Effect of low-dose terazosin on arterial stiffness improvement: A pilot study.

Arterial stiffness, a prominent hallmark of ageing arteries, is a predictor of all-cause mortality. Strategies for promoting healthy vascular ageing are encouraged. Here we conducted a pilot study to evaluate the potential effects of low-dose Terazosin on arterial stiffness. We enrolled patients aged over 40 with elevated arterial stiffness, defined as a brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s, who were administered Terazosin (0.5 and 1.0 mg/day) from December 2020 to June 2023. Treatment responses were assessed every 3 months. Linear regression analysis was used to characterise the improvement. We matched cases who took Terazosin for 1 year with Terazosin-free controls using propensity score matching (PSM). Our findings demonstrate that Terazosin administration significantly affected arterial stiffness. (1) Arterial stiffness significantly improved (at least a 5% reduction in baPWV) in 50.0% of patients at 3 months, 48.6% at 6 months, 59.3% at 9 months, and 54.4% at 12 months, respectively. (2) Those with higher baseline baPWV and hypertension exhibited a significantly reduced risk of non-response. (3) Terazosin was associated with a reduction of baPWV at 1-year follow-up (linear regression: ß = -165.16, p < 0.001). This pilot study offers valuable insights into the potential significance of Terazosin in improving arterial stiffness and paves the way for future randomised clinical trials in combating vascular ageing.

Wastewater Target Pathogens of Public Health Importance for Expanded Sampling, Houston, Texas, USA.

Building on the success of initiatives put forth during the COVID-19 pandemic response, US health officials are expanding wastewater surveillance programs to track other target pathogens and diseases of public health interest. The Houston Health Department in Houston, Texas, USA, conducted a hypothesis-generating study whereby infectious disease subject matter experts suggested potential targets. This study addressed 2 criteria recommended by the National Academies of Sciences, Engineering, and Medicine for selecting wastewater targets. Results can be used as a basis of a questionnaire for a future population-based study to recommend targets of highest priority to include for expanded wastewater sampling.

Beat Pilot Tone (BPT): Simultaneous MRI and RF motion sensing at arbitrary frequencies.

PURPOSE: To introduce a simple system exploitation with the potential to turn MRI scanners into general-purpose radiofrequency (RF) motion monitoring systems. METHODS: Inspired by Pilot Tone (PT), this work proposes Beat Pilot Tone (BPT), in which two or more RF tones at arbitrary frequencies are transmitted continuously during the scan. These tones create motion-modulated standing wave patterns that are sensed by the receiver coil array, incidentally mixed by intermodulation in the receiver chain, and digitized simultaneously with the MRI data. BPT can operate at almost any frequency as long as the intermodulation products lie within the bandwidth of the receivers. BPT's mechanism is explained in electromagnetic simulations and validated experimentally. RESULTS: Phantom and volunteer experiments over a range of transmit frequencies suggest that BPT may offer frequency-dependent sensitivity to motion. Using a semi-flexible anterior receiver array, BPT appears to sense cardiac-induced body vibrations at microwave frequencies ( ≥ $$ \ge $$ 1.2 GHz). At lower frequencies, it exhibits a similar cardiac signal shape to PT, likely due to blood volume changes. Other volunteer experiments with respiratory, bulk, and head motion show that BPT can achieve greater sensitivity to motion than PT and greater separability between motion types. Basic multiple-input multiple-output ( 4 × 22 $$ 4\times 22 $$ MIMO) operation with simultaneous PT and BPT in head motion is demonstrated using two transmit antennas and a 22-channel head-neck coil. CONCLUSION: BPT may offer a rich source of motion information that is frequency-dependent, simultaneous, and complementary to PT and the MRI exam.

Sequence-agnostic motion-correction leveraging efficiently calibrated Pilot Tone signals.

