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Causal mechanistic reasoning is a thinking strategy that can help students explain complex phenomena using core ideas commonly emphasized in separate undergraduate courses, as it requires students to identify underlying entities, unpack their relevant properties and interactions, and link them to construct mechanistic explanations. As a cross-disciplinary group of biologists, chemists, and teacher educators, we designed a scaffolded set of tasks that require content knowledge from biology and chemistry to construct nested hierarchical mechanistic explanations that span three scales (molecular, macromolecular, and cellular). We examined student explanations across seven introductory and upper-level biology and chemistry courses to determine how the construction of mechanistic explanations varied across courses and the relationship between the construction of mechanistic explanations at different scales. We found non-, partial, and complete mechanistic explanations in all courses and at each scale. Complete mechanistic explanation construction was lowest in introductory chemistry, about the same across biology and organic chemistry, and highest in biochemistry. Across tasks, the construction of a mechanistic explanation at a smaller scale was associated with constructing a mechanistic explanation for larger scales; however, the use of molecular scale disciplinary resources was only associated with complete mechanistic explanations at the macromolecular, not cellular scale.

International students in Australia risk financial insecurity and as a result, may make suboptimal health decisions. Limited research has explored the experiences of international students' health-related financial decision making. In-depth interviews were conducted with 31 international students to explore how financial situation influences their decisions in Australia. Data were thematically analysed. Findings highlight that limited income can impact overall wellbeing and health-related decision making. When making financial health-related decisions, participants prioritised urgent health needs and education. Participants who perceived their financial situation limited were less willing to spend money on mental health services, social activities, and food. This study suggests that students may consider the long-term financial benefits of studying abroad when making decisions, but they do not consider the long-term health implications of stress and wellbeing. Enabling students to improve their financial situation and lower their expenses could enhance wellbeing and facilitate health-related decision making.

Perfectionism is a personality orientation associated with mental health and adjustment problems. Recent evidence demonstrates that perfectionism is widespread among students and on the rise, with recent generations of students placing increasingly more importance on perfection. Whilst the extant literature is vast, it tends to focus on psychopathology and identification of perfectionism correlates rather than the experience of student perfectionism. Furthermore, the education literature is scant and there is a need to understand the deeper processes and nuances of perfectionism, particularly within health professions education where intense study demands, competition to gain entry to educational programmes, and professional cultures may nurture the problem. This phenomenological study explored the lived experiences of ten physiotherapy students as they wrestled with perfectionism in the various facets of their studies. Semi-structured interviews were undertaken, and participants completed log sheets to document perfectionism-related experiences. Idiographic profiles were composed and interview transcripts were analysed, drawing upon features of both phenomenological and thematic analysis. Perfectionism was found to have toxic consequences for the learning experience. Harmful phenomenological experiences included perpetual and excessive achievement striving, punitive self-criticism and health and wellbeing difficulties. A range of sabotaging learning behaviours such as self-handicapping and feedback avoidance was also illuminated, and cultural and organisational influences perceived to foster perfectionism emerged. Findings are discussed in relation to underlying processes and implications for educators. The prospect of findings transferring to other educational contexts is highlighted.

This article draws on data from a specially commissioned representative survey, which elicited responses from 7691 teachers in primary and secondary schools in England, to examine how teachers perceive young people's engagement with a variety of different conspiracy theories in school settings and how they respond to them. Approximately 40% of teachers report encountering students who supported conspiracy theories. In response, teachers use a wide range of contradictory strategies, including opening up discussion, closing it down, challenging students in class and reporting individuals as safeguarding concerns. The research evidence suggests that several of these strategies are likely to be ineffective or even backfire to reinforce conspiracy thinking. Unsurprisingly then, few teachers report successful responses. The article concludes that the evidence of possible negative impacts of unprepared teachers confronting conspiracy theories at school means that teachers need to be better equipped through training, support and further research.

