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ABSTRACT Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has revolutionized the treatment of cystic fibrosis (CF) for most affected individuals but the effects of treatment on sinus microbiota are still unknown. Changes to the airway microbiota in CF are associated with disease state and alterations to the bacterial community after ETI initiation may require changes to clinical management regimens. We collected sinus swab samples from the middle meatus in an observational study of 38 adults with CF and chronic rhinosinusitis (CRS) from 2017 to 2021 and captured the initiation of ETI therapy. We performed 16S and custom amplicon sequencing to characterize the sinus microbiota pre- and post-ETI. Real-time quantitative PCR (RT-qPCR) was performed to estimate total bacterial abundance. Sinus samples from people with CF (pwCF) clustered into three community types, dependent on the dominant bacterial organism: a Pseudomonas-dominant, Staphylococcus-dominant, and mixed dominance cluster. Shannon’s diversity index was low and not significantly altered post-ETI. Total bacterial load was not significantly lowered post-ETI. Pseudomonas spp. abundance was significantly reduced post-ETI, but eradication was not observed. Staphylococcus spp. became the dominant organism in most individuals post-ETI and we showed the presence of methicillin-resistant Staphylococcus aureus (MRSA) in the sinus both pre- and post-ETI. We also demonstrated that the sinus microbiome is predictive of the presence of Pseudomonas spp., Staphylococcus spp., and Serratia spp. in the sputum. Pseudomonas spp. and Staphylococcus spp., including MRSA, persist in the sinuses of pwCF after ETI therapy, indicating that these pathogens will continue to be important in CF airway disease management in the era of highly effective modulator therapies (HEMT).IMPORTANCEHighly effective modulator therapies (HEMT), such as elexacaftor/tezacaftor/ivacaftor (ETI), for cystic fibrosis (CF) have revolutionized patient care and quality of life for most affected individuals. The effects of these therapies on the microbiota of the airways are still unclear, though work has already been published on changes to microbiota in the sputum. Our study presents evidence for reduced relative abundance of Pseudomonas spp. in the sinuses following ETI therapy. We also show that Staphylococcus spp. becomes the dominant organism in the sinus communities of most individuals in this cohort after ETI therapy. We identified methicillin-resistant Staphylococcus aureus (MRSA) in the sinus microbiota both pre- and post-therapy. These findings demonstrate that pathogen monitoring and treatment will remain a vital part of airway disease management for people with cystic fibrosis (pwCF) in the era of HEMT.

Abstract Despite an increasing desire to use historical cohorts as “synthetic” controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012–2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

ABSTRACTToday, more than 90% of people with cystic fibrosis (pwCF) are eligible for the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy called elexacaftor/tezacaftor/ivacaftor (ETI) and its use is widespread. Given the drastic respiratory symptom improvement experienced by many post-ETI, clinical studies are already underway to reduce the number of respiratory therapies, including antibiotic regimens, that pwCF historically relied on to combat lung disease progression. Early studies suggest that bacterial burden in the lungs is reduced post-ETI, yet it is unknown how chronic Pseudomonas aeruginosa populations are impacted by ETI. We found that pwCF remain infected throughout their upper and lower respiratory tract with their same strain of P. aeruginosa post-ETI, and these strains continue to evolve in response to the newly CFTR-corrected airway. Our work underscores the continued importance of CF airway microbiology in the new era of highly effective CFTR modulator therapy.IMPORTANCEThe highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