PURPOSE: This study leverages externally generated Pilot Tone (PT) signals to perform motion-corrected brain MRI for sequences with arbitrary k-space sampling and image contrast. THEORY AND METHODS: PT signals are promising external motion sensors due to their cost-effectiveness, easy workflow, and consistent performance across contrasts and sampling patterns. However, they lack robust calibration pipelines. This work calibrates PT signal to rigid motion parameters acquired during short blocks (˜4 s) of motion calibration (MC) acquisitions, which are short enough to unobstructively fit between acquisitions. MC acquisitions leverage self-navigated trajectories that enable state-of-the-art motion estimation methods for efficient calibration. To capture the range of patient motion occurring throughout the examination, distributed motion calibration (DMC) uses data acquired from MC scans distributed across the entire examination. After calibration, PT is used to retrospectively motion-correct sequences with arbitrary k-space sampling and image contrast. Additionally, a data-driven calibration refinement is proposed to tailor calibration models to individual acquisitions. In vivo experiments involving 12 healthy volunteers tested the DMC protocol's ability to robustly correct subject motion. RESULTS: The proposed calibration pipeline produces pose parameters consistent with reference values, even when distributing only six of these approximately 4-s MC blocks, resulting in a total acquisition time of 22 s. In vivo motion experiments reveal significant ( p < 0.05 $$ p<0.05 $$ ) improved motion correction with increased signal to residual ratio for both MPRAGE and SPACE sequences with standard k-space acquisition, especially when motion is large. Additionally, results highlight the benefits of using a distributed calibration approach. CONCLUSIONS: This study presents a framework for performing motion-corrected brain MRI in sequences with arbitrary k-space encoding and contrast, using externally generated PT signals. The DMC protocol is introduced, promoting observation of patient motion occurring throughout the examination and providing a calibration pipeline suitable for clinical deployment. The method's application is demonstrated in standard volumetric MPRAGE and SPACE sequences.

Improving newborn screening test performance for metachromatic leukodystrophy: Recommendation from a pre-pilot study that identified a late-infantile case for treatment.

Metachromatic leukodystrophy (MLD) is a devastating rare neurodegenerative disease. Typically, loss of motor and cognitive skills precedes early death. The disease is characterised by deficient lysosomal arylsulphatase A (ARSA) activity and an accumulation of undegraded sulphatide due to pathogenic variants in the ARSA gene. Atidarsagene autotemcel (arsa-cel), an ex vivo haematopoietic stem cell gene therapy was approved for use in the UK in 2021 to treat early-onset forms of pre- or early-symptomatic MLD. Optimal outcomes require early diagnosis, but in the absence of family history this is difficult to achieve without newborn screening (NBS). A pre-pilot MLD NBS study was conducted as a feasibility study in Manchester UK using a two-tiered screening test algorithm. Pre-established cutoff values (COV) for the first-tier C16:0 sulphatide (C16:0-S) and the second-tier ARSA tests were evaluated. Before the pre-pilot study, initial test validation using non­neonatal diagnostic bloodspots demonstrated ARSA pseudodeficiency status was associated with normal C16:0-S results for age (n = 43) and hence not expected to cause false positive results in this first-tier test. Instability of ARSA in bloodspot required transfer of NBS bloodspots from ambient temperature to -20°C storage within 7-8 days after heel prick, the earliest possible in this UK pre-pilot study. Eleven of 3687 de-identified NBS samples in the pre-pilot were positive for C16:0-S based on the pre-established COV of ≥170 nmol/l or ≥ 1.8 multiples of median (MoM). All 11 samples were subsequently tested negative determined by the ARSA COV of <20% mean of negative controls. However, two of 20 NBS samples from MLD patients would be missed by this C16:0-S COV. A further suspected false negative case that displayed 4% mean ARSA activity by single ARSA analysis for the initial test validation was confirmed by genotyping of this NBS bloodspot, a severe late infantile MLD phenotype was predicted. This led to urgent assessment of this child by authority approval and timely commencement of arsa-cel gene therapy at 11 months old. Secondary C16:0-S analysis of this NBS bloodspot was 150 nmol/l or 1.67 MoM. This was the lowest result reported thus far, a new COV of 1.65 MoM is recommended for future pilot studies. Furthermore, preliminary data of this study showed C16:1-OH sulphatide is more specific for MLD than C16:0-S. In conclusion, this pre-pilot study adds to the international evidence that recommends newborn screening for MLD, making it possible for patients to benefit fully from treatment through early diagnosis.

