Protocol of a drug-drug interaction study between bictegravir/emtricitabine/tenofovir alafenamide and feminizing hormones in trans women living with HIV.

AIMS: Trans/transfeminine women are disproportionally affected by HIV. Concerns regarding negative drug-drug interactions (DDIs) between ART drugs and gender-affirming hormone therapy (GAHT), specifically feminizing hormone therapy (FHT), may contribute to the lower ART uptake by trans women with HIV compared with their cis counterparts. The aim of this study is to investigate the bidirectional pharmacokinetic effects of components of FHT regimens (oral oestradiol and androgen-suppressing medications) with the ART regimen (bictegravir/emtricitabine/tenofovir alafenamide [B/F/TAF)]. METHODS: We present a protocol for a three-armed, parallel-group, longitudinal (6-month), DDI study. Group 1 includes 15 3trans women with HIV taking FHT and ART; group 2 includes 15 premenopausal cis women with HIV taking ART; group 3 includes 15 trans women without HIV taking FHT. Women with HIV must be on or switch to B/F/TAF at baseline and be virally suppressed for ≥3 months. Trans women must be taking a stable regimen of ≥2 mg daily oral oestradiol and an anti-androgen (pharmaceutical, and/or surgical, and/or medical) for ≥3 months. Plasma ART drug concentrations will be sampled at Month 2 and compared between groups 1 and 2. Serum oestradiol concentrations will be sampled at baseline and Month 2 visits and compared between groups 1 and 3. The primary outcomes are B/F/TAF pharmacokinetic parameters (Cmin, Cmax and AUC) and oestradiol concentrations (Cmin, C4h, Cmax and AUC) at month 2. DISCUSSION: This study is of global importance as it provides critical information regarding safe coadministration of B/F/TAF and FHT, both of which are life-saving therapies for trans women with HIV.

Oestradiol concentrations in trans women with HIV suppressed on unboosted integrase inhibitor regimens versus trans women without HIV taking oral oestradiol: a pilot study.

BACKGROUND: Feminizing hormone therapy (FHT) is essential to many trans women. Concern about negative drug interactions between FHT and ART can be an ART adherence barrier among trans women with HIV. OBJECTIVES: In this single-centre, parallel group, cross-sectional pilot study, we measured serum oestradiol concentrations in trans women with HIV taking FHT and unboosted integrase strand transfer inhibitor (INSTI)-based ART versus trans women without HIV taking FHT. METHODS: We included trans women with and without HIV, aged ≥18 years, taking ≥2 mg/day of oral oestradiol for at least 3 months plus an anti-androgen. Trans women with HIV were on suppressive ART ≥3 months. Serum oestradiol concentrations were measured prior to medication dosing and 2, 4, 6 and 8 h post-dose. Median oestradiol concentrations were compared between groups using Wilcoxon rank-sum tests. RESULTS: Participants (n = 8 with HIV, n = 7 without) had a median age of 32 (IQR: 28, 39) years. Among participants, the median oral oestradiol dose was 4 mg (range 2-6 mg). Participants had been taking FHT for a median of 4 years (IQR: 2, 8). Six trans women with HIV were taking bictegravir/emtricitabine/tenofovir alafenamide and two were taking dolutegravir/abacavir/lamivudine. All oestradiol concentrations were not significantly different between groups. Eleven (73%) participants had target oestradiol concentrations in the range 200-735 pmol/L at C4h (75% among women with HIV, 71% among those without HIV). CONCLUSIONS: Oestradiol concentrations were not statistically different in trans women with HIV compared with those without HIV, suggesting a low probability of clinically relevant drug-drug interactions between FHT and unboosted INSTI-based ART.

Feminizing hormone therapy in a Canadian cohort of transgender women with and without HIV.

