the fiber background loss to <10 dB/km at 1400 nm should enable construction of an E-band fiber amplifier with a noise figure < 5 dB and a small signal gain > 20 dB over 30 nm of bandwidth. Such an amplifier would have a form factor and optical properties similar to current erbium fiber amplifiers, enabling modern fiber optic communication systems to operate in the E-band with amplifier technology similar to that employed in the C and L bands.

Scalable waveguide design for three-level operation in Neodymium doped fiber laser.

We have constructed a double clad neodymium doped fiber laser operating on the three-level 4F3/2→4I9/2 transition. The laser has produced 11.5 W at 925 nm with 55% slope efficiency when pumped at 808 nm, comparable to the best previous results for a double-clad fiber configuration on this transition. Higher power pumping with both 808 nm and 880 nm sources resulted in an output of 27 W, albeit at lower slope efficiency. In both cases, output power was limited by available pump, indicating the potential for further power scaling. To suppress the stronger four-level 4F3/2→4I11/2 transition we developed a waveguide that provides spectral filtering distributed along the length of the fiber, based on an all-solid micro-structured optical fiber design, with resonant inclusions creating a leakage path to the cladding. The waveguide supports large mode areas and provides strong suppression at selectable wavelength bands, thus easing the restrictions on core and cladding sizes that limited power scaling of previous approaches.

1.2W laser amplification at 1427nm on the 4F3/2 to 4I13/2 spectral line in an Nd3+ doped fused silica optical fiber.

A 9.3dB improvement in optical gain and a 100x improvement in total optical power over prior published experimental results from the 4F3/2 to 4I13/2 transition in an Nd3+ doped fused silica optical fiber is demonstrated. This is enabled via an optical fiber waveguide design that creates high spectral attenuation in the 1050-1120nm-wavelength range, a continuous spectral filter for the primary 4F3/2 to 4I11/2 optical transition. A maximum output power at 1427nm of 1.2W was attained for 43mW coupled seed laser power and 22.2W of coupled pump diode laser power at 880nm a net optical gain of 14.5dB. Reducing the coupled seed laser power to 2.5mW enabled the system to attain 19.3dB of gain for 16.5W of coupled pump power. Four issues limited results; non-optimal seed laser wavelength, amplified spontaneous emission on the 4F3/2 to 4I9/2 optical transition, low absorption of pump light from the cladding and high spectral attenuation in the 1350-1450nm range. Future fibers that mitigate these issues should lead to significant improvements in the efficiency of the laser amplifier, though the shorter wavelength region of the transition from 1310nm to >1350nm is still expected to be limited by excited state absorption.

Current patient and healthcare worker attitudes to eHealth and the personally controlled electronic health record in major hospitals.

BACKGROUND: The current health system in Australia is comprised of both electronic- and paper-based medical records. The Federal Government has approved funding for the development of an individual health identifier and a universally adopted online health repository. AIMS: To determine attitudes and beliefs of patients and healthcare workers regarding the use of stored medical information and the personally controlled electronic health record (PCEHR) in selected major hospitals in Victoria. METHODS: Qualitative survey of patients and healthcare workers (n = 600 each group) conducted during 2014 across five major hospitals in Melbourne to measure the awareness, attitudes and barriers to electronic health and the PCEHR. RESULTS: Of the patients, 93.3% support the concept of a shared electronic healthcare record, 33.7% were aware of the PCEHR and only 11% had registered. The majority of healthcare workers believed that the presence of a shared health record would result in an increased appropriateness of care and patient safety by reducing adverse drug events and improving the timeliness of care provided. However, only 46% of healthcare workers were aware of the PCEHR. CONCLUSIONS: This study provides a baseline evaluation of perceptions surrounding eHealth and PCHER in acute health services in five metropolitan centres. While there appears to be a readiness for adoption of these strategies for healthcare documentation, patients require motivation to register for the PCEHR, and healthcare workers require more information on the potential benefits to them to achieve more timely and efficient care.

Low-loss high-speed speckle reduction using a colloidal dispersion.

We present a simple and robust approach to reduce laser speckle, which has limited the adoption of lasers in imaging and display applications. We use colloidal solutions that can quickly reduce speckle contrast due to the Brownian motion of the scattering particles. The high insertion loss associated with propagation through a colloidal solution was overcome by using white paint to cover the sides of the cuvette and an optical fiber to deliver the laser light deep into the colloidal solution, enabling transmission greater than 90%. The diffused laser output followed a Lambertian distribution and produced speckle contrast below 4% at an integration time of 129 µs. The ability for colloidal solutions to achieve fast speckle reduction without power consumption while maintaining high transmission, low cost, a compact size, and a long lifetime makes our approach useful for a wide range of laser imaging and projection applications.

HLA-DR3-DQ2 mice do not develop ataxia in the presence of high titre anti-gliadin antibodies.

Recently, it has been suggested that anti-gliadin antibodies (αGAb) may produce "gluten ataxia", even in the absence of celiac disease enteropathy. αGAb are reportedly present in 12-50 % of patients with sporadic ataxia, but also in 12 % of the general population, such that the importance of αGAb as a cause of sporadic ataxia is not conclusively settled. We aimed to determine whether mice transgenic for HLA-DR3-DQ2 and immunised with gliadin to achieve high titres of αGAb would develop ataxia and/or cerebellar damage. From 6 weeks of age, HLA-DR3-DQ2 transgenic mice were immunised fortnightly with gliadin (n = 10) or a saline control (n = 6) in adjuvant. Serum titres were measured by αGAb enzyme-linked immunosorbent assay. At 24 weeks of age, mice were tested for locomotor function using the accelerating rotarod, ledged beam, ink-paw gait, and several neurological severity score subtests. Brains were then collected and processed for immunohistochemistry. Sections were analysed for lymphocytic infiltration, changes in morphology and Purkinje cell (PC) dendritic volume and the number of PCs counted via unbiased stereology. Gliadin-immunised mice developed high αGAb titres while controls did not. There was no statistically significant difference between the gliadin and sham-immunised HLA-DR3-DQ2 mice on any of the tests of motor coordination, in lymphocytic infiltration, PC number or in dendritic volume. High levels of αGAb are not sufficient to produce ataxia or cerebellar damage in HLA-DR3-DQ2 transgenic mice.