A novel test and treat program for hepatitis C virus infection utilizing HCV core antigen testing, among police and general population, Islamabad, Pakistan, 2022.

Hepatitis C virus core antigen (HCVcAg) testing can simplify and decrease costs of HCV infection confirmation compared to molecular testing (nucleic acid testing). We piloted HCVcAg testing for the confirmation of active infection. The study was conducted during June through December 2022 among the police and the general population of Islamabad, Pakistan age 18 years and older. Initial screening for HCV antibody was conducted using a rapid diagnostic test (RDT) for all consenting participants. Those who tested positive had venous blood samples tested for HCVcAg, platelets and aspartate aminotransferase (AST). Persons with HCVcAg values ≥3 fmol/L were defined as viremic, and they were offered treatment with direct acting antiviral (DAA) medications, sofosbuvir and daclatasvir. Aspartate aminotransferase to platelet ratio index (APRI) was calculated for each HCV infected person, and those with an APRI score <1.5 received treatment for 12 weeks, while those with APRI ≥ to 1.5 received 24 weeks of treatment. A total of 15,628 persons were screened for anti-HCV using RDT and 643 (4.1%) tested positive. HCVcAg values of ≥3 fmol/L was found in 399/643 (62.1%), and all were offered and accepted treatment. Of those treated, 273/399 (68.4%) returned for a follow-up SVR and HCVcAg was not detected in 261/273, a 95.6% cure rate. The pilot study demonstrated the effectiveness of reaching and treating an urban population using RDT for screening and HCVcAg for confirmation of infection and test of cure.

Development of a robotic cluster for automated and scalable cell therapy manufacturing.

BACKGROUND AIMS: The production of commercial autologous cell therapies such as chimeric antigen receptor T cells requires complex manual manufacturing processes. Skilled labor costs and challenges in manufacturing scale-out have contributed to high prices for these products. METHODS: We present a robotic system that uses industry-standard cell therapy manufacturing equipment to automate the steps involved in cell therapy manufacturing. The robotic cluster consists of a robotic arm and customized modules, allowing the robot to manipulate a variety of standard cell therapy instruments and materials such as incubators, bioreactors, and reagent bags. This system enables existing manual manufacturing processes to be rapidly adapted to robotic manufacturing, without having to adopt a completely new technology platform. Proof-of-concept for the robotic cluster's expansion module was demonstrated by expanding human CD8+ T cells. RESULTS: The robotic cultures showed comparable cell yields, viability, and identity to those manually performed. In addition, the robotic system was able to maintain culture sterility. CONCLUSIONS: Such modular robotic solutions may support scale-up and scale-out of cell therapies that are developed using classical manual methods in academic laboratories and biotechnology companies. This approach offers a pathway for overcoming manufacturing challenges associated with manual processes, ultimately contributing to the broader accessibility and affordability for personalized immunotherapies.

RGD-p21Ras-scFv expressed prokaryotically on a pilot scale inhibits ras-driven colorectal cancer growth by blocking p21Ras-GTP.