The adoption of digital technologies in higher education offers new opportunities for student learning but also adds complexity to course design and development processes. Although practice varies across institutions and nations, a common response is that teams of people are now involved in the development and creation of blended and online courses. Members of such teams typically include instructional designers, academics, learning designers and technologists, and production teams, and courses are developed over time, often across separate locations and organisations. These factors are creating a need for tools that support the sharing of design information in distributed course design teams. This paper introduces such a course design tool, EdVee, which supports pedagogical innovation through the sharing and visualisation of constructive alignment of learning outcomes, content, learning, and teaching activities and assessment. Key concepts that underpin EdVee are drawn from systems engineering and product development. We demonstrate its value to course design through two case studies: the design of a new course and the evaluation of an existing course.

Institutional transformation and inclusion have slowly become more prominent in the strategies of historically white institutions in South Africa. Despite these efforts, progress towards these goals has been limited. In this article, we reflect on our conversations about transforming our curricula and teaching practices as an interdisciplinary Community of Practice. Our conversations grappled with the lack of curricular transformation at Stellenbosch University, despite its aspirational transformation plan. We argue that difficult interdisciplinary conversations are key to interrupting our teaching practices and are crucial in the decolonising process. These conversations must be ongoing and enduring, because through sharing our stories we support agents of curriculum transformation in our different contexts. Our conceptual conversations explored various theories about decoloniality, and here we employ ubuntu pedagogy, as well as the concepts of redistribution, recognition and representation from social justice theory. We harness the collaborative energy of an interdisciplinary Community of Practice, with its associated storytelling, reading, writing and reflecting to harness the diversity of personal and disciplinary perspectives. We include some reflective vignettes to illustrate our process. Contribution: The relevance of this study, beyond our contexts, arises from a gap in the decolonising process, from its theory to its practice. We argue that even a good institutional transformation plan will not guarantee the decoloniality of curricula. More is needed. Systemic change is needed, and difficult interdisciplinary conversations are part of this process. There must be recognition and representation of marginalised voices and specific context-related redistribution of curricula, so that transformation plans and theories can take effect.

Abstract We sought to evaluate the genomic and transcriptomic landscapes in primary and metastatic germ cell tumors (GCTs; N = 138) to uncover factors that drive cisplatin resistance. Prevalence was calculated for platinum-resistant alterations (PRAs; KRAS, TP53, and KIT mutations, and MDM2 amplification) and high copy number amplifications (CNA ≥ 6 copies). Tumors were designated as chemo-naïve (PreC, N = 66) or post-chemotherapy (PostC, N = 17). A transcriptomic signature associated with platinum sensitivity (PSS, high suggests increased sensitivity) was applied. KIT mutations were observed in 14.5% of primary versus 1.8% of met and 0% of lymph. TP53 mutations were identified in 10% of primary GCTs versus 17% of met and 16.7% of lymph. MDM2 CNAs were similar between sites. PRA-positive PreC GCTs had significantly lower average PSS scores compared to PRA-negative tumors. Lower PSS scores in chemo-naïve tumors were associated with PRAs, suggesting a potential mechanism for platinum resistance.

Purpose To describe the first reported instance of an acute chorioretinal inflammatory response to cabozantinib. Methods Case report. Results A 54-year-old Asian male presented with blurred vision 2 weeks following the commencement of cabozantinib for metastatic renal cell carcinoma. Ophthalmic examination revealed bilateral exudative retinal detachments and choroiditis in a pattern similar to Vogt–Koyanagi–Harada disease. Further investigations revealed latent tuberculosis (TB), and management of this ocular adverse event was with cabozantinib cessation, high-dose oral prednisone, single-agent anti-TB therapy, and methotrexate. Return of visual function and ocular anatomy occurred within 1 month. Conclusions Modern pharmacotherapy for metastatic cancer may increase survival, but a range of ocular and systemic adverse events are frequently seen. Screening and early intervention can mitigate adverse events and treatment burden, while maximizing benefits for this disadvantaged patient group.