BACKGROUND: Potential bidirectional drug-drug interactions between feminizing hormone therapy (FHT) and antiretroviral therapy (ART) are of concern for trans women with HIV and their healthcare providers. This study aimed to characterize patterns of FHT and ART among trans women with HIV and to compare serum hormone levels to trans women without HIV. METHODS: Charts of trans women were reviewed at seven HIV primary care or endocrinology clinics in Toronto and Montreal from 2018 to 2019. ART regimens, FHT use, serum estradiol, and serum testosterone levels were compared on the basis of HIV status (positive, negative, missing/unknown). RESULTS: Of 1495 trans women, there were 86 trans women with HIV, of whom 79 (91.8%) were on ART. ART regimens were most commonly integrase inhibitor-based (67.4%), many boosted with ritonavir or cobicistat (45.3%). Fewer (71.8%) trans women with HIV were prescribed FHT, compared to those without HIV (88.4%) and those with missing/unknown status (90.2%, p < 0.001). Among trans women on FHT with recorded serum estradiol (n = 1153), there was no statistical difference in serum estradiol between those with HIV (median: 203 pmol/L, IQR: 95.5, 417.5) and those with negative (200 mol/L [113, 407]) or missing/unknown HIV status (227 pmol/L [127.5, 384.5) (p = 0.633). Serum testosterone concentrations were also similar between groups. CONCLUSIONS: In this cohort, trans women with HIV were prescribed FHT less often than trans women with negative or unknown HIV status. There was no difference in serum estradiol or testosterone levels of trans women on FHT regardless of HIV status, providing reassurance regarding potential drug-drug interactions between FHT and ART.

EANM practice guideline for quantitative SPECT-CT.

PURPOSE: Quantitative SPECT-CT is a modality of growing importance with initial developments in post radionuclide therapy dosimetry, and more recent expansion into bone, cardiac and brain imaging together with the concept of theranostics more generally. The aim of this document is to provide guidelines for nuclear medicine departments setting up and developing their quantitative SPECT-CT service with guidance on protocols, harmonisation and clinical use cases. METHODS: These practice guidelines were written by members of the European Association of Nuclear Medicine Physics, Dosimetry, Oncology and Bone committees representing the current major stakeholders in Quantitative SPECT-CT. The guidelines have also been reviewed and approved by all EANM committees and have been endorsed by the European Association of Nuclear Medicine. CONCLUSION: The present practice guidelines will help practitioners, scientists and researchers perform high-quality quantitative SPECT-CT and will provide a framework for the continuing development of quantitative SPECT-CT as an established modality.

EANM guidelines for PET-CT and PET-MR routine quality control.

We present guidelines by the European Association of Nuclear Medicine (EANM) for routine quality control (QC) of PET-CT and PET-MR systems. These guidelines are partially based on the current EANM guidelines for routine quality control of Nuclear Medicine instrumentation but focus more on the inherent multimodal aspect of the current, state-of-the-art PET-CT and PET-MR scanners. We briefly discuss the regulatory context put forward by the International Electrotechnical Commission (IEC) and European Commission (EC) and consider relevant guidelines and recommendations by other societies and professional organizations. As such, a comprehensive overview of recommended quality control procedures is provided to ensure the optimal operational status of a PET system, integrated with either a CT or MR system. In doing so, we also discuss the rationale of the different tests, advice on the frequency of each test and present the relevant MR and CT tests for an integrated system. In addition, we recommend a scheme of preventive actions to avoid QC tests from drifting out of the predefined range of acceptable performance values such that an optimal performance of the PET system is maintained for routine clinical use.

Tomographic imaging of carbon dioxide in the exhaust plume of large commercial aero-engines.

We report here the first implementation of chemically specific imaging in the exhaust plume of a gas turbine typical of those used for propulsion in commercial aircraft. The method used is chemical species tomography (CST) and the target species is CO2, absorbing in the near-infrared at 1999.4 nm. A total of 126 beams propagate transverse to the plume axis, along 7 m paths in a coplanar geometry, to probe a central region of diameter ≈1.5m. The CO2 absorption spectrum is measured using tunable diode laser spectroscopy with wavelength modulation, using the second harmonic to first harmonic (2f/1f) ratio method. The engine is operated over the full range of thrust, while data are recorded in a quasi-simultaneous mode at frame rates of 1.25 and 0.3125 Hz. Various data inversion methodologies are considered and presented for image reconstruction. At all thrust levels a persistent ring structure of high CO2 concentration is observed in the central region of the measurement plane, with a raised region in the middle of the plume assumed to be due to the engine's boat tail. With its potential to target various exhaust species, the CST method outlined here offers a new approach to turbine combustion research, turbine engine development, and aviation fuel research and development.