Fiber-coupled, Littrow-grating cavity displacement sensor.

We have demonstrated a compact, optical-fiber-fed, optical displacement sensor utilizing a Littrow-mounted diffraction grating to form a low-finesse Fabry-Perot cavity. Length changes of the cavity are read out via the Pound-Drever-Hall rf modulation technique at 925 MHz. The sensor has a nominal working distance of 2 cm and a total dynamic range of 160 nm. The displacement noise floor was less than 3x10(-10) m/sqrt[Hz] above 10(-2) Hz, limited by the frequency drift of the reference laser. A frequency-stabilized laser would reduce the noise floor to below 10(-12) m/sqrt[Hz]. The use of a 925 MHz modulation frequency demonstrates high-precision readout of a low-finesse compact resonant cavity.

Influence of age and moderate-intensity exercise training on heart rate variability in young and mature adults.

The purpose of this study was to examine the influence of age and moderate-intensity exercise training on heart rate variability (HRV), and to elucidate further the mechanism of training-induced bradycardia and cardioprotection. Electrocardiograms were recorded from 12 young (18-24 yrs) and 12 mature (29-43 yrs) individuals during supine rest and submaximal moderate exercise. Recordings were obtained prior to, midway, and following 16 weeks of aerobic exercise training designed to improve cardiorespiratory fitness and health. Training resulted in augmented estimated VO2max and bradycardia during rest and submaximal exercise. Total and low frequency components of HRV during exercise were significantly increased for the mature subjects following training whereas other measures of HRV were not significantly changed for either group. It was concluded that training of moderate intensity was insufficient to induce changes in the autonomic control of heart rate for young to mature subjects. The lack of significant HRV changes may suggest the existence of a vagal critical point, below which training-induced increases in vagal modulation may be forthcoming, and above which changes in vagal modulation may be negligible. Training-induced bradycardia and the cardioprotective effect of regular aerobic exercise may result from factors other than an increased vagal modulation.

Heart rate variability and endogenous sex hormones during the menstrual cycle in young women.

To our knowledge, the relationship between all four endogenous female sex hormones and resting cardiac autonomic function has not been studied. The aim of the current study was to examine the association between the normal endogenous levels of oestrogen (17beta-oestradiol), progesterone, luteinising hormone and follicle-stimulating hormone and heart rate variability (HRV) during the menstrual cycle in young eumenorrheic women. Ten healthy, young, female subjects volunteered for this study. HRV and endogenous hormone levels were recorded at three phases of the menstrual cycle: menses (day 3.8 +/- 0.5), ovulation (day 15.8 +/- 0.7) and luteal (day 22.1 +/- 0.4) to ensure HRV recordings at times of low (menses) and high (ovulation and luteal) hormonal influence. Heart rate recordings were obtained from supine resting subjects and analysed on a Holter analysis system. Total power (TP, 0-1.0 Hz), low frequency (LF, 0.041-0.15 Hz), high frequency (HF, 0.15-0.80 Hz) and LF/HF components of HRV were examined. Despite a significantly greater HR at ovulation and normal cyclic variations in all endogenous sex hormone levels, no measure of HRV was significantly different between menstrual cycle phases. Significant correlations between oestrogen levels and absolute measures of HRV at ovulation were identified. The results of the current study demonstrated that the normal cyclic variations in endogenous sex hormone levels during the menstrual cycle were not significantly associated with changes in cardiac autonomic control as measured by HRV. Significant correlation between peak oestrogen levels and HRV measures at ovulation provided further support for the reported cardioprotective effects of oestrogen in healthy females.

Influence of intensive cycling training on heart rate variability during rest and exercise.

The current study examined whether changes in heart rate variability (HRV) following intensive cycling training contribute to the mechanism of training-induced bradycardia. Thirteen healthy untrained subjects, ages 18-27 years, underwent recordings of heart rate (HR) and VO2max before and after 8 weeks of cycling, 25-60 min/day, 5 days/week at > 80% maximum HR (HRmax). Heart rate recordings were obtained during supine rest and submaximal exercise and were analysed for the following components of HRV: low frequency (LF, 0.041-0.15 Hz); high frequency (HF, 0.15-0.40 Hz); LF/HF ratio and total power (TP, 0-0.40 Hz). At posttraining, VO2max was significantly increased while HR was significantly reduced at rest and all absolute exercise work rates. Training-induced lower HR was accompanied by significantly greater HF and TP during rest as well as LF, HF, and TP during all absolute exercise work rates. Posttraining HR and the majority of HRV measures were similar to pretraining values at the same relative exercise intensity (% HRmax). These results indicated that 8 weeks of intensive cycling training increased HRV and cardiac vagal modulation during rest and absolute exercise work rates but had little effect during relative exercise work rates. Increased vagal modulation resulting from intensive exercise training may contribute to the mechanism of training-induced bradycardia.