Abstract Background Prehabilitation and recovery programmes aim to optimise patients’ physical fitness and mental well-being before, during and after cancer treatment. This paper aimed to understand the impact of such a programme on emotional well-being in individuals undergoing cancer surgery. The programme was multi-modal, containing physical activity, well-being and nutritional support. Methods Qualitative interviews were conducted with 16 individuals who participated in a prehabilitation and recovery programme. Twenty-four health care staff involved in referral completed an online survey. An inductive, thematic analysis was conducted, integrating perspectives of patients and staff, structured with the Framework approach. Results Patients seemed to experience emotional benefits from the programme, appearing less anxious and more confident in their ability to cope with treatment. They seemed to value having something positive to focus on and control over an aspect of treatment. Ongoing, implicit psychological support provided by Exercise Specialists, who were perceived as expert, available and caring, seemed valued. Some patients appeared to appreciate opportunities to talk about cancer with peers and professionals. Discomfort with talking about cancer with other people, outside of the programme, was expressed. Conclusions Participation in a prehabilitation and recovery programme appeared to yield valuable emotional well-being benefits, even without referral to specialist psychological support. Study registration The study protocol was uploaded onto the Open Science Framework 24 September 2020 ( https://osf.io/347qj/ ).

Astringency is not considered one of the modern gustatory tastes. The understanding of astringency perception has evolved considerably over the past eighty years, but the exact mechanism is still undefined. This review aims to identify the current theory of astringency perception in the context of red wine. While astringency perception is a complicated mechanism that is not yet well understood, much research has focused on it. The studies discussed up to now have been done using red wine or wine-derived polyphenols. In a red wine context, astringency is driven by polyphenol concentration, galloylation and degree of polymerisation. Compounds that do not bind protein but are still strong astringent agonists are present in red wine. Among them, the role of polysaccharides and oligosaccharides is not clear, as these compounds are difficult to purify in quantities large enough for use in sensory studies. The literature strongly points to astringency being a compound perception. There is a stage of early protein binding, possibly as a “neutralising” effect for small amounts of dietary tannins with little actual perception, building into a more pronounced effect as tannin concentrations increase. A loss of lubrication in the oral cavity might announce the overpowering salivary protein capacity resulting from tannin concentrations, with direct detection of some astringent compounds once protein in the salivary fluid and the salivary pellicle are depleted.

Abstract Aims Given the increasing number of Hematopoietic Stem Cell Transplantations (HSCT) performed world-wide, the increasing likelihood of survival following HSCT, and the profound physical, psychosocial, and emotional impact of HSCT on survivors, their carers and families, it is important to identify factors that may contribute to or support post-traumatic growth (PTG) after transplant. In this study, we aimed to investigate the prevalence of PTG in an Australian cohort of long-term allogeneic HSCT survivors and describe associations between PTG and relevant clinical, sociodemographic and psychological variables. Methods This was a large, multi-centre, cross sectional survey of Australian HSCT-survivors inviting all those transplanted in New South Wales between 2000 and 2012. Respondents completed the PTG Inventory (PTGI), the Sydney Post-BMT Survey, FACT-BMT, DASS 21, The Chronic Graft versus Host Disease (GVHD) Activity Assessment–Patient Self-Report (Form B), the Lee Chronic GVHD Symptom Scale, and the Fear of Cancer Recurrence Scale. Data was analysed using independent t-tests, one-way analysis of variance, and pearson’s correlations, and hierarchical multiple regression adjusted for potential confounders and to ascertain independent associations of explanatory variables with PTG. Results Of 441 respondents, 99% reported some level of PTG with 67% reporting moderate to high levels of PTG. Female gender, younger age, complementary therapy use, anxiety, psychological distress and psychosocial care, and higher quality of life were associated with higher levels of PTG. Importantly, we also found that PTG was not associated with either chronic GVHD or post-HSCT morbidity. Conclusions In this study – the largest study of PTG in long-term allogeneic HSCT survivors - we found that growth appears ubiquitous, with 99% of survivors reporting some degree of PTG and 67% reporting moderate-high levels of PTG. Importantly, we found no association with GVHD or chronic physical post-HSCT morbidity, or adverse financial, occupational or sexual impacts. This suggests that it is the necessity for and experience of, HSCT itself that foments personal growth. Accordingly, healthcare professionals should be alert to the profound and wide-ranging impact of HSCT - and the degree to which survivor’s may experience PTG. Identifying interventions that may assist HSCT survivors cope and building their resilience is of utmost importance.