Advances in PET/CT Technology: An Update.

This article reviews the current evolution and future directions in PET/CT technology focusing on three areas: time of flight, image reconstruction, and data-driven gating. Image reconstruction is considered with advances in point spread function modelling, Bayesian penalised likelihood reconstruction, and artificial intelligence approaches. Data-driven gating is examined with reference to respiratory motion, cardiac motion, and head motion. For each of these technological advancements, theory will be briefly discussed, benefits of their use in routine practice will be detailed and potential future developments will be discussed. Representative clinical cases will be presented, demonstrating the huge opportunities given to the PET community by hardware and software advances in PET technology when it comes to lesion detection, disease characterization, accurate quantitation and quicker scans. Through this review, hospitals are encouraged to embrace, evaluate and appropriately implement the wide range of new PET technologies that are available now or in the near future, for the improvement of patient care.

A preliminary evaluation of a high temporal resolution data-driven motion correction algorithm for rubidium-82 on a SiPM PET-CT system.

BACKGROUND: In myocardial perfusion PET, images are acquired during vasodilator stress, increasing the likelihood of intra-frame motion blurring of the heart in reconstructed static images to assess relative perfusion. This work evaluated a prototype data-driven motion correction (DDMC) algorithm designed specifically for cardiac PET. METHODS: A cardiac torso phantom, with a solid defect, was scanned stationary and being manually pulled to-and-fro in the axial direction with a random motion. Non-motion-corrected (NMC) and DDMC images were reconstructed. Total perfusion deficit was measured in the defect and profiles through the cardiac insert were defined. In addition, 46 static perfusion images from 36 rubidium-82 MPI patients were selected based upon a perception of motion blurring in the images. NMC and DDMC images were reconstructed, blinded, and scored on image quality and perceived motion. RESULTS: Phantom data demonstrated near-perfect recovery of myocardial wall visualization and defect quantification with DDMC compared with the stationary phantom. Quality of clinical images was NMC: 10 non-diagnostic, 31 adequate, and 5 good; DDMC images: 0 non-diagnostic, 6 adequate, and 40 good. CONCLUSION: The DDMC algorithm shows great promise in rubidium MPI PET with substantial improvements in image quality and the potential to salvage images considered non-diagnostic due to significant motion blurring.

The prevalence of image degradation due to motion in rest-stress rubidium-82 imaging on a SiPM PET-CT system.

BACKGROUND: Motion of the heart is known to affect image quality in cardiac PET. The prevalence of motion blurring in routine cardiac PET is not fully appreciated due to challenges identifying subtle motion artefacts. This study utilizes a recent prototype Data-Driven Motion Correction (DDMC) algorithm to generate corrected images that are compared with non-corrected images to identify visual differences in relative rubidium-82 perfusion images due to motion. METHODS: 300 stress and 300 rest static images were reconstructed with DDMC and without correction (NMC). The 600 DDMC/NMC image pairs were assigned Visual Difference Score (VDS). The number of non-diagnostic images were noted. A "Dwell Fraction" (DF) was derived from the data to quantify motion and predict image degradation. RESULTS: Motion degradation (VDS = 1 or 2) was evident in 58% of stress images and 33% of rest images. Seven NMC images were non-diagnostic-these originated from six studies giving a 2% rate of non-diagnostic studies due to motion. The DF metric was able to effectively predict image degradation. The DDMC heart identification and tracking was successful in all images. CONCLUSION: Motion degradation is present in almost half of all relative perfusion images. The DDMC algorithm is a robust tool for predicting, assessing and correcting image degradation.

