LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

Assessment of a Non-Invasive Brain Pulse Monitor to Measure Intra-Cranial Pressure Following Acute Brain Injury.

Background: Intracranial pressure (ICP) monitoring requires placing a hole in the skull through which an invasive pressure monitor is inserted into the brain. This approach has risks for the patient and is expensive. We have developed a non-invasive brain pulse monitor that uses red light to detect a photoplethysmographic (PPG) signal arising from the blood vessels on the brain's cortical surface. The brain PPG and the invasive ICP waveform share morphological features which may allow measurement of the intracranial pressure. Methods: We enrolled critically ill patients with an acute brain injury with invasive ICP monitoring to assess the new monitor. A total of 24 simultaneous invasive ICP and brain pulse monitor PPG measurements were undertaken in 12 patients over a range of ICP levels. Results: The waveform morphologies were similar for the invasive ICP and brain pulse monitor PPG approach. Both methods demonstrated a progressive increase in the amplitude of P2 relative to P1 with increasing ICP levels. An automated algorithm was developed to assess the PPG morphological features in relation to the ICP level. A correlation was demonstrated between the brain pulse waveform morphology and ICP levels, R2=0.66, P < 0.001. Conclusion: The brain pulse monitor's PPG waveform demonstrated morphological features were similar to the invasive ICP waveform over a range of ICP levels, these features may provide a method to measure ICP levels. Trial Registration: ACTRN12620000828921.

Identification of ß-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions.

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of ß-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 ß-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of ß-lactams screened were active against Mtb, many without a ß-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.

Facilitators and barriers to pediatric clinical trial recruitment and retention in rural and community settings: A scoping review of the literature.

Children in rural settings are under-represented in clinical trials, potentially contributing to rural health disparities. We performed a scoping review describing available literature on barriers and facilitators impacting participation in pediatric clinical trials in rural and community-based (nonclinical) settings. Articles identified via PubMed, CINAHL, Embase, and Web of Science were independently double-screened at title/abstract and full-text levels to identify articles meeting eligibility criteria. Included articles reported on recruitment or retention activities for US-based pediatric clinical studies conducted in rural or community-based settings and were published in English through January 2021. Twenty-seven articles describing 31 studies met inclusion criteria. Most articles reported on at least one study conducted in an urban or suburban or unspecified community setting (n = 23 articles; 85%); fewer (n = 10; 37%) reported on studies that spanned urban and rural settings or were set in rural areas. More studies discussed recruitment facilitators (n = 25 studies; 81%) and barriers (n = 19; 61%) versus retention facilitators (n = 15; 48%) and barriers (n = 8; 26%). Descriptions of recruitment and retention barriers and facilitators were primarily experiential or subjective. Recruitment and retention facilitators were similar across settings and included contacts/reminders, community engagement, and relationship-building, consideration of participant logistics, and incentives. Inadequate staff and resources were commonly cited recruitment and retention barriers. Few studies have rigorously examined optimal ways to recruit and retain rural participants in pediatric clinical trials. To expand the evidence base, future studies examining recruitment and retention strategies should systematically assess and report rurality and objectively compare relative impact of different strategies.

Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment.

The receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical. We have applied a state-of-the-art, multi-modal imaging platform to assess the in vivo effects of pharmacological inhibition of MERTK in mice. This involved the application of mass spectrometry imaging (MSI) to characterize the ocular spatial distribution of our highly selective MERTK inhibitor; AZ14145845, together with histopathology and transmission electron microscopy to characterize pathological and ultra-structural change in response to MERTK inhibition. In addition, we assessed the utility of a human retinal in vitro cell model to identify perturbation of phagocytosis post MERTK inhibition. We identified high localized total compound concentrations in the retinal pigment epithelium (RPE) and retinal lesions following 28 days of treatment with AZ14145845. These lesions were present in 4 of 8 treated animals, and were characterized by a thinning of the outer nuclear layer, loss of photoreceptors (PR) and accumulation of photoreceptor outer segments at the interface of the RPE and PRs. Furthermore, the lesions were very similar to that shown in the RCS rat and MERTK knock-out mouse, suggesting a MERTK-induced mechanism of PR cell death. This was further supported by the observation of reduced phagocytosis in the human retinal cell model following treatment with AZ14145845. Our study provides a viable, translational strategy to investigate the pre-clinical toxicity of MERTK inhibitors but is equally transferrable to novel chemotypes.

Best Practices for Conducting Clinical Trials With Indigenous Children in the United States.

We provide guidance for conducting clinical trials with Indigenous children in the United States. We drew on extant literature and our experience to describe 3 best practices for the ethical and effective conduct of clinical trials with Indigenous children. Case examples of pediatric research conducted with American Indian, Alaska Native, and Native Hawaiian communities are provided to illustrate these practices. Ethical and effective clinical trials with Indigenous children require early and sustained community engagement, building capacity for Indigenous research, and supporting community oversight and ownership of research. Effective engagement requires equity, trust, shared interests, and mutual benefit among partners over time. Capacity building should prioritize developing Indigenous researchers. Supporting community oversight and ownership of research means that investigators should plan for data-sharing agreements, return or destruction of data, and multiple regulatory approvals. Indigenous children must be included in clinical trials to reduce health disparities and improve health outcomes in these pediatric populations. Establishment of the Environmental Influences on Child Health Outcomes Institutional Development Award States Pediatric Clinical Trials Network (ECHO ISPCTN) in 2016 creates a unique and timely opportunity to increase Indigenous children's participation in state-of-the-art clinical trials.

A continuous-time Markov model for estimating readmission risk for hospital inpatients.

Research concerning hospital readmissions has mostly focused on statistical and machine learning models that attempt to predict this unfortunate outcome for individual patients. These models are useful in certain settings, but their performance in many cases is insufficient for implementation in practice, and the dynamics of how readmission risk changes over time is often ignored. Our objective is to develop a model for aggregated readmission risk over time - using a continuous-time Markov chain - beginning at the point of discharge. We derive point and interval estimators for readmission risk, and find the asymptotic distributions for these probabilities. Finally, we validate our derived estimators using simulation, and apply our methods to estimate readmission risk over time using discharge and readmission data for surgical patients.

Laboratory Demonstration and Preliminary Techno-Economic Analysis of an Onsite Wastewater Treatment System.

Providing safe and reliable sanitation services to the billions of people currently lacking them will require a multiplicity of approaches. Improving onsite wastewater treatment to standards enabling water reuse would reduce the need to transport waste and fresh water over long distances. Here, we describe a compact, automated system designed to treat the liquid fraction of blackwater for onsite water reuse that combines cross-flow ultrafiltration, activated carbon, and electrochemical oxidation. In laboratory testing, the system consistently produces effluent with 6 ≤ pH ≤ 9, total suspended solids (TSS) < 30 mg L-1, and chemical oxygen demand (COD) < 150 mg L-1. These effluent parameters were achieved across a wide range of values for influent TSS (61-820 mg L-1) and COD (384-1505 mg L-1), demonstrating a robust system for treating wastewater of varying strengths. A preliminary techno-economic analysis (TEA) was conducted to elucidate primary cost drivers and prioritize research and development pathways toward commercial feasibility. The ultrafiltration system is the primary cost driver, contributing to >50% of both the energy and maintenance costs. Several scenario parameters showed an outsized impact on costs relative to technology parameters. Specific technological improvements for future prototype development are discussed.

IDeA States Pediatric Clinical Trials Network for Underserved and Rural Communities.

The National Institutes of Health's Environmental Influences on Child Health Outcomes (ECHO) program aims to study high-priority and high-impact pediatric conditions. This broad-based health initiative is unique in the National Institutes of Health research portfolio and involves 2 research components: (1) a large group of established centers with pediatric cohorts combining data to support longitudinal studies (ECHO cohorts) and (2) pediatric trials program for institutions within Institutional Development Awards states, known as the ECHO Institutional Development Awards States Pediatric Clinical Trials Network (ISPCTN). In the current presentation, we provide a broad overview of the ISPCTN and, particularly, its importance in enhancing clinical trials capabilities of pediatrician scientists through the support of research infrastructure, while at the same time implementing clinical trials that inform future health care for children. The ISPCTN research mission is aligned with the health priority conditions emphasized in the ECHO program, with a commitment to bringing state-of-the-science trials to children residing in underserved and rural communities. ISPCTN site infrastructure is critical to successful trial implementation and includes research training for pediatric faculty and coordinators. Network sites exist in settings that have historically had limited National Institutes of Health funding success and lacked pediatric research infrastructure, with the initial funding directed to considerable efforts in professional development, implementation of regulatory procedures, and engagement of communities and families. The Network has made considerable headway with these objectives, opening two large research studies during its initial 18 months as well as producing findings that serve as markers of success that will optimize sustainability.