Abstract Background ‘Prehabilitation’ interventions aim to enhance individuals’ physical fitness prior to cancer treatment, typically involve exercise training as a key component, and may continue to support physical activity, strength, and fitness during or after treatment. However, uptake of prehabilitation is variable. This study investigated how patients from diverse socio-economic status groups perceived an exemplar prehabilitation and recovery programme, aiming to understand factors impacting acceptability, engagement and referral. Methods This research was conducted in the context of the Prehab4Cancer and Recovery Programme, a prehabilitation and recovery programme available across Greater Manchester, UK. Qualitative, semi-structured phone/video-call interviews were conducted with 18 adult patient participants referred to the programme (16 ‘engagers’, 2 ‘non-engagers’; half the sample lived in localities with low socio-economic status scores). An online questionnaire with free-response and categorical-response questions was completed by 24 ‘clinician’ participants involved in referral (nurses, doctors and other staff roles). An inductive, multi-perspective, thematic analysis was performed, structured using the Framework approach. Results Discussing and referring patients to prehabilitation can be challenging due to large quantities of information for staff to cover, and for patients to absorb, around the time of diagnosis. The programme was highly valued by both participant groups; the belief that participation would improve recovery seemed a major motivator for engagement, and some ‘clinicians’ felt that prehabilitation should be treated as a routine part of treatment, or extended to support other patient groups. Engagers seemed to appreciate a supportive approach where they did not feel forced to do any activity and tailoring of the programme to meet individual needs and abilities was appreciated. Initial engagement could be daunting, but gaining experience with the programme seemed to increase confidence. Conclusions The prehabilitation programme was highly valued by engagers. Introducing prehabilitation at a challenging time means that personalised approaches might be needed to support engagement, or participation could be encouraged at a later time. Strategies to support individuals lacking in confidence, such as buddying, may be valuable. Study registration The study protocol was uploaded onto the Open Science Framework 24 September 2020 ( https://osf.io/347qj/ ).

Abstract Mitral interventions remain technically challenging owing to the anatomical complexity and heterogeneity of mitral pathologies. As such, multi-disciplinary pre-procedural planning assisted by advanced cardiac imaging is pivotal to successful outcomes. Modern imaging techniques offer accurate 3D renderings of cardiac anatomy; however, users are required to derive a spatial understanding of complex mitral pathologies from a 2D projection thus generating an ‘imaging gap’ which limits procedural planning. Physical mitral modelling using 3D printing has the potential to bridge this gap and is increasingly being employed in conjunction with other transformative technologies to assess feasibility of intervention, direct prosthesis choice and avoid complications. Such platforms have also shown value in training and patient education. Despite important limitations, the pace of innovation and synergistic integration with other technologies is likely to ensure that 3D printing assumes a central role in the journey towards delivering personalised care for patients undergoing mitral valve interventions.

Abstract Biocompatibility and the ability to mediate the appropriate flux of ions, urea, and uremic toxins between blood and dialysate components are key parameters for membranes used in dialysis. Oxone-mediated TEMPO-oxidized cellulose nanomaterials have been demonstrated to be excellent additives in the production and tunability of ultrafiltration and dialysis membranes. In the present study, nanocellulose ionic liquid membranes (NC-ILMs) were tested in vitro and ex vivo. An increase in flux of up to two orders of magnitude was observed with increased rejection (about 99.6%) of key proteins compared to that of polysulfone (PSf) and other commercial membranes. NC-ILMs have a sharper molecular weight cut-off than other phase inversion polymeric membranes, allowing for high throughput of urea and a uremic toxin surrogate and limited passage of proteins in dialysis applications. Superior anti-fouling properties were also observed for the NC-ILMs, including a > 5-h operation time with no systemic anticoagulation in blood samples. Finally, NC-ILMs were found to be biocompatible in rat ultrafiltration and dialysis experiments, indicating their potential clinical utility in dialysis and other blood filtration applications. These superior properties may allow for a new class of membranes for use in a wide variety of industrial applications, including the treatment of patients suffering from renal disease.