BACKGROUND: Ras gene mutation and/or overexpression are drivers in the progression of cancers, including colorectal cancer. Blocking the Ras signaling has become a significant strategy for cancer therapy. Previously, we constructed a recombinant scFv, RGD-p21Ras-scFv by linking RGD membrane-penetrating peptide gene with the anti-p21Ras scFv gene. Here, we expressed prokaryotically RGD-p21Ras-scFv on a pilot scale, then investigated the anti-tumor effect and the mechanism of blocking Ras signaling. METHODS: The E. coli bacteria which could highly express RGD-p21Ras-scFv was screened and grown in 100 L fermentation tank to produce RGD-p21Ras-scFv on optimized induced expression conditions. The scFv was purified from E. coli bacteria using His Ni-NTA column. ELISA was adopted to test the immunoreactivity of RGD-p21Ras-scFv against p21Ras proteins, and the IC50 of RGD-p21Ras-scFv was analyzed by CCK-8. Immunofluorescence colocalization and pull-down assays were used to determine the localization and binding between RGD-p21Ras-scFv and p21Ras. The interaction forces between RGD-p21Ras-scFv and p21Ras after binding were analyzed by molecular docking, and the stability after binding was determined by molecular dynamics simulations. p21Ras-GTP interaction was detected by Ras pull-down. Changes in the MEK-ERK /PI3K-AKT signaling paths downstream of Ras were detected by WB assays. The anti-tumor activity of RGD-p21Ras-scFv was investigated by nude mouse xenograft models. RESULTS: The technique of RGD-p21Ras-scFv expression on a pilot scale was established. The wet weight of the harvested bacteria was 31.064 g/L, and 31.6 mg RGD-p21Ras-scFv was obtained from 1 L of bacterial medium. The purity of the recombinant antibody was above 85%, we found that the prepared on a pilot scale RGD-p21Ras-scFv could penetrate the cell membrane of colon cancer cells and bind to p21Ras, then led to reduce of p21Ras-GTP (active p21Ras). The phosphorylation of downstream effectors MEK-ERK /PI3K-AKT was downregulated. In vivo antitumor activity assays showed that the RGD-p21Ras-scFv inhibited the proliferation of colorectal cancer cell lines. CONCLUSION: RGD-p21Ras-scFv prokaryotic expressed on pilot-scale could inhibited Ras-driven colorectal cancer growth by partially blocking p21Ras-GTP and might be able to be a hidden therapeutic antibody for treating RAS-driven tumors.

Construction of an economical xylose-utilizing Saccharomyces cerevisiae and its ethanol fermentation.

Traditional industrial Saccharomyces cerevisiae could not metabolize xylose due to the lack of a specific enzyme system for the reaction from xylose to xylulose. This study aims to metabolically remould industrial S. cerevisiae for the purpose of utilizing both glucose and xylose with high efficiency. Heterologous gene xylA from Piromyces and homologous genes related to xylose utilization were selected to construct expression cassettes and integrated into genome. The engineered strain was domesticated with industrial material under optimizing conditions subsequently to further improve xylose utilization rates. The resulting S. cerevisiae strain ABX0928-0630 exhibits a rapid growth rate and possesses near 100% xylose utilization efficiency to produce ethanol with industrial material. Pilot-scale fermentation indicated the predominant feature of ABX0928-0630 for industrial application, with ethanol yield of 0.48 g/g sugars after 48 hours and volumetric xylose consumption rate of 0.87 g/l/h during the first 24 hours. Transcriptome analysis during the modification and domestication process revealed a significant increase in the expression level of pathways associated with sugar metabolism and sugar sensing. Meanwhile, genes related to glycerol lipid metabolism exhibited a pattern of initial increase followed by a subsequent decrease, providing a valuable reference for the construction of efficient xylose-fermenting strains.

A pilot randomised controlled trial of acceptance and commitment therapy for medication decision-making and quality of life in women with breast cancer: The ACTION trial.

OBJECTIVE: Non-adherence to adjuvant endocrine therapy (AET) in women with breast cancer is common and associated with medication side-effects and distress. We co-designed an Acceptance and Commitment Therapy intervention (ACTION) to enhance medication decision-making and quality of life (QoL). We undertook a pilot trial of ACTION to inform the feasibility of a phase III trial, and to examine intervention acceptability. METHODS: This was a multi-site, exploratory, two-arm, individually randomised external pilot trial. Women with early breast cancer prescribed AET were randomised (1:1) to receive usual care (UC) or UC + ACTION. The ACTION intervention comprised a remotely delivered one-to-one ACT session followed by three group sessions delivered by clinical psychologists, alongside a website containing ideas for the self-management of side effects. RESULTS: Of the 480 women screened for eligibility, 260 (54.2%) were approached and 79 (30.4%) randomised. 71 (89.9%) women provided data at 3-month and 70 (88.6%) at 6-month 40 women were randomised to receive UC + ACTION and 32 (80.0%) completed the intervention. Most (75.0%) accessed the website at least once. ACTION was acceptable to participants (Borkovec & Nau Scale: mean = 7.8 [SD = 2.7] out of 10). Signals of effectiveness in favour of the UC + ACTION arm were observed for medication adherence (Adherence Starts with Knowledge questionnaire-12), QoL (work and social adjustment scale), health-related QoL (functional assessment of cancer therapy[FACT] general and FACT-ES-19/23), distress (generalised anxiety disorder -7, patient health questionnaire-9) and psychological flexibility (valuing questionnaire). CONCLUSIONS: The ACTION intervention was acceptable to patients. There were promising signals for effectiveness on primary and secondary outcomes. A phase III randomised controlled trial is feasible. TRIAL REGISTRATION: ISRCTN12027752.