Abstract Introduction Vanadium is a widely used transition metal in industrial applications, but it also poses significant neurotoxic and environmental risks. Previous studies have shown that exposure to vanadium may lead to neurodegenerative diseases and neuropathic pain, raising concerns about its impact on human health and the ecosystem. To address vanadium neurotoxicity, through targeting NMDA glutamate and dopamine signaling, both involved in neurodegenerative disorders, shows promise. Using Caenorhabditis elegans as a model, we evaluated a novel compound with a mixed NMDA glutamate receptor-dopamine transporter pharmacology, ZA-II-05 and found it effectively ameliorated vanadium-induced neurotoxicity, suggesting a potential neuroprotective role. Methods Synchronized young adult worms were assigned to four different experimental groups; Controls; 100 mM of Vanadium; Vanadium and 1 mg/ml ZA-II-05; and ZA-II-05 alone. These were examined with different markers, including DAPI, MitoTracker Green and MitoSox stains for assessment of nuclei and mitochondrial density and oxidative stress, respectively. Results Exposure to vanadium in C. elegans resulted in decreased nuclear presence and reduction in mitochondrial content were also analyzed based on fluorescence in the pharyngeal region, signifying an increase in the production of reactive oxygen species, while vanadium co-treatment with ZA-II-05 caused a significant increase in nuclear presence and mitochondrial content. Discussion Treatment with ZA-II-05 significantly preserved cellular integrity, exhibiting a reversal of the detrimental effects induced by vanadium by modulating and preserving the normal function of chemosensory neurons and downstream signaling pathways. This study provides valuable insights into the mechanisms of vanadium-induced neurotoxicity and offers perspectives for developing therapeutic interventions for neurodegenerative diseases related to environmental toxins.

Abstract Background Adaptation of evidence-based interventions (EBIs) often occurs when implemented in new local contexts and settings. It is unclear, however, during which phase of implementation adaptations are most frequently made and how these changes may impact the fidelity, effectiveness, and sustainability of the EBI. Pediatric Early Warning Systems (PEWS) are EBIs for early identification of deterioration in hospitalized children with cancer. This study evaluates adaptations of PEWS made among resource-variable pediatric oncology hospitals in Latin America implementing and sustaining PEWS. Methods We conducted a cross-sectional survey among pediatric oncology centers participating in Proyecto Escala de Valoración de Alerta Temprana (EVAT), a collaborative to implement PEWS. Adaptations to PEWS were assessed via 3 multiple choice and 1 free text question administered as part of a larger study of PEWS sustainability. Descriptive statistics quantitatively described what, when, and why adaptations were made. Qualitative analysis of free text responses applied the Framework for Reporting Adaptations and Modifications Expanded (FRAME) to describe respondent perspectives on PEWS adaptations. Results We analyzed 2,094 responses from 58 pediatric oncology centers across 19 countries in Latin America. Participants were predominantly female (82.5%), consisting of nurses (57.4%) and physicians (38.2%) who were PEWS implementation leaders (22.1%) or clinical staff (69.1%). Respondents described multiple PEWS adaptations across all implementation phases, with most occurring during the planning and piloting of EBIs. Adaptations included changes to PEWS content (algorithm, scoring tool, terminology, and use frequency) and context (personnel delivering or population). Respondents felt adaptations streamlined monitoring, enhanced effectiveness, improved workflow, increased comprehension, and addressed local resource limitations. Qualitative analysis indicated that most adaptations were categorized as fidelity consistent and planned; fidelity inconsistent adaptations were unplanned responses to unanticipated challenges. Conclusion Adaptations made to PEWS across implementation phases demonstrate how EBIs are adapted to fit dynamic, real-world clinical settings. This research advances implementation science by highlighting EBI adaptation as a potential strategy to promote widespread implementation and sustainability in hospitals of all resource levels.