MacroH2A histone variants are shown to mark a subset of enhancers in both normal and cancer cells. In mice, macroH2A deficiency is shown to facilitate increased activity of transcription stem cell-associated transcription factors.

Autonomous vehicles face challenges in ensuring cyber-physical security due to their reliance on image data from cameras processed by machine learning. These algorithms, however, are vulnerable to anomalies in the imagery, leading to decreased recognition accuracy and presenting security concerns. Current machine learning models struggle to predict unexpected vehicular situations, particularly with unpredictable objects and unexpected anomalies. To combat this, scholars are focusing on active inference, a method that can adapt models based on human cognition. This paper aims to incorporate active inference into autonomous vehicle systems. Multiple studies have delved into this approach, showing its potential to address security gaps in this field. Specifically, these frameworks have proven effective in handling unforeseen vehicular anomalies.

Autonomous driving (AD) has developed tremendously in parallel with the ongoing development and improvement of deep learning (DL) technology. However, the uptake of artificial intelligence (AI) in AD as the core enabling technology raises serious cybersecurity issues. An enhanced attack surface has been spurred on by the rising digitization of vehicles and the integration of AI features. The performance of the autonomous vehicle (AV)-based applications is constrained by the DL models' susceptibility to adversarial attacks despite their great potential. Hence, AI-enabled AVs face numerous security threats, which prevent the large-scale adoption of AVs. Therefore, it becomes crucial to evolve existing cybersecurity practices to deal with risks associated with the increased uptake of AI. Furthermore, putting defense models into practice against adversarial attacks has grown in importance as a field of study amongst researchers. Therefore, this study seeks to provide an overview of the most recent adversarial defensive and attack models developed in the domain of AD.

Little is known about how climate intervention through stratospheric aerosol injection (SAI) may affect the climatology of the Southern Hemisphere extratropical cyclones under warming scenarios. To address this knowledge gap, we tracked extratropical cyclones from 2015 to 2099 in a set of projections of three international projects: the Assessing Responses and Impacts of Solar Climate Intervention on the Earth System with Stratospheric Aerosol Injection (ARISE), the Stratospheric Aerosol Geoengineering Large Ensemble (GLENS), and the Geoengineering Model Intercomparison Project (GeoMIP/G6sulfur). Comparisons were performed between no-SAI and SAI scenarios as well as between different timeslices and their reference period (2015–2024). Among the findings, both no-SAI and SAI project a decrease in cyclone frequency towards the end of the century although weaker under SAI scenarios. On the other hand, cyclones tend to be stronger under no-SAI scenarios while keeping their intensity more similar to the reference period under SAI scenarios. This means that under SAI scenarios the climatology of cyclones is less affected by global warming than under no-SAI. Other features of these systems, such as travelling distance, lifetime, and mean velocity show small differences between no-SAI and SAI scenarios and between reference and future periods.

Introduction Non-alcoholic fatty liver disease is the most common chronic liver disease worldwide affecting 20%–25% in the USA and Europe with a 60%–80% lifetime prevalence for people with type 2 diabetes (T2D). Fibrosis has repeatedly been demonstrated to be the major determinant of liver disease morbidity and mortality and there is currently no routine screening for liver fibrosis in at-risk T2D population.Methods and analysis This 12-month prospective cohort study of automated fibrosis testing uses the fibrosis-4 score (FIB-4) in patients with T2D linked to the investigation of hospital-based versus community-based second-tier transient elastography (TE) testing. We plan to include >5000 participants across 10 General Practitioner (GP) practices in East London and Bristol. This will determine the rate of undiagnosed significant liver fibrosis in a T2D population, the feasibility of two-tier liver fibrosis screening using FIB-4 at the diabetes annual review and subsequent TE delivered either in the community or secondary care settings. This will include an intention-to-treat analysis for all those invited to attend for diabetes annual review. A qualitative substudy regarding the acceptability of the fibrosis screening pathway will comprise semistructured interviews/focus groups with primary care staff (GPs and practice nurses), and patients taking part in the wider study.Ethics and dissemination This study received a favourable opinion from the Cambridge East research ethics committee. The results of this study will be disseminated in peer-reviewed scientific journals, conference presentations and local diabetes lay panel meetings.Trial registration number ISRCTN14585543.