Impact of the COVID-19 pandemic on radiology department emergency ultrasound utilization.

PURPOSE: To analyze the change in utilization of healthcare resources through a review of ultrasound examinations performed in the emergency department of an urban healthcare system in NYC during the time of peak COVID-19 outbreak. METHODS: This is a retrospective review analyzing ED ultrasound exams performed by the radiology department of an urban healthcare system during the 8-week time period of the peak COVID-19 outbreak in NYC, compared to a time-matched period one year prior. Data regarding the examination type and indication were obtained in addition to patient demographics and indicators of outcomes including admission, length of stay, and mortality. RESULTS: There was a 58% decrease in ED ultrasounds performed by the radiology department during the COVID-19 time period. Exams performed during the pandemic compared to the pre-pandemic period were more likely to be performed on men (28.3 vs 18.0%, p < 0.01), older patients (36 vs. 35 years, p = 0.02), and patients subsequently admitted (17.8 vs. 13.4%, p = 0.03). There was also a difference in the distribution of exam type (p = 0.01). There was no difference in death, rate of surgery/intervention performed, or distribution of clinical indication. When correcting for gender, there was only an increase in studies leading to hospital admission in the female-only group (14.9 vs. 10.7%, p = 0.05). CONCLUSION: COVID-19 had a drastic impact on the utilization of emergency department ultrasounds performed by the radiology department, with a decrease in total exams performed and changes in patient demographics, including a higher proportion of male patients and increases in some markers of disease severity, including rate of hospital admission.

Surface boulder banding indicates Martian debris-covered glaciers formed over multiple glaciations.

Glacial landforms, including lobate debris aprons, are a global water ice reservoir on Mars preserving ice from past periods when high orbital obliquity permitted nonpolar ice accumulation. Numerous studies have noted morphological similarities between lobate debris aprons and terrestrial debris-covered glaciers, an interpretation supported by radar observations. On Earth and Mars, these landforms consist of a core of flowing ice covered by a rocky lag. Terrestrial debris-covered glaciers advance in response to climate forcing driven by obliquity-paced changes to ice mass balance. However, on Mars, it is not known whether glacial landforms emplaced over the past 300 to 800 formed during a single, long deposition event or during multiple glaciations. Here, we show that boulders atop 45 lobate debris aprons exhibit no evidence of monotonic comminution but are clustered into bands that become more numerous with increasing latitude, debris apron length, and pole-facing flow orientation. Boulder bands are prominent at glacier headwalls, consistent with debris accumulation during the current Martian interglacial. Terrestrial glacier boulder bands occur near flow discontinuities caused by obliquity-driven hiatuses in ice accumulation, forming internal debris layers. By analogy, we suggest that Martian lobate debris aprons experienced multiple cycles of ice deposition, followed by ice destabilization in the accumulation zone, leading to boulder-dominated lenses and subsequent ice deposition and continued flow. Correlation between latitude and boulder clustering suggests that ice mass-balance works across global scales on Mars. Lobate debris aprons may preserve ice spanning multiple glacial/interglacial cycles, extending Mars climate records back hundreds of millions of years.

Assessment of motion correction in dynamic rubidium-82 cardiac PET with and without frame-by-frame adjustment of attenuation maps for calculation of myocardial blood flow.

BACKGROUND: Patient motion during pharmacological stressing can have substantial impact on myocardial blood flow (MBF) estimated from dynamic PET. This work evaluated a motion correction algorithm with and without adjustment of the PET attenuation map. METHODS: Frame-by-frame motion correction was performed by three users on 30 rubidium-82 studies. Data were divided equally into three groups of motion severity [mild (M1), moderate (M2) and severe (M3)]. MBF data were compared for non-motion corrected (NC), motion-corrected-only (MC) and with adjustment of the attenuation map (MCAC). Percentage differences of MBF were calculated in the coronary territories and 17-segment polar plots. Polar plots of spill-over were also generated from the data. RESULTS: Median differences of 23% were seen in the RCA and 18% for the LAD in the M3 category for MC vs NC images. Differences for MCAC vs MC images were considerably smaller and typically < 10%. Spill-over plots for MC and MCAC were notably more uniform compared with NC images. CONCLUSION: Motion correction for dynamic rubidium data is desirable for future MBF software updates. Adjustment of the PET attenuation map results in only marginal differences and therefore is unlikely to be an essential requirement. Assessing the uniformity of spill-over plots is a useful visual aid for verifying motion correction techniques.