The Great Barrier Reef (GBR), Australia, has a long history of palaeoenvironmental coral research. However, it can be logistically difficult to find the relevant research and records, which are often unpublished or exist as “grey literature”. This hinders researchers' abilities to efficiently assess the current state of coral core studies on the GBR and thus identify any key knowledge gaps. This study presents the Great Barrier Reef Coral Skeletal Records Database (GBRCD), which compiles 208 records from coral skeletal research conducted since the early 1990s. The database includes records from the Holocene, from ∼8000 years ago, to the present day; records are from the northern, central, and southern GBR from inshore and offshore locations. Massive Porites spp. coral records comprise the majority (92.5 %) of the database, and the remaining records are from Acropora, Isopora, or Cyphastrea spp. The database includes 78 variables, with Sr/Ca, U/Ca, and Ba/Ca being the most frequently measured. Most records measure data over 10 or more years and are at monthly or lower resolution. The GBRCD is machine readable and easily searchable so that users can find records relevant to their research, e.g. by filtering for site name, time period, or coral type. It is publicly available as comma-separated values (CSV) data and metadata files with entries linked by the unique record ID and as Linked Paleo Data (LiPD) files. The GBRCD is publicly available from the NOAA National Center for Environmental Information World Data Service for Paleoclimatology at https://doi.org/10.25921/hqxk-8h74 (Arzey et al., 2024). The intention is to update the GBRCD annually, depending on the availability of relevant new GBR records or submission of legacy records to the GBRCD for archiving. The collection and curation of existing GBR coral research data provide researchers with the ability to analyse common proxies such as Sr/Ca across multiple locations and/or examine regional to reef-scale trends. The database is also suitable for multi-proxy comparisons and combination or composite analyses to determine overarching changes recorded by the proxies. This database represents the first comprehensive compilation of coral records from the GBR. It enables the investigation of multiple environmental factors via various proxy systems for the GBR, northeastern Australia, and potentially the broader Indo-Pacific region.

Abstract Background Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation. Methods Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations. Results The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR

Abstract Background Antimicrobial stewardship programs (ASP) often function naturally as facilitators within clinical hospital settings, by working with individuals and teams to reduce unnecessary antibiotics. Within implementation science, facilitation has been studied and evaluated as an implementation strategy that can accelerate and improve fidelity to implementation efforts. This study describes a novel, virtual facilitation strategy developed and served as an intervention within the optimizing perioperative antibiotics for children trial (OPERATIC trial). This paper: (1) describes ASP team’s preferences for and use of a facilitation workshop and (2) describes sustained use of facilitation skills throughout the study period. Methods Study participants included antimicrobial stewardship team members from the nine children’s hospitals that participated in this study and completed facilitation training. All individuals who completed facilitation training were asked to evaluate the training through an online survey. Additionally, site leads were interviewed by the site coordinator every other month and asked about their team’s use of facilitation skills throughout the rest of the study period. Survey data were managed and coded in R, and qualitative interview data were analyzed using rapid methodology. Results 30 individuals, including both physicians and pharmacists, completed the evaluation. Individuals largely rated themselves as novice facilitators (53%). Individuals reported satisfaction with virtual facilitation and identified different components of the workshops as valuable. An additional 108 interviews were performed throughout the study period. These interviews found that facilitators reported using all skills throughout the study period and described varied use of skills over time. All nine sites applied facilitation strategies, team building techniques, and communication/conflict skills at some point during the intervention phase. Conclusion We describe the use of virtual facilitation as an acceptable and appropriate strategy to enhance facilitation skills for ASP teams working to reduce unnecessary postoperative antibiotics. Participants reported different useful components of facilitation training and described using differing facilitation skills throughout the trial. Overall, the use of facilitation skills continued throughout the duration of the study period. This paper outlines how facilitation training can be conducted virtually in a way that is feasible and acceptable to clinicians. Trial registration NCT04366440, April 24, 2020.

Abstract Drought has a significant, negative impact on crop production; and these effects are poised to increase with climate change. Plants acclimate to drought and water stress through diverse physiological responses, primarily mediated by the hormone abscisic acid (ABA). Because plants lose the majority of their water through stomatal pores on aerial surfaces of plants, stomatal closure is one of the rapid responses mediated by ABA to reduce transpirational water loss. The dynamic changes in the transcriptome of stomatal guard cells in response to ABA have been investigated in the model plant Arabidopsis thaliana. However, guard cell transcriptomes have not been analyzed in agronomically valuable crops such as a major oilseed crop, rapeseed. In this study, we investigated the dynamics of ABA-regulated transcriptomes in stomatal guard cells of Brassica napus and conducted comparison analysis with the transcriptomes of A. thaliana. We discovered changes in gene expression indicating alterations in a host of physiological processes, including stomatal movement, metabolic reprogramming, and light responses. Our results suggest the existence of both immediate and delayed responses to ABA in Brassica guard cells. Furthermore, the transcription factors and regulatory networks mediating these responses are compared to those identified in Arabidopsis. Our results imply the continuing evolution of ABA responses in Brassica since its divergence from a common ancestor, involving both protein-coding and non-coding nucleotide sequences. Together, our results will provide a basis for developing strategies for molecular manipulation of drought tolerance in crop plants.

Abstract Background Though artificial intelligence holds great value for healthcare, it may also amplify health inequalities through risks of bias. In this paper, we explore bias risks in targeted medicines manufacturing. Targeted medicines manufacturing refers to the act of making medicines targeted to individual patients or to subpopulations of patients within a general group, which can be achieved, for example, by means of cell and gene therapies. These manufacturing processes are increasingly reliant on digitalised systems which can be controlled by artificial intelligence algorithms. Whether and how bias might turn up in the process, however, is uncertain due to the novelty of the development. Methods Examining stakeholder views across bioethics, precision medicine, and artificial intelligence, we document a range of opinions from eleven semi-structured interviews about the possibility of bias in AI-driven targeted therapies manufacturing. Result Findings show that bias can emerge in upstream (research and development) and downstream (medicine production) processes when manufacturing targeted medicines. However, interviewees emphasized that downstream processes, particularly those not relying on patient or population data, may have lower bias risks. The study also identified a spectrum of bias meanings ranging from negative and ambivalent to positive and productive. Notably, some participants highlighted the potential for certain biases to have productive moral value in correcting health inequalities. This idea of “corrective bias” problematizes the conventional understanding of bias as primarily a negative concept defined by systematic error or unfair outcomes and suggests potential value in capitalizing on biases to help address health inequalities. Our analysis also indicates, however, that the concept of “corrective bias” requires further critical reflection before they can be used to this end.

Abstract We installed a meteorological recording system at Badwater (elev. −75 m), the lowest point in Death Valley, California and recorded data over the period 1998–2019. A second station (the Outhouse Station) was established nearby from 2014 to 2019. Here, we report on and publicly archive the data from these two stations. Of interest was the comparison between two air temperature measurements at the Badwater Station, the first with an aspirated platinum resistance temperature device and the second with a thermistor probe in a passive sun shield. During the hottest periods of the summer when temperatures were typically between 30°C at night and 50°C daily peak, the passively shielded sensor indicated up to 0.5°C warmer than the aspirated temperature sensor due to radiative effects. The data suggest a correction for radiative heating of (T–35)/30, for T > 35°C, where, T, is the uncorrected temperature reading of a passively shielded sensor subtracted after any calibration at lower temperatures. Our station was the first precision temperature measurements at Badwater. A longer record exists for the reporting station near the visitor's centre at the Furnace Creek. The summer temperature maxima at the Badwater site correlate well with the values the same day from the Furnace Creek site. The daily maximum temperatures in winter at the Badwater site appear to be about 1°C lower than at the Furnace Creek site. The largest differences are in the minimum temperatures for which the Badwater site averages about 2–3°C warmer than the Furnace Creek site.

Abstract Background Although significant advances have been made in the conceptualization of sustainability, having pragmatic, psychometrically valid tools remains a need within the field. Our previous work has developed frameworks and tools to assess both program sustainability and clinical sustainability capacity. This work presents new, psychometrically tested short versions of the Program Sustainability Assessment Tool (PSAT) and the Clinical Sustainability Assessment Tool (CSAT). Methods These methods were conducted in identical, parallel processes for the CSAT and PSAT. Previously collected data for these instruments was obtained across a variety of settings, contexts, and participants. We first conducted testing to determine cronbach’s alpha of shortened domains (3 items each) and then conducted Confirmatory Factor Analysis to ensure that the domains were still appropriate for the tool. After, the team met to review the results and determine the final versions of the short PSAT and short CSAT. Results The short PSAT retained cronbach’s alpha’s of 0.82 – 0.91 for each domain of the tool, with which maintains excellent reliability for the tool. Confirmatory factor analysis highlights that the short PSAT retains conceptual distinction across the 8 domains, with CFI scores greater than 0.90, RMSEA scores below 0.6, and SRMR scores less than 0.08. The short CSAT had cronbach’s alpha of 0.84 – 0.92 for each of the domains of the tool, also suggesting excellent reliability of the domains within the measure after dropping two items/domain. Confirmatory factor analysis of the short CSAT meets the same specifications as above, again highlighting conceptual distinction across the domains. Conclusion Each tool was able to be shortened to three items per domain while maintaining strong psychometric properties. This results in a tool that takes less time to complete, meeting one of the key calls for pragmatic measures within implementation science. This advances our abilities to measure and test sustainability within implementation science.

ABSTRACT: Early lactation is a critical period for dairy cows, as energy requirements rapidly increase with the onset of lactation; however, early-lactation DMI in pasture-based systems are under measured. The objectives of this study were (1) to measure and profile total DMI (TDMI) and animal performance of dairy cows during early lactation in a pasture-based system, (2) to investigate early-lactation energy balance in pasture-based systems, and (3) to examine production efficiencies, including TDMI and milk solids production per 100 kg of BW. Eighty spring-calving dairy cows were allocated to a grazing group as they calved over a 2-yr period (2021 and 2022). Cows were offered a daily herbage allowance to achieve a postgrazing sward height of 4 cm, with silage supplementation when necessary due to inclement weather. Total DMI was measured using the n-alkane technique over a 12-wk period from February 1, 2021, to April 23, 2022. Total DMI and daily milk yield were significantly affected by parity with both variables being greatest for third-parity animals (17.7 kg of DM and 26.3 kg/cow per day, respectively), lowest for first parity (13.2 kg of DM and 19.6 kg/cow per day, respectively) and intermediate for second-parity animals (16.8 kg of DM and 24.1 kg/cow per day, respectively). Peak TDMI was reached on wk 10 for first-parity animals (14.6 kg of DM), wk 11 for second parity animals (19.3 kg of DM) and wk 12 for third-parity animals (19.9 kg of DM). Parity also had a significant effect on unité fouragère lait (UFL; feed units for milk) feed balance as first-parity animals experienced a greater degree of negative energy balance (−3.2 UFL) compared with second- and third-parity animals (−2.3 UFL). Breed and parity had an effect on production efficiencies during the first 12 wk of lactation as Jersey × Holstein Friesian cows had greater TDMI/100 kg of BW and milk solids/100 kg of BW compared with Holstein Friesian cows.

Abstract Background The context of practice is often not explicit in the discourse around the personal and professional resilience of nurses. The unique factors related to providing nursing care in home and community care may provide novel insight into the resilience of this health workforce. Therefore, this research addressed how nurses build and maintain resilience working in the home and community care sector. Method A qualitative study was conducted between November 2022 to August 2023 using 36 in-depth interviews (29 registered practical nurses [RPNs], five supervisors of RPNs, two family/care partners (FCPs) of clients receiving home and community care services). Analysis was consistent with a grounded theory approach including coding and comparative methods. Results The factors of personal and professional resilience were not distinct but rather mixed together in the experience of nurses having resilience working in the home and community care sector. The process of building and maintaining resilience as home and community care nurses was informed by three categories: (1) The conditions of working in HCC; (2) The rapport RPNs held with FCPs; and (3) The nurses’ ability for supporting the ‘self’. Multiple components to inform these categories were identified and illustrated by the words of the nurse participants. Conclusion The process of building and maintaining resilience by RPNs working in the home and community care sector was guided by the day-to-day experiences of providing care for clients and the conditions of being a mobile health care provider. However, nurses may sense when they need to support their ‘self’ and must be empowered to request and receive support to do so.

Abstract End-stage kidney disease (ESKD) is fatal without treatment by kidney replacement therapies (KRTs). However, access to these treatment modalities can be problematic given the high costs. This systematic review (SR) aims to provide an updated economic evaluation of pairwise comparisons of KRTs and the implications for the proportion of patients with access to the KRT modalities, i.e., kidney transplantation (KT), hemodialysis (HD), and peritoneal dialysis (PD). This SR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020. We searched studies in PubMed, Embase, Scopus, and Cost Effectiveness Analysis (CEA) registry, from inception to March 2023. Thirteen studies were included with pairwise comparisons among three KRTs, with varying proportions of patients for each modality. Seven studies were from high-income countries, including five from Europe. Summary findings are presented on a cost-effectiveness plane and incremental net benefit (INB). KT was the most cost-effective intervention across the pairwise comparisons. KT and PD were both more cost-effective alternatives to HD. HD was more costly and less effective than PD in all studies except one. Concurrent efforts to increase both KT and PD represented the best scenario to improve treatment options for ESKD patients.

Abstract Commonly comprised of cyanobacteria, algae, bacteria and fungi, hypolithic communities inhabit the underside of cobblestones and pebbles in diverse desert biomes. Notwithstanding their abundance and widespread geographic distribution and their growth in the driest regions on Earth, the source of water supporting these communities remains puzzling. Adding to the puzzle is the presence of cyanobacteria that require liquid water for net photosynthesis. Here we report results from six-year monitoring in the Negev Desert (with average annual precipitation of ~ 90 mm) during which periodical measurements of the water content of cobblestone undersides were carried out. We show that while no effective wetting took place following direct rain, dew or fog, high vapor flux, induced by a sharp temperature gradient, took place from the wet subsurface soil after rain, resulting in wet-dry cycles and wetting of the cobblestone undersides. Up to 12 wet-dry cycles were recorded following a single rain event, which resulted in vapor condensation on the undersides of the cobblestones, with the daily wet phase lasting for several hours during daylight. This ‘concealed mechanism’ expands the distribution of photoautotrophic organisms into hostile regions where the abiotic conditions limit their growth, and provides the driving force for important evolutionary processes not yet fully explored.

Abstract Activating transcription factor 4 (ATF4) plays a central role in the integrated stress response (ISR) and one overlapping branch of the unfolded protein response (UPR). We recently reported that the splicing inhibitor isoginkgetin (IGG) induced ATF4 protein along with several known ATF4-regulated transcripts in a response that resembled the ISR and UPR. However, the contribution of ATF4-dependent and -independent transcriptional responses to IGG exposure was not known. Here we used RNA-sequencing in HCT116 colon cancer cells and an isogenic subline lacking ATF4 to investigate the contribution of ATF4 to IGG-induced changes in gene expression. Approximately 85% of the IGG-responsive DEGs in HCT116 cells were also differentially expressed in response to the ER stressor thapsigargin (Tg) and these were enriched for genes associated with the UPR and ISR. Most of these were positively regulated by IGG with impaired responses in the ATF4-deficient cells. Nonetheless, there were DEGs that responded similarly in both cell lines. The ATF4-independent IGG-induced DEGs included several metal responsive transcripts encoding metallothionines and a zinc transporter. Taken together, the predominant IGG response was ATF4-dependent in these cells and resembled the UPR and ISR while a second less prominent response involved the ATF4-independent regulation of metal responsive mRNAs.

Abstract Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 pleiotropic cancer locus in squamous cell lung carcinoma. Overall, we report twelve novel risk loci for overall lung cancer, lung adenocarcinoma, and squamous cell lung carcinoma, nine of which are externally replicated. Finally, we perform PheWAS on polygenic risk scores for lung cancer, with and without conditioning on smoking. The unconditioned lung cancer polygenic risk score is associated with smoking status in controls, illustrating a reduced predictive utility in non-smokers. Additionally, our polygenic risk score demonstrates smoking-independent pleiotropy of lung cancer risk across neoplasms and metabolic traits.