A hybrid approach to sample size re-estimation in cluster randomized trials with continuous outcomes.

This study presents a hybrid (Bayesian-frequentist) approach to sample size re-estimation (SSRE) for cluster randomised trials with continuous outcome data, allowing for uncertainty in the intra-cluster correlation (ICC). In the hybrid framework, pre-trial knowledge about the ICC is captured by placing a Truncated Normal prior on it, which is then updated at an interim analysis using the study data, and used in expected power control. On average, both the hybrid and frequentist approaches mitigate against the implications of misspecifying the ICC at the trial's design stage. In addition, both frameworks lead to SSRE designs with approximate control of the type I error-rate at the desired level. It is clearly demonstrated how the hybrid approach is able to reduce the high variability in the re-estimated sample size observed within the frequentist framework, based on the informativeness of the prior. However, misspecification of a highly informative prior can cause significant power loss. In conclusion, a hybrid approach could offer advantages to cluster randomised trials using SSRE. Specifically, when there is available data or expert opinion to help guide the choice of prior for the ICC, the hybrid approach can reduce the variance of the re-estimated required sample size compared to a frequentist approach. As SSRE is unlikely to be employed when there is substantial amounts of such data available (ie, when a constructed prior is highly informative), the greatest utility of a hybrid approach to SSRE likely lies when there is low-quality evidence available to guide the choice of prior.

Feasibility of a clinic-based, multicomponent hydroxyurea adherence intervention for adolescents and young adults with sickle cell disease.

Despite the effectiveness of hydroxyurea, adherence remains low for adolescents and young adults (AYA) living with sickle cell disease (SCD). This study evaluated the feasibility, acceptability, and initial efficacy of a clinic-based, multicomponent (e.g., storytelling, problem solving) intervention with 20 AYA living with SCD. Results found that adherence significantly improved from intervention to follow-up 1 [t(19) = -2.213, p = .039]. AYA also were generally satisfied with the intervention. These findings, although promising, should be replicated on a larger scale.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD). OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

Thermodynamic Inhibition of Microbial Sulfur Disproportionation in a Multisubunit Designed Sulfur-Siderite Packed Bioreactor.

Sulfur disproportionation (S0DP) poses a challenge to the robust application of sulfur autotrophic denitrification due to unpredictable sulfide production, which risks the safety of downstream ecosystems. This study explored the S0DP occurrence boundaries with nitrate loading and temperature effects. The boundary values increased with the increase in temperature, exhibiting below 0.15 and 0.53 kg-N/m3/d of nitrate loading at 20 and 30 °C, respectively. A pilot-scale sulfur-siderite packed bioreactor (150 m3/d treatment capacity) was optimally designed with multiple subunits to dynamically distribute the loading of sulfur-heterologous electron acceptors. Operating two active and one standby subunit achieved an effective denitrification rate of 0.31 kg-N/m3/d at 20 °C. For the standby subunit, involving oxygen by aeration effectively transformed the facultative S0DP functional community from S0DP metabolism to aerobic respiration, but with enormous sulfur consumption resulting in ongoing sulfate production of over 3000 mg/L. Meanwhile, acidification by the sulfur oxidation process could reduce the pH to as low as 2.5, which evaluated the Gibbs free energy (ΔG) of the S0DP reaction to +2.56 kJ, thermodynamically suppressing the S0DP occurrence. Therefore, a multisubunit design along with S0DP inhibition strategies of short-term aeration and long-term acidification is suggested for managing S0DP in various practical sulfur-packed bioreactors.