Abstract MicroRNAs (miRNAs) are single-stranded non-coding RNA molecules that play a regulatory role in gene expression and cancer cell signaling. We previously identified miR-628-5p (miR-628) as a potential biomarker in serum samples from men with prostate cancer (PCa) (Srivastava et al. in Tumour Biol 35:4867–4873, 10.1007/s13277-014-1638-1, 2014). This study examined the detailed cellular phenotypes and pathways regulated by miR-628 in PCa cells. Since obesity is a significant risk factor for PCa, and there is a correlation between levels of the obesity-associated hormone leptin and PCa development, here we investigated the functional relationship between leptin and miR-628 regulation in PCa. We demonstrated that exposure to leptin downregulated the expression of miR-628 and increased cell proliferation/migration in PCa cells. We next studied the effects on cancer-related phenotypes in PCa cells after altering miR-628 expression levels. Enforced expression of miR-628 in PCa cells inhibited cell proliferation, reduced PCa cell survival/migration/invasion/spheroid formation, and decreased markers of cell stemness. Mechanistically, miR-628 binds with the JAG1-3′UTR and inhibits the expression of Jagged-1 (JAG1). JAG1 inhibition by miR-628 downregulated Notch signaling, decreased the expression of Snail/Slug, and modulated epithelial-mesenchymal transition and invasiveness in PC3 cells. Furthermore, expression of miR-628 in PCa cells increased sensitivity towards the drugs enzalutamide and docetaxel by induction of cell apoptosis. Collectively our data suggest that miR-628 is a key regulator of PCa carcinogenesis and is modulated by leptin, offering a novel therapeutic opportunity to inhibit the growth of advanced PCa.

Summary: The cystic fibrosis (CF) respiratory tract harbors pathogenic bacteria that cause life-threatening chronic infections. Of these, Pseudomonas aeruginosa becomes increasingly dominant with age and is associated with worsening lung function and declining microbial diversity. We aimed to understand why P. aeruginosa dominates over other pathogens to cause worsening disease. Here, we show that P. aeruginosa responds to dynamic changes in iron concentration, often associated with viral infection and pulmonary exacerbations, to become more competitive via expression of the TseT toxic effector. However, this behavior can be therapeutically targeted using the iron chelator deferiprone to block TseT expression and competition. Overall, we find that iron concentration and TseT expression significantly correlate with microbial diversity in the respiratory tract of people with CF. These findings improve our understanding of how P. aeruginosa becomes increasingly dominant with age in people with CF and provide a therapeutically targetable pathway to help prevent this shift.

Background: Blood lactate concentration in the postoperative period is a marker of physiological stress and a predictor of complications and mortality. Cardiopulmonary exercise testing (CPET) is a common preoperative risk stratification tool. We aimed to investigate the association between preoperative CPET results and postoperative lactate concentration with postoperative mortality after major noncardiac surgery. Methods: We analysed data from patients undergoing major noncardiac surgery in a tertiary UK centre between 2007 and 2014 who had preoperative CPET and postoperative lactate measurements. Univariate and multivariate analyses were performed to assess the association between lactate concentration, CPET results, or both and mortality. Results: We analysed data from 1075 patients. A mean lactate concentration >2 mM in the first 12, 24, and 48 h after surgery was associated with odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day mortality of 3.9 (2.1–7.3; P

ABSTRACT Chronic rhinosinusitