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The professional identity of scientists has historically been cultivated to value research over teaching, which can undermine initiatives that aim to reform science education. Course-Based Research Experiences (CRE) and the inclusive Research and Education Communities (iREC) are two successful and impactful reform efforts that integrate research and teaching. The aim of this study is to explicate the professional identity of instructors who implement a CRE within an established iREC and to explore how this identity contributes to the success of these programs. 97 CRE instructors from the Science Education Alliance (SEA) iREC participated in a 2-year, multi-stage, qualitative research project that involved weekly reflective journaling, autoethnographic description, small group evaluation and writing, and large-scale community checking. The resulting description of professional identity consisted of shared values (inclusivity, student success, community membership, ownership/agency, science, overcoming failure, and persistence), specified roles (mentor, advocate, scientist, educator, motivator, collaborator, community builder, learner, evaluator and project manager) and a stated sense of self (dedicated, resilient, pride in students, multiskilled, valued, community member, responsible and overworked). Analysis of individual reflective diary entries revealed how a professional identity underpinned and facilitated the ways in which faculty addressed challenges that arose and worked toward the success of every student. It is the self-concept of the professional identity of the instructor in the context of the CRE classroom that directed the extended commitment and effort that these instructors evidently put into their work with students, which facilitated student engagement, student persistence, and their collective scientific output. The study concludes that a professional identity of STEM faculty in the context of a CRE and iREC combines being a researcher and educator, and that this integrated identity is central for current initiatives aimed at transforming undergraduate STEM education.

Abstract Evidence for seed transmission of phytoplasmas has grown in several pathosystems including coconut (Cocos nucifera). Bogia coconut syndrome (BCS) is a disease associated with the lethal yellowing syndrome associated with the presence of ‘Candidatus Phytoplasma noviguineense’ that affects coconut, betel nut (Areca catechu) and bananas (Musa spp.) in Papua New Guinea. Coconut and betel nut drupes were sampled from BCS-infected areas in Papua New Guinea, dissected, the extracted nucleic acid was used in polymerase chain reaction (PCR), and loop mediated isothermal amplification (LAMP) used to check for presence of phytoplasma DNA. In a second study, drupes of both plant species were collected from multiple field sites and grown in insect-proof cages. Leaf samples taken at 6 months were also tested with PCR and LAMP. The studies of dissected coconut drupes detected phytoplasma DNA in several tissues including the embryo. Drupes from betel nut tested negative. Among the seedlings, evidence of possible seed transmission was found in both plant species. The results demonstrate the presence of ‘Ca. P. noviguineense’ in coconut drupes and seedlings, and in seedlings of betel nut; factors that need to be considered in ongoing management and containment efforts.

Abstract The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in creating single-stranded DNA gaps and inducing sensitivity requires the FANCJ DNA helicase. Yet, how FANCJ relates to PARP1 inhibition or trapping, which contribute to PARPi toxicity, remains unclear. Here, we find PARPi effectiveness hinges on S-phase PARP1 activity, which is reduced in FANCJ deficient cells as G-quadruplexes sequester PARP1 and MSH2. Additionally, loss of the FANCJ-MLH1 interaction diminishes PARP1 activity; however, depleting MSH2 reinstates PARPi sensitivity and gaps. Indicating sequestered and trapped PARP1 are distinct, FANCJ loss increases PARPi resistance in cells susceptible to PARP1 trapping. However, with BRCA1 deficiency, the loss of FANCJ mirrors PARP1 loss or inhibition, with the detrimental commonality being loss of S-phase PARP1 activity. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA1 deficient cells and emphasize the importance of understanding drug mechanisms for enhancing therapeutic response.

Abstract Background Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. Methods The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. Results Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. Conclusions We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

In this study, we examined the impact of the number and type of arterial grafts, and surgical dressing type, on deep and organ/space surgical site infection following coronary artery bypass graft procedures. Bilateral internal mammary artery grafts and negative pressure wound therapy were associated with higher odds of infection.

Amongst the many treatments available for the removal of emerging contaminants in wastewater, microalgal cultures have been shown to be effective. However, the effectiveness of exposure of a native microalgal consortium to emerging contaminants such as bisphenol-A (BPA) and triclosan (TCS) to determine the half-maximum effective concentrations (EC50) has not yet been determined. The effect on growth and nutrient removal of such a treatment as well as on the production of biomolecules such as carbohydrates, lipids, and proteins are, at present, unknown. In this study, the EC50 of BPA and TCS (96-hour experiments) was determined using a consortium of native microalgae (Scenedesmus obliquus and Desmodesmus sp.) to define the maximum tolerance to these contaminants. The effect of BPA and TCS in synthetic wastewater (SWW) was investigated in terms of microalgal growth, chlorophyll a (Chl-a), carbohydrate, lipid, and protein content, as well as nutrient removal. Assays were performed in heterotrophic conditions (12/12 light/dark cycles). EC50-96 h values of 17 mg/L and 325 µg/L for BPA and TCS, respectively, were found at 72 h. For an initial microalgal inoculum of ≈ 300 mg TSS/L (total suspended solids per litre), growth increased by 16.1% when exposed to BPA and 17.78% for TCS. At ≈ 500 mg TSS/L, growth increased by 8.25% with BPA and 9.92% with TCS, respectively. At the EC50-96 h concentrations determined in the study, BPA and TCS did not limit the growth of microalgae in wastewater. Moreover, they were found to stimulate the content of Chl-a, carbohydrates, lipids, proteins, and enhance nutrient removal. Availability of data and material: Data sharing not applicable to this article as no datasets were generated or analysed during the present study.