RNA drug discovery: Conformational restriction enhances specific modulation of the T-box riboswitch function.

Antibacterial drug resistance is a global health concern that requires multiple solution approaches including development of new antibacterial compounds acting at novel targets. Targeting regulatory RNA is an emerging area of drug discovery. The T-box riboswitch is a regulatory RNA mechanism that controls gene expression in Gram-positive bacteria and is an exceptional, novel target for antibacterial drug design. We report the design, synthesis and activity of a series of conformationally restricted oxazolidinone-triazole compounds targeting the highly conserved antiterminator RNA element of the T-box riboswitch. Computational binding energies correlated with experimentally-derived Kd values indicating the predictive capabilities for docking studies within this series of compounds. The conformationally restricted compounds specifically inhibited T-box riboswitch function and not overall transcription. Complex disruption, computational docking and RNA binding specificity data indicate that inhibition may result from ligand binding to an allosteric site. These results highlight the importance of both ligand affinity and RNA conformational outcome for targeted RNA drug design.

The Changing Face of Academic Surgery: Overrepresentation of Women among Surgeon-Scientists with R01 Funding.

BACKGROUND: There has been a recent focus on sex-based disparities within the field of academic surgery. However, the proportion of female surgeons conducting NIH-funded research is unknown. STUDY DESIGN: The NIH RePORTER (Research Portfolio Online Reporting Tools Expenditures and Results) was queried for R01 grants from surgery departments for which the principal investigator (PI) had a primary medical degree, as of October 2018. Characteristics of the PI and their respective grants were collected. Institutional faculty profiles were reviewed for PI and departmental characteristics. PIs were stratified by sex and compared using standard univariate statistics. RESULTS: There were a total of 212 R01 grants in surgery departments held by 159 PIs. Of these, 26.4% (n = 42) of R01-funded surgeons were female compared with the reported 19% of academic surgery female faculty (as reported by the Association of American Medical Colleges; p = 0.02). Women with R01 grants were more likely to be first-time grant recipients with no concurrent or previous NIH funding (21.4% vs 8.6%; p = 0.03) and less likely to have a previous R01 or equivalent grant (54.8% vs 73.5%; p = 0.03). Women were more likely to be from departments with a female surgery chair (31.0% vs 13.7%; p = 0.01) or a department with > 30% female surgeons (35.0% vs 18.2%; p = 0.03). CONCLUSIONS: Although female surgeons remain a minority in academic surgery, they hold a greater than anticipated proportion of NIH funding, with a high number of first-time grants, forming a crucial component of the next generation of surgeon-scientists.

Recent update on basic mechanisms of spinal cord injury.

Spinal cord injury (SCI) is a life-shattering neurological condition that affects between 250,000 and 500,000 individuals each year with an estimated two to three million people worldwide living with an SCI-related disability. The incidence in the USA and Canada is more than that in other countries with motor vehicle accidents being the most common cause, while violence being most common in the developing nations. Its incidence is two- to fivefold higher in males, with a peak in younger adults. Apart from the economic burden associated with medical care costs, SCI predominantly affects a younger adult population. Therefore, the psychological impact of adaptation of an average healthy individual as a paraplegic or quadriplegic with bladder, bowel, or sexual dysfunction in their early life can be devastating. People with SCI are two to five times more likely to die prematurely, with worse survival rates in low- and middle-income countries. This devastating disorder has a complex and multifaceted mechanism. Recently, a lot of research has been published on the restoration of locomotor activity and the therapeutic strategies. Therefore, it is imperative for the treating physicians to understand the complex underlying pathophysiological mechanisms of SCI.