Energetic Comparison of Flow-Electrode Capacitive Deionization and Membrane Technology: Assessment on Applicability in Desalination Fields.

Flow-electrode capacitive deionization (FCDI) is a promising technology for sustainable water treatment. However, studies on the process have thus far been limited to lab-scale conditions and select fields of application. Such limitation is induced by several shortcomings, one of which is the absence of a comprehensive process model that accurately predicts the operational performance and the energy consumption of FCDI. In this study, a simulation model is newly proposed with initial validation based on experimental data and is then utilized to elucidate the performance and the specific energy consumption (SEC) of FCDI under multiple source water conditions ranging from near-groundwater to high salinity brine. Further, simulated pilot-scale FCDI system was compared with actual brackish water reverse osmosis (BWRO) and seawater reverse osmosis (SWRO) plant data with regard to SEC to determine the feasibility of FCDI as an alternative to the conventional membrane processes. Analysis showed that FCDI is competent for operation against brackish water solutions under all possible operational conditions with respect to the BWRO. Moreover, its distinction can be extended to the SWRO for seawater conditions through optimization of its total effective membrane area via scale-up. Accordingly, future directions for the advancement of FCDI was suggested to ultimately prompt the commercialization of the FCDI process.

Sorting Out the Latest Advances in Separators and Pilot-Scale Microbial Electrochemical Systems for Wastewater Treatment: Concomitant Development, Practical Application, and Future Perspective.

To date, dozens of pilot-scale microbial fuel cell (MFC) devices have been successfully developed worldwide for treating various types of wastewater. The availability and configurations of separators are determining factors for the economic feasibility, efficiency, sustainability, and operability of these devices. Thus, the concomitant advances between the separators and pilot-scale MFC configurations deserve further clarification. The analysis of separator configurations has shown that their evolution proceeds as follows: from ion-selective to ion-non-selective, from nonpermeable to permeable, and from abiotic to biotic. Meanwhile, their cost is decreasing and their availability is increasing. Notably, the novel MFCs configured with biotic separators are superior to those configured with abiotic separators in terms of wastewater treatment efficiency and capital cost. Herein, a highly comprehensive review of pilot-scale MFCs (>100 L) has been conducted, and we conclude that the intensive stack of the liquid cathode configuration is more advantageous when wastewater treatment is the highest priority. The use of permeable biotic separators ensures hydrodynamic continuity within the MFCs and simplifies reactor configuration and operation. In addition, a systemic comparison is conducted between pilot-scale MFC devices and conventional decentralized wastewater treatment processes. MFCs showed comparable cost, higher efficiency, long-term stability, and significant superiority in carbon emission reduction. The development of separators has greatly contributed to the availability and usability of MFCs, which will play an important role in various wastewater treatment scenarios in the future.

Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

OBJECTIVES: Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth but current evidence on dosing, candidacy, and outcomes are limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. METHODS: This single-centre, open-label, pilot phase 1 safety and feasibility clinical trial included 25 pregnant individuals with a fetal diagnosis of SVP. Participants self-administered continuous supplemental oxygen using medical-grade oxygen concentrators for up to 24 hours per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation by echocardiography and late-gestational cardiovascular magnetic resonance, early outcomes including brain growth and pre-operative brain injury, and 18-month neurodevelopmental outcomes by the Bayley Scales of Infant and Toddler Development 3rd Edition compared to a contemporary fetal SVP cohort that received standard of care (SOC). RESULTS: Among 25 participants, the average maternal age at conception was 35 years, and fetal SVP diagnoses included 16 right ventricle dominant, 8 left ventricle dominant, and 1 indeterminant ventricular morphology. Participants started the trial at approximately 29.3 gestational weeks and took MSO for a median 16.1 hours per day for 63 days, cumulating a median 1029 hours of oxygen intake from enrollment until delivery. The only treatment-associated adverse events were nasal complications that were typically resolved by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio, nor head circumference to abdominal circumference ratio Z-scores over gestation compared to SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over gestation compared to SOC (p=0.02), this was likely due to initial baseline differences in placental resistance. At late-gestational cardiovascular magnetic resonance, MSO was not associated with any significant increase in umbilical vein oxygen saturation, fetal oxygen delivery, or fetal cerebral oxygen delivery. Similarly, we observed no differences in newborn outcomes including brain volume and pre-operative brain injury, nor mortality by 18 months of age, nor neurodevelopmental outcomes at 18 months of age. CONCLUSIONS: This pilot phase 1 clinical trial indicates low-dose maternal supplemental oxygen therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with any significant changes in fetal circulatory physiology or improvements in early neurologic or neurodevelopmental outcomes. This article is protected by copyright. All rights reserved.

Perioperative randomised controlled trials: to pilot or not to pilot?

The science of pilot trials is evolving, and understanding of their role in medical research is increasing. Perioperative randomised controlled trials often test interventions that are inherently multidisciplinary and complex; therefore, there might be compelling reasons to conduct pilot studies to assess feasibility and inform trial design. As pilot studies themselves require resources, investigators should not squander this opportunity; they should design them so that they properly address the sources of uncertainty regarding the success of the definitive trial.

Personalised perioperative dosing of ivabradine in noncardiac surgery: a single-centre, randomised, placebo-controlled, double-blind feasibility pilot trial.

BACKGROUND: Perioperative myocardial injury after noncardiac surgery is associated with postoperative mortality. Heart rate (HR) is an independent risk factor for perioperative myocardial injury. In this pilot trial we tested the feasibility of a randomised, placebo-controlled trial of personalised HR-targeted perioperative ivabradine. METHODS: This was a single-centre, randomised, placebo-controlled, double-blind, parallel group, feasibility pilot trial conducted at Geneva University Hospitals. We included patients ≥75 yr old or ≥45 yr old with cardiovascular risk factors planned for intermediate- or high-risk surgery. Patients were randomised to receive ivabradine (2.5, 5.0, or 7.5 mg) or placebo according to their HR, twice daily, from the morning of surgery until postoperative day 2. Primary outcomes were appropriate dosage and blinding success rates. RESULTS: Between October 2020 and January 2022, we randomised 78 patients (recruitment rate of 1.3 patients week-1). Some 439 of 444 study drug administrations were adequate (99% appropriate dosage rate). The blinding success rate was 100%. There were 137 (31%) administrations of Pill A (placebo in both groups for HR ≤70 beats min-1). Nine (11.5%) patients had a high-sensitive cardiac troponin T elevation ≥14 ng L-1 between any two measurements. The number of bradycardia episodes was eight in the placebo group and nine in the ivabradine group. CONCLUSIONS: This pilot study demonstrates the feasibility of, and provides guidance for, a future trial testing the efficacy of personalised perioperative ivabradine. Future studies should include patients at higher risk of cardiac complications. CLINICAL TRIAL REGISTRATION: NCT04436016.

The dermatopathologist-patient consultation program: A pilot study on patient perspectives and interest.

BACKGROUND: Despite the integral contribution of dermatopathologists in diagnosing skin lesions, their role often remains unclear to patients, likely due to little face-to-face interaction. More healthcare systems have begun introducing patient-pathologist consultation programs that allow patients to discuss results with a pathologist and view tissue under a microscope. To our knowledge, only one study has been published exploring patient perspectives of these programs and no studies exist regarding interest in dermatopathology. METHODS: An anonymous survey was distributed via online support groups for various dermatologic diagnoses. RESULTS: Patients demonstrated a high level of interest in the dermatopathologist-patient consultation program, with 81.3% expressing at least moderate interest in discussing their diagnosis with a dermatopathologist and 79.2% expressing at least moderate interest in examining their tissue under the microscope with a dermatopathologist. The rationale for interest included various themes: (1) knowledge/understanding, (2) empowerment, (3) emotional support, (4) general interest, and (5) improved trust. CONCLUSIONS: Patients with cancerous and non-cancerous dermatologic diagnoses demonstrate high interest in a dermatopathologist-patient consultation program. Efforts to pilot this type of program can build upon the infrastructure of current pathologist consultation programs. Future efforts should be taken by hospital leadership, clinicians, and dermatopathologists to determine physician interest and address logistical challenges to the implementation of these programs.