Abstract Background The sources of information on clinical trial monitoring do not give information in an accessible language and do not give detailed guidance. In order to enable communication and to build clinical trial monitoring tools on a strong easily communicated foundation, we identified the need to define monitoring in accessible language. Methods In a three-step process, the material from sources that describe clinical trial monitoring were synthesised into principles of monitoring. A poll regarding their applicability was run at a UK national academic clinical trials monitoring meeting. Results The process derived 5 key principles of monitoring: keeping participants safe and respecting their rights, having data we can trust, making sure the trial is being run as it was meant to be, improving the way the trial is run and preventing problems before they happen. Conclusion From the many sources mentioning monitoring of clinical trials, the purpose of monitoring can be summarised simply as 5 principles. These principles, given in accessible language, should form a firm basis for discussion of monitoring of clinical trials.

Abstract Background Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. Methods Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. Results We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. Discussion Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently.

Abstract Both TP53 and ESR1 mutations occur frequently in estrogen receptor positive (ER+) metastatic breast cancers (MBC) and their distinct roles in breast cancer tumorigenesis and progression are well appreciated. Recent clinical studies discovered mutual exclusivity between TP53 and ESR1 mutations in metastatic breast cancers; however, mechanisms underlying this intriguing clinical observation remain largely understudied and unknown. Here, we explored the interplay between TP53 and ESR1 mutations using publicly available clinical and experimental data sets. We first confirmed the robust mutational exclusivity using six independent cohorts with 1,056 ER+ MBC samples and found that the exclusivity broadly applies to all ER+ breast tumors regardless of their clinical and distinct mutational features. ESR1 mutant tumors do not exhibit differential p53 pathway activity, whereas we identified attenuated ER activity and expression in TP53 mutant tumors, driven by a p53-associated E2 response gene signature. Further, 81% of these p53-associated E2 response genes are either direct targets of wild-type (WT) p53-regulated transactivation or are mutant p53-associated microRNAs, representing bimodal mechanisms of ER suppression. Lastly, we analyzed the very rare cases with co-occurrences of TP53 and ESR1 mutations and found that their simultaneous presence was also associated with reduced ER activity. In addition, tumors with dual mutations showed higher levels of total and PD-L1 positive macrophages. In summary, our study utilized multiple publicly available sources to explore the mechanism underlying the mutual exclusivity between ESR1 and TP53 mutations, providing further insights and testable hypotheses of the molecular interplay between these two pivotal genes in ER+ MBC.

The coronavirus disease 2019 (COVID-19) pandemic highlighted the lack of agreement regarding the definition of aerosol-generating procedures and potential risk to healthcare personnel. We convened a group of Massachusetts healthcare epidemiologists to develop consensus through expert opinion in an area where broader guidance was lacking at the time.

Background: The World Health Organization estimates that between 80,000 and 180,000 medical personnel perished as a result of COVID-19. Although studies about nurses’ organizational commitment during the COVID-19 pandemic have been conducted, the sources of motivations and resilience strategies of nurses in providing a quality healthcare service amidst the COVID-19 pandemic have yet to be explored. Objective: This study aimed to investigate how motivation and resilience influence nurses to serve and cater to patients during the COVID-19 pandemic. Methods: A sequential exploratory mixed approach was used in this study between July and August 2022. The Connor-Davidson Resilience Scale (CD-RISC-10), Work Extrinsic and Intrinsic Motivations scale (WEIMS), and Garbee and Killacky’s Intent to Stay Scale (GKISS) were used to measure resilience, motivation, and intention to stay, among 50 nurses within Metro Manila. Quantitative data were analyzed using quantile regression, while qualitative data from eight participants were analyzed using thematic analysis. Results: The majority of the nurses were working 12 hours and above (52%) and earning a bi-weekly income of PHP 15,001 to 20,000 (96%). The GKISS scores of most respondents indicated their likelihood of remaining in their current profession was moderately low (Mdn = 12.5; IQR = 12-14). It was also found that there was no sufficient statistical evidence to conclude that intention to stay was associated with resilience (p = 0.914) and work motivation (p = 0.560). The qualitative strand of this study explored the significant influences of motivation, resilience strategies, and sources of intention to stay among Filipino nurses while facing the COVID-19 pandemic. The primary motivations of nurses lie in family, passion for work, and career development, while the resilience strategies include adaptiveness, time management skills, and self-fulfillments. On the other hand, the intent to stay greatly lies in serving the people and the country. Conclusion: This study concludes that positive and negative resilience and motivations from different facets of the social life of Filipino nurses, including passion, familial ties, patient care, and faith are the antecedents influencing the intention to serve in the healthcare service. In terms of staying for an extended period in a nursing career, the study found that institutionalized interventions, adequate compensation and benefits, and a good workplace are determinants of staying longer in the Philippines as Filipino nurses.

Abstract Background A promising approach to reduce the increasing costs of clinical trials is the use of routinely collected health data as participant data. However, the quality of this data could limit its usability as trial participant data. Methods The BOSS trial is a randomised controlled trial comparing regular endoscopies versus endoscopies at need in patients with Barrett’s oesophagus with primary endpoint death. Data on death and cancer collected every 2 years after randomisation (trial-specific data) were compared to data received annually (all patients on one date) from the routinely collected health data source National Health Service (NHS) Digital. We investigated completeness, agreement and timeliness and looked at the implications for the primary trial outcome. Completeness and agreement were assessed by evaluating the number of reported and missing cases and any disparities between reported dates. Timeliness was considered by graphing the year a death was first reported in the trial-specific data against that for NHS Digital data. Implications on the primary trial outcome, overall survival, of using one of the data sources alone were investigated using Kaplan-Meier graphs. To assess the utility of cause of death and cancer diagnoses, oesophageal cancer cases were compared. Results NHS Digital datasets included more deaths and often reported them sooner than the trial-specific data. The number reported as being from oesophageal cancer was similar in both datasets. Due to time lag in reporting and missing cases, the event rate appeared higher using the NHS Digital data. Conclusion NHS Digital death data is useful for calculating overall survival where trial-specific follow-up is only every 2 years from randomisation and the follow-up requires patient response. The cancer data was not a large enough sample to assess usability. We suggest that this assessment of registry data is done for more phase III RCTs and for more registry data to get a more complete picture of when RCHD would be useful in phase III RCT. Trial registration ISRCTN54190466 (BOSS) 1 Oct 2009.

The authors, representing community practitioners, faculty, students, and administration, collaborated to produce guidelines for university-community partnerships that reflect social work’s commitment to social justice in practice, education, and research. The respective experiences and voices of the authors contribute to a wider perspective on the explicit social justice implications of partnership formation for community-based participatory research, which is a vision shared by many disciplines. These guidelines introduce a communication outline that may augment the creation and maintenance of thriving university-community partnerships across multiple disciplines that promote social justice.

Cataracts are lens opacities that are among the most common causes of blindness. It is commonly believed that cataracts develop through the accumulation of damage to lens proteins. However, recent evidence suggests that cataracts can result from calcium ion accumulation and the precipitation of calcium-containing salts. To test for the presence of precipitates and to identify their components, we studied the lenses of mice that develop cataracts due to mutations of connexin46 and connexin50. Micro-computed tomography showed the presence of radio-dense mineral in the mutant lenses, but not in wild-type lenses. Three-dimensional reconstructions of the scans showed that the distribution of the radio-dense mineral closely paralleled the location and morphology of the cataracts. The mutant lens homogenates also contained insoluble particles that stained with Alizarin red (a dye that stains Ca2+ deposits). Using attenuated total internal reflection micro–Fourier transform infrared spectroscopy, we identified the mineral as calcium phosphate in the form of apatite. Taken together, these data support the novel paradigm that cataracts are formed through pathological mineralization within the lens.

Abstract Background Routinely collected electronic health records (EHRs) have the potential to enhance randomised controlled trials (RCTs) by facilitating recruitment and follow-up. Despite this, current EHR use is minimal in UK RCTs, in part due to ongoing concerns about the utility (reliability, completeness, accuracy) and accessibility of the data. The aim of this manuscript is to document the process, timelines and challenges of the application process to help improve the service both for the applicants and data holders. Methods This is a qualitative paper providing a descriptive narrative from one UK clinical trials unit (MRC CTU at UCL) on the experience of two trial teams’ application process to access data from three large English national datasets: National Cancer Registration and Analysis Service (NCRAS), National Institute for Cardiovascular Outcomes Research (NICOR) and NHS Digital to establish themes for discussion. The underpinning reason for applying for the data was to compare EHRs with data collected through case report forms in two RCTs, Add-Aspirin (ISRCTN 74358648) and PATCH (ISRCTN 70406718). Results The Add-Aspirin trial, which had a pre-planned embedded sub-study to assess EHR, received data from NCRAS 13 months after the first application. In the PATCH trial, the decision to request data was made whilst the trial was recruiting. The study received data after 8 months from NICOR and 15 months for NHS Digital following final application submission. This concluded in May 2020. Prior to application submission, significant time and effort was needed particularly in relation to the PATCH trial where negotiations over consent and data linkage took many years. Conclusions Our experience demonstrates that data access can be a prolonged and complex process. This is compounded if multiple data sources are required for the same project. This needs to be factored in when planning to use EHR within RCTs and is best considered prior to conception of the trial. Data holders and researchers are endeavouring to simplify and streamline the application process so that the potential of EHR can be realised for clinical trials.

In the genome, repetitive guanine-rich sequences have the potential to spontaneously fold into non-canonical DNA secondary structures known as G-quadruplex (G4). Using novel single-molecule imaging approaches, the authors reveal that G4 formation within active replication forks locally perturb replisome dynamics and damage response signaling, which require RPA and FANCJ for regulation.

Abstract Background Wild-type yeasts have been successfully used to obtain food products, yet their full potential as fermenting microorganisms for large-scale ethanol fuel production has to be determined. In this study, wild-type ethanologenic yeasts isolated from a secondary effluent were assessed for their capability to ferment saccharified microalgae sugars. Results Yeast species in wastewater were identified sequencing the Internal Transcribed Spacers 1 and 2 regions of the ribosomal cluster. Concurrently, microalgae biomass sugars were saccharified via acid hydrolysis, producing 5.0 ± 0.3 g L−1 of fermentable sugars. Glucose consumption and ethanol production of yeasts in hydrolyzed-microalgae liquor were tested at different initial sugar concentrations and fermentation time. The predominant ethanologenic yeast species was identified as Candida sp., and glucose consumption for this strain and S. cerevisiae achieved 75% and 87% of the initial concentration at optimal conditions, respectively. Relatively similar ethanol yields were determined for both species, achieving 0.45 ± 0.05 (S. cerevisiae) and 0.46 ± 0.05 g ethanol per g glucose (Candida sp.). Conclusion Overall, the results provide a first insight of the fermentation capacities of specific wild-type Candida species, and their potential role in ethanol industries seeking to improve their cost-efficiency.

Abstract The COVID-19 pandemic has affected how clinical trials are managed, both within existing portfolios and for the rapidly developed COVID-19 trials. Sponsors or delegated organisations responsible for monitoring trials have needed to consider and implement alternative ways of working due to the national infection risk necessitating restricted movement of staff and public, reduced clinical staff resource as research staff moved to clinical areas, and amended working arrangements for sponsor and sponsor delegates as staff moved to working from home. Organisations have often worked in isolation to fast track mitigations required for the conduct of clinical trials during the pandemic; this paper describes many of the learnings from a group of monitoring leads based in United Kingdom Clinical Research Collaboration (UKCRC) Clinical Trials Unit (CTUs) within the UK. The UKCRC Monitoring Task and Finish Group, comprising monitoring leads from 9 CTUs, met repeatedly to identify how COVID-19 had affected clinical trial monitoring. Informed consent is included as a specific issue within this paper, as review of completed consent documentation is often required within trial monitoring plans (TMPs). Monitoring is defined as involving on-site monitoring, central monitoring or/and remote monitoring. Monitoring, required to protect the safety of the patients and the integrity of the trial and ensure the protocol is followed, is often best done by a combination of central, remote and on-site monitoring. However, if on-site monitoring is not possible, workable solutions can be found using only central or central and remote monitoring. eConsent, consent by a third person, or via remote means is plausible. Minimising datasets to the critical data reduces workload for sites and CTU staff. Home working caused by COVID-19 has made electronic trial master files (TMFs) more inviting. Allowing sites to book and attend protocol training at a time convenient to them has been successful and worth pursuing for trials with many sites in the future. The arrival of COVID-19 in the UK has forced consideration of and changes to how clinical trials are conducted in relation to monitoring. Some developed practices will be useful in other pandemics and others should be incorporated into regular use.

Arizona has been at the forefront of groundwater management since the establishment of the Groundwater Management Act in 1980. The Central Arizona Groundwater Replenishment District (CAGRD) is a groundwater management mechanism that facilitates development in regions of Central Arizona where the use of groundwater is limited by law. Several stakeholders have raised concerns about some of the CAGRD’s operations; however, stakeholders have yet to agree on the definition of the problems, let alone how the CAGRD might be improved. This study uses statistical and inductive thematic content analysis of a survey to determine (1) the CAGRD issues that stakeholders view as problems and (2) whether opinions differ significantly among different stakeholder groups. This study also uses deductive thematic content analysis to examine semi-structured interviews with CAGRD experts in order to find potential solutions to the CAGRD-related issues that are considered problems by stakeholders. The survey results show that long-term uncertainties related to the availability of renewable water supplies and hydrologic disconnect, where groundwater pumping and replenishment take place in different sub-basins, are stakeholders’ chief concerns. Sector affiliation and CAGRD membership status are associated with stakeholders’ opinions on some, but not all, questions. The potential policy changes offered address problems identified by stakeholders. This research will inform forthcoming policy discussions regarding groundwater management in Central Arizona as the state’s decision makers look to improve the CAGRD in the context of water scarcity exacerbated by climate change.

This Special Issue is intended to highlight both recent work to advance the physical understanding of transboundary aquifers and factors relevant in successful collaboration on transboundary groundwater resource use. The collected papers address: (1) the identification and prioritization of the needs and strategies for sustainable groundwater development and use, along with the complexities introduced by working across borders with differing governance frameworks, institutions, cultures, and sometimes languages; (2) the characterization of the physical framework of the aquifer, stressors on the aquifer system, and how those stressors influence the availability of groundwater in terms of its quantity and quality; and (3) the incorporation of stakeholder input and prioritization directly into the process of aquifer assessment and model building. The papers provide insights into the state of knowledge regarding the physical characterization of important transboundary aquifers, primarily along the U.S.–Mexico border and the opportunities for greater stakeholder involvement in resource evaluation and prioritization. They point the way towards a future focus that combines both of these aspects of transboundary aquifer assessment for informing groundwater management discussions by policymakers.

Introduction Langerhans cell histiocytosis (LCH) is a rare disease that encompasses a spectrum of clinical syndromes. It is characterized by the proliferation and infiltration of white blood cells into organs or organ systems. Reports of management of these lesions have included biopsy, resection, curettage, radiation and/or chemotherapy. Case Presentation A 40-year-old man presented with a history of right proptosis and retro-orbital pain and was found to have a lytic mass involving the greater wing of the sphenoid extending into the right orbit. A stereotactic needle biopsy using neuronavigation demonstrated this to be LCH. After no further treatment, the mass spontaneously resolved, with virtual normalization of the orbital MRI at 10 months following the needle biopsy. The bony defect of the temporal bone caused by the mass also re-ossified following the needle biopsy. Discussion This report highlights the potential for an isolated LCH lesion to regress after simple needle biopsy, an outcome only rarely reported previously. Thus, expectant management of such lesions following biopsy or initial debridement should be considered prior to proceeding with additional treatment.

Background For medical conditions with numerous interventions worthy of investigation, there are many advantages of a multi-arm multi-stage (MAMS) platform trial approach. However, there is currently limited knowledge on uptake of the MAMS design, especially in the late-phase setting. We sought to examine uptake and characteristics of late-phase MAMS platform trials, to enable better planning for teams considering future use of this approach.Design We examined uptake of registered, late-phase MAMS platforms in the EU clinical trials register, Australian New Zealand Clinical Trials Registry, International Standard Randomised Controlled Trial Number registry, Pan African Clinical Trials Registry, WHO International Clinical Trial Registry Platform and databases: PubMed, Medline, Cochrane Library, Global Health Library and EMBASE. Searching was performed and review data frozen on 1 April 2021. MAMS platforms were defined as requiring two or more comparison arms, with two or more trial stages, with an interim analysis allowing for stopping of recruitment to arms and typically the ability to add new intervention arms.Results 62 late-phase clinical trials using an MAMS approach were included. Overall, the number of late-phase trials using the MAMS design has been increasing since 2001 and been accelerated by COVID-19. The majority of current MAMS platforms were either targeting infectious diseases (52%) or cancers (29%) and all identified trials were for treatment interventions. 89% (55/62) of MAMS platforms were evaluating medications, with 45% (28/62) of the MAMS platforms having at least one or more repurposed medication as a comparison arm.Conclusions Historically, late-phase trials have adhered to long-established standard (two-arm) designs. However, the number of late-phase MAMS platform trials is increasing, across a range of different disease areas. This study highlights the potential scope of MAMS platform trials and may assist research teams considering use of this approach in the late-phase randomised clinical trial setting.PROSPERO registration number CRD42019153910.

Abstract Background Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples. Methods The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant’s dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies. Results In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians’ time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion. Conclusion Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.

Abstract Background Clinical trials generally each collect their own data despite routinely collected health data (RCHD) increasing in quality and breadth. Our aim is to quantify UK-based randomised controlled trials (RCTs) accessing RCHD for participant data, characterise how these data are used and thereby recommend how more trials could use RCHD. Methods We conducted a systematic review of RCTs accessing RCHD from at least one registry in the UK between 2013 and 2018 for the purposes of informing or supplementing participant data. A list of all registries holding RCHD in the UK was compiled. In cases where registries published release registers, these were searched for RCTs accessing RCHD. Where no release register was available, registries were contacted to request a list of RCTs. For each identified RCT, information was collected from all publicly available sources (release registers, websites, protocol etc.). The search and data extraction were undertaken between January and May 2019. Results We identified 160 RCTs accessing RCHD between 2013 and 2018 from a total of 22 registries; this corresponds to only a very small proportion of all UK RCTs (about 3%). RCTs accessing RCHD were generally large (median sample size 1590), commonly evaluating treatments for cancer or cardiovascular disease. Most of the included RCTs accessed RCHD from NHS Digital (68%), and the most frequently accessed datasets were mortality (76%) and hospital visits (55%). RCHD was used to inform the primary trial (82%) and long-term follow-up (57%). There was substantial variation in how RCTs used RCHD to inform participant outcome measures. A limitation was the lack of information and transparency from registries and RCTs with respect to which datasets have been accessed and for what purposes. Conclusions In the last five years, only a small minority of UK-based RCTs have accessed RCHD to inform participant data. We ask for improved accessibility, confirmed data quality and joined-up thinking between the registries and the regulatory authorities. Trial registration PROSPERO CRD42019123088 .

Abstract Background Despite the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) encouraging the use of risk-based monitoring for trials in 2013, there remains a lack of evidence-based guidelines on how to monitor. We surveyed the academic United Kingdom Clinical Research Collaboration (UKCRC) registered clinical trials units (CTUs) to find out their policy on monitoring of phase III randomised clinical trials of an investigational medicinal product (CTIMPs). Methods An online survey of monitoring policy with sections on the CTU, central monitoring and on-site monitoring was sent to all 50 UKCRC registered CTUs in November 2018. Descriptive data analysis and tabulations are reported using the total number answering each question. Results A total of 43/50 (86%) of CTUs responded with 38 conducting phase III randomised CTIMP trials. Of these 38 CTUs, 34 finished the survey. Most CTUs (36/37, 97%) use a central monitoring process to guide, target or supplement site visits. More than half (19/36, 53%) of CTUs do not use an automated monitoring report when centrally monitoring trials and all units use trial team knowledge to make a final decision on whether an on-site visit is required. A total of 31/34 (91%) CTUs used triggers to decide whether or not to conduct an on-site monitoring visit. On-site, a mixture of source data verification and checking of processes was carried out. The CTUs overwhelmingly (27/34, 79%) selected optimising central monitoring as their most pressing concern. Conclusion The survey showed a wide variation in phase III randomised CTIMP trial monitoring practices by academic clinical trials units within a single research-active country. We urgently need to develop evidence-based regulator-agreed guidance for CTUs on best practice for both central and on-site monitoring and to develop tools for all CTUs to use.

Abstract Label‐free fluorescence imaging of kidney sections can provide important morphological information, but its utility has not been tested in a histology processing workflow. We tested the feasibility of label‐free imaging of paraffin‐embedded sections without deparaffinization and its potential usefulness in generating actionable data. Kidney tissue specimens were obtained during percutaneous nephrolithotomy or via diagnostic needle biopsy. Unstained non‐deparaffinized sections were imaged using widefield fluorescence microscopy to capture endogenous fluorescence. Some samples were also imaged with confocal microscopy and multiphoton excitation to collect second harmonic generation (SHG) signal to obtain high‐quality autofluorescence images with optical sectioning. To adjudicate the label‐free signal, the samples or corresponding contiguous sections were subsequently deparaffinized and stained with Lillie's allochrome. Label‐free imaging allowed the recognition of various kidney structures and enabled morphological qualification for adequacy. SHG and confocal imaging yielded quantifiable high‐quality images for tissue collagens and revealed specific patterns in glomeruli and various tubules. Disease specimens from patients with diabetic kidney disease and focal segmental glomerulosclerosis showed distinctive signatures compared to specimens from healthy controls with normal kidney function. Quantitative cytometry could also be performed when DAPI is added in situ before imaging. These results show that label‐free imaging of non‐deparaffinized sections provides useful information about tissue quality that could be beneficial to nephropathologists by maximizing the use of scarce kidney tissue. This approach also provides quantifiable features that could inform on the biology of health and disease.

Hospitals are increasingly consolidating into health systems. Some systems have appointed healthcare epidemiologists to lead system-level infection prevention programs. Ideal program infrastructure and support resources have not been described. We informally surveyed 7 healthcare epidemiologists with recent experience building and leading system-level infection prevention programs. Key facilitators and barriers for program structure and implementation are described.

The COVID-19 pandemic has challenged healthcare systems worldwide. In the Philippines, long-term care for patients with conditions identified through newborn screening (NBS) is coordinated through Newborn Screening Continuity Clinics (NBSCCs). These clinics are integral to achieving optimal outcomes by providing follow-up oversight and assistance for individuals identified through screening. Continuity of NBSCC care for NBS during the COVID-19 pandemic was both challenging and necessary and was accomplished through innovative strategies of dedicated personnel. Following the discontinuation of the community quarantine, a situation assessment survey was completed by each NBSCC to better understand the challenges encountered and their effect on patient care. Performance data from each NBSCC were reviewed both before and after an extended community quarantine (2018–2021) to evaluate the impact of NBSCC disaster contingency plans in overcoming the resultant challenges (transportation, supply chain, etc.). Thematic analysis of the survey showed three primary challenges: Operations, communications, and safety. In 2018 and 2019, successful patient contacts were 70.6% and 70.2%, respectively. During the pandemic, successful contacts were 74.9% in 2020 and 76.8% in 2021, demonstrating that the contact approaches taken by the NBSCCs were sufficient to maintain (and even improve) patient contacts. The number of unresponsive patients decreased during the pandemic likely due to decreased mobility and improved follow-up actions from the NBSCCs.

Background and Objectives: This study aims to describe the earliest renal lesions in patients with von Hippel-Lindau (VHL) disease, especially the multicellular microscopic pathologic events, to get information into the genesis of renal neoplasms in this condition. Materials and Methods: Multicellular events were identified, and 3dimensional reconstruction was performed in grossly normal kidney parenchyma from VHL disease patients by using H&E-stained slides previously prepared. Results: The lesions were measured and the volume of clusters was calculated. Immunohistochemistry was performed for downstream HIF-target protein carbonic anhydrase 9 (CAIX) as well as CD34 for assessment of angiogenesis. We divided lesions into four types according to lesion height/size. The number of lesions was markedly decreased from lesion 1 (smallest) to lesion 2, then from lesions 2 to 3, and again from lesion 3 to 4. Distribution was highly consistent in the four cases, and the same decrement pattern was seen in all blocks studied. The volumes of clusters were measured and divided into three categories according to their volume. The most frequent pathologic event in VHL kidneys was category 1 (smallest volume), then category 2, and then category 3. Conclusion: We demonstrate that tracking histologic and morphologic changes in 3 dimensions of multicellular microscopic pathologic events enabled us to confirm a protracted sequence of events from smaller to larger cellular amplification events in VHL kidney.

Abstract Background Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer’s disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer’s disease compared to those who are receiving placebo. Methods/design ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer’s dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer’s Disease Assessment Scale—Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer’s Disease Cooperative Study—Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. Discussion Alzheimer’s disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer’s treatment. Trial registration ClinicalTrials.gov, NCT01843075. Registration 30 April 2013.

Abstract Introduction The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM’s uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce. Methods To help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM. Results An initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design. Conclusions The framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.

This project aims to evaluate the potential of reused grey water in concrete and mortar in order to preserve fresh water for drinking purposes. Using both Treated Grey Water and Raw Grey Water (TGW and RGW, respectively) led to a significant increase in the initial setting time and a decrease in the concrete slump value. In addition, there was no effect on mortar soundness properties. The mortar and concrete compressive strength results obtained at 7 days moist curing time showed a significant increase. Mortar and concrete mixes using TGW cast at curing times of 28, 120, and 200 days led to no significant effects on compressive strength. On the contrary, the RGW achieved slightly negative impact on compressive strength at all curing ages. According to the American Society for Testing and Materials (ASTM C109), TGW and RGW are suitable for mortar and concrete production. Furthermore, these results are in harmony with established requirements for ASTM C94.In conclusion, TGW and RGW are potential alternatives for fresh water in the concrete manufacturing industry. Keywords: Grey water, Compressive strength, Mixing water, Concrete, Mortar

The impact of climate uncertainties is already evident in the border communities of the United States and Mexico. This semi-arid to arid border region has faced increased vulnerability to water scarcity, propelled by droughts, warming atmosphere, population growth, ecosystem sensitivity, and institutional asymmetries between the two countries. In this study, we assessed the annual water withdrawal, which is essential for maintaining long-term sustainable conditions in the Santa Cruz River Aquifer in Mexico, which is part of the U.S.–Mexico Transboundary Santa Cruz Aquifer. For this assessment, we developed a water balance model that accounts for the water fluxes into and out of the aquifer’s basin. A central component of this model is a hydrologic model that uses precipitation and evapotranspiration demand as input to simulate the streamflow into and out of the basin, natural recharge, soil moisture, and actual evapotranspiration. Based on the precipitation record for the period 1954–2020, we found that the amount of groundwater withdrawal that maintains sustainable conditions is 23.3 MCM/year. However, the record is clearly divided into two periods: a wet period, 1965–1993, in which the cumulative surplus in the basin reached ~380 MCM by 1993, and a dry period, 1994–2020, in which the cumulative surplus had been completely depleted. Looking at a balanced annual groundwater withdrawal for a moving average of 20-year intervals, we found the sustainable groundwater withdrawal to decline from a maximum of 36.4 MCM/year in 1993 to less than 8 MCM/year in 2020. This study underscores the urgency for adjusted water resources management that considers the large inter-annual climate variability in the region.

This research aims to assess the relationship between behavioral variables on the environment: ecolabel awareness, trust, ecolabel knowledge, ecolabel availability, and environmental concerns of intention to buy. Data was collected through questionnaires with non-probability sampling method which included a total sample of 230 respondents. Hypothesis testing was conducted by applying Structural Equation Modeling (SEM). The results shows that there are six out of ten supported hypotheses and four unsupported hypotheses. The six hypotheses supported are (1) there is positive relationship between attitude and trust in buying environmentally friendly product, (2) there is positive relationship between ecolabel awareness and ecolabel attention, (3) there is positive relationship between ecolabel awareness and intention to buy, (4) there is positive relationship between trust in buying environmentally product and ecolabel attention, (5) there is positive relationship between trust in buying environmentally product and intention to buy, and (6) there is positive relationship between ecolabel availability and ecolabel attention. This research also contributes theoretical contributions, managerial implications, and recommendations for further research

Summary: The DNA helicase FANCJ is mutated in hereditary breast and ovarian cancer and Fanconi anemia (FA). Nevertheless, how loss of FANCJ translates to disease pathogenesis remains unclear. We addressed this question by analyzing proteins associated with replication forks in cells with or without FANCJ. We demonstrate that FANCJ-knockout (FANCJ-KO) cells have alterations in the replisome that are consistent with enhanced replication stress, including an aberrant accumulation of the fork remodeling factor helicase-like transcription factor (HLTF). Correspondingly, HLTF contributes to fork degradation in FANCJ-KO cells. Unexpectedly, the unrestrained DNA synthesis that characterizes HLTF-deficient cells is FANCJ dependent and correlates with S1 nuclease sensitivity and fork degradation. These results suggest that FANCJ and HLTF promote replication fork integrity, in part by counteracting each other to keep fork remodeling and elongation in check. Indicating one protein compensates for loss of the other, loss of both HLTF and FANCJ causes a more severe replication stress response. : Peng et al. find that loss of FANCJ enhances the replisome association of helicase-like transcription factor (HLTF). HLTF depletion suppresses fork degradation in FANCJ-deficient cells, and FANCJ depletion suppresses aberrant fork elongation in HLTF-deficient cells. However, the combined loss of HLTF and FANCJ causes severe replication stress. Keywords: FANCJ/BACH1/BRIP1, Fanconi anemia, hereditary breast cancer, DNA replication, replication stress response, helicase, replisome, fork protection, fork degradation, iPOND

Abstract Understanding the context from which evidence emerges is of paramount importance in reaching robust conclusions in scientific inquiries. This is as true of the present as it is of the past. In a trans‐disciplinary study such as More et al. (2017, https://doi.org/10.1002/2017GH000064) and many others appearing in this and similar journals, a proper analysis of context demands the use of historical evidence. This includes demographic, epidemiological, and socio‐economic data—common in many studies of the impact of anthropogenic pollution on human health—and, as in this specific case, also geoarchaeological evidence. These records anchor climate and pollution data in the geographic and human circumstances of history, without which we lose a fundamental understanding of the data itself. This article addresses Hinkley (2018, https://doi.org/10.1002/2018GH000105) by highlighting the importance of context, focusing on the historical and archaeological evidence, and then discussing atmospheric deposition and circulation in the specific region of our study. Since many of the assertions in Bindler (2018, https://doi.org/10.1002/2018GH000135) are congruent with our findings and directly contradict Hinkley (2018), this reply refers to Bindler (2018), whenever appropriate, and indicates where our evidence diverges.

Sharing scientific data and information is often cited within academic literature as an initial step of water cooperation, but the transfer of research findings into policy and practice is often slow and inconsistent. Certain attributes—including salience, credibility, and legitimacy of scientific information; iterative information production; and sociocultural factors—may influence how easily scientific information can be used in management and policymaking. However, transnationality usually complicates these sorts of interactions. Accordingly, we argue that the production of scientific information and transboundary water cooperation build upon each other bidirectionally, each informing and enhancing the other. We employ a case-study analysis of the Transboundary Aquifer Assessment Program (TAAP), a binational collaborative effort for scientific assessment of aquifers shared between Mexico and the United States. Here, information sharing was possible only by first completing a formal, jointly agreed-upon cooperative framework in 2009. This framework resulted in a collaborative science production process, suggesting that the relationship between sharing data and information and transboundary groundwater governance is iterative and self-reinforcing. In keeping with the publication of the TAAP’s first binational scientific report in 2016, we demonstrate the bidirectional relationship between science production and water governance in the TAAP and explore remaining challenges after scientific assessment.

Abstract Contrary to widespread assumptions, next‐generation high (annual to multiannual) and ultra‐high (subannual) resolution analyses of an Alpine glacier reveal that true historical minimum natural levels of lead in the atmosphere occurred only once in the last ~2000 years. During the Black Death pandemic, demographic and economic collapse interrupted metal production and atmospheric lead dropped to undetectable levels. This finding challenges current government and industry understanding of preindustrial lead pollution and its potential implications for human health of children and adults worldwide. Available technology and geographic location have limited previous ice core investigations. We provide new high‐ (discrete, inductively coupled plasma mass spectrometry, ICP‐MS) and ultra‐high resolution (laser ablation inductively coupled plasma mass spectrometry, LA‐ICP‐MS) records of atmospheric lead deposition extracted from the high Alpine glacier Colle Gnifetti, in the Swiss‐Italian Alps. We show that contrary to the conventional wisdom, low levels at or approaching natural background occurred only in a single 4 year period in ~2000 years documented in the new ice core, during the Black Death (~1349–1353 C.E.), the most devastating pandemic in Eurasian history. Ultra‐high chronological resolution allows for the first time detailed and decisive comparison of the new glaciochemical data with historical records. Historical evidence shows that mining activity ceased upwind of the core site from ~1349 to 1353, while concurrently on the glacier lead (Pb) concentrations—dated by layer counting confirmed by radiocarbon dating—dropped to levels below detection, an order of magnitude beneath figures deemed low in earlier studies. Previous assumptions about preindustrial “natural” background lead levels in the atmosphere—and potential impacts on humans—have been misleading, with significant implications for current environmental, industrial, and public health policy, as well as for the history of human lead exposure. Trans‐disciplinary application of this new technology opens the door to new approaches to the study of the anthropogenic impact on past and present human health.