PET Imaging of T Cells: Target Identification and Feasibility Assessment.

Imaging T cells using positron emission tomography (PET) would be highly useful for diagnosis and monitoring in immunology and oncology patients. There are, however, no obvious targets that can be used to develop imaging agents for this purpose. We evaluated several potential target proteins with selective expression in T cells, and for which lead molecules were available: protein kinase C isozyme θ (PKC θ), lymphocyte-specific protein tyrosine kinase (Lck), zeta-chain-associated protein kinase 70 (ZAP70), and interleukin-2-inducible T-cell kinase (Itk). Ultimately, we focused on Itk and identified a tool molecule with properties suitable for in vivo imaging of T cells: (5aR)-5,5-difluoro-5a-methyl-N-(1-((S)-3-(methylsulfonyl)phenyl)(tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide (23). Although it does not have the optimal profile for clinical use, this molecule indicates that it might be possible to develop Itk-selective PET ligands for imaging the distribution of T cells in patients.

An evaluation of the fixed concentration procedure for assessment of acute inhalation toxicity.

Acute inhalation studies are conducted in animals as part of chemical hazard identification and for classification and labelling. Current methods employ death as an endpoint (Organisation for Economic Co-operation and Development (OECD) test guideline (TG) 403 and TG436) while the recently approved fixed concentration procedure (FCP) (OECD TG433) uses fewer animals and replaces lethality as an endpoint with evident toxicity. Evident toxicity is the presence of clinical signs that predict that exposure to the next highest concentration will cause severe toxicity or death in most animals. Approval of TG433 was the result of an international initiative, led by the National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs), which collected data from six laboratories on clinical signs recorded for inhalation studies on 172 substances. This paper summarises previously published data and describes the additional analyses of the dataset that were essential for approval of the TG.

Plastic pollution in the Labrador Sea: An assessment using the seabird northern fulmar Fulmarus glacialis as a biological monitoring species.

Plastic is now one among one of the most pervasive pollutants on the planet, and ocean circulation models predict that the Arctic will become another accumulation zone. As solutions to address marine plastic emerge, is essential that baselines are available to monitor progress towards targets. The northern fulmar (Fulmarus glacialis), a widely-distributed seabird species, has been used as a biological monitor for plastic pollution in the North Sea, and could be a useful monitoring species elsewhere. We quantified plastic ingested by northern fulmars from the southeastern Canadian waters of the Labrador Sea with the objective of establishing a standardized baseline for future comparisons. Over two years we sampled 70 fulmars and found that 79% had ingested plastic, with an average of 11.6 pieces or 0.151g per bird. Overall, 34% of all fulmars exceeded the Ecological Quality Objective for marine litter, having ingested >0.1g of plastic.

Communities ready for takeoffIntegrating social assets for biofuel site-selection modeling.

Although much of the social science literature supports the importance of community assets for success in many policy areas, these assets are often overlooked when selecting communities for new infrastructure facilities. Extensive collaboration is crucial for the success of environmental and economic projects, yet it often is not adequately addressed when making siting decisions for new projects. This article develops a social asset framework that includes social, creative, and human capital to inform site-selection decisions. This framework is applied to the Northwest Advanced Renewables Alliance project to assess community suitability for biofuel-related developments. This framework is the first to take all necessary community assets into account, providing insight into successful site selection beyond current models. The framework not only serves as a model for future biorefinery projects but also guides tasks that depend on informed location selection for success.

Anther smuts of Silene acaulis and S. uniflora in the Outer Hebrides, including an assessment of ITS genotypes of Microbotryum silenes-acaulis.

Anther smuts on Silene acaulis and S. uniflora from the Outer Hebrides, Scotland, UK), are analysed using morphological and molecular techniques, and found to represent Microbotryum silenes-acaulis and M. silenes-inflatae, respectively. This is the first identification of caryophyllaceous anther smuts in the Outer Hebrides according to modern species concepts and the first report of Microbotryum silenes-acaulis confirmed by molecular analysis from the British Isles. Additionally, the genetic structure of Microbotryum silenes-acaulis, based on all currently available ITS sequences, is analysed and discussed. Seven ITS genotypes are determined for Microbotryum silenes-acaulis, including three genotypes in North America and four genotypes in Europe. Compared to European accessions, all North American accessions share specific nucleotides and are genetically divergent.

Regional Assessment of Human Fecal Contamination in Southern California Coastal Drainages.

Host-associated genetic markers that allow for fecal source identification have been used extensively as a diagnostic tool to determine fecal sources within watersheds, but have not been used in routine monitoring to prioritize remediation actions among watersheds. Here, we present a regional assessment of human marker prevalence among drainages that discharge to the U.S. southern California coast. Approximately 50 samples were analyzed for the HF183 human marker from each of 22 southern California coastal drainages under summer dry weather conditions, and another 50 samples were targeted from each of 23 drainages during wet weather. The HF183 marker was ubiquitous, detected in all but two sites in dry weather and at all sites during wet weather. However, there was considerable difference in the extent of human fecal contamination among sites. Similar site ranking was produced regardless of whether the assessment was based on frequency of HF183 detection or site average HF183 concentration. However, site ranking differed greatly between dry and wet weather. Site ranking also differed greatly when based on enterococci, which do not distinguish between pollution sources, vs. HF183, which distinguishes higher risk human fecal sources from other sources, indicating the additional value of the human-associated marker as a routine monitoring tool.

Biochemical Screening for Nonadherence Is Associated With Blood Pressure Reduction and Improvement in Adherence.

We hypothesized that screening for nonadherence to antihypertensive treatment using liquid chromatography-tandem mass spectrometry-based biochemical analysis of urine/serum has therapeutic applications in nonadherent hypertensive patients. A retrospective analysis of hypertensive patients attending specialist tertiary care centers was conducted in 2 European countries (United Kingdom and Czech Republic). Nonadherence to antihypertensive treatment was diagnosed using biochemical analysis of urine (United Kingdom) or serum (Czech Republic). These results were subsequently discussed with each patient, and data on follow-up clinic blood pressure (BP) measurements were collected from clinical files. Of 238 UK patients who underwent biochemical urine analysis, 73 were nonadherent to antihypertensive treatment. Their initial urinary adherence ratio (the ratio of detected to prescribed antihypertensive medications) increased from 0.33 (0-0.67) to 1 (0.67-1) between the first and the last clinic appointments. The observed increase in the urinary adherence ratio in initially nonadherent UK patients was associated with the improved BP control; by the last clinic appointment, systolic and diastolic BPs were ≈19.5 and 7.5 mm Hg lower than at baseline (P=0.001 and 0.009, respectively). These findings were further corroborated in 93 nonadherent hypertensive patients from Czech Republic-their average systolic and diastolic BPs dropped by ≈32.6 and 17.4 mm Hg, respectively (P<0.001), on appointments after the biochemical analysis. Our data show that nonadherent hypertensive patients respond to liquid chromatography-tandem mass spectrometry-based biochemical analysis with improved adherence and significant BP drop. Such repeated biochemical analyses should be considered as a therapeutic approach in nonadherent hypertensive patients.

Communities ready for takeoff.

Although much of the social science literature supports the importance of community assets for success in many policy areas, these assets are often overlooked when selecting communities for new infrastructure facilities. Extensive collaboration is crucial for the success of environmental and economic projects, yet it often is not adequately addressed when making siting decisions for new projects. This article develops a social asset framework that includes social, creative, and human capital to inform site-selection decisions. This framework is applied to the Northwest Advanced Renewables Alliance project to assess community suitability for biofuel-related developments. This framework is the first to take all necessary community assets into account, providing insight into successful site selection beyond current models. The framework not only serves as a model for future biorefinery projects but also guides tasks that depend on informed location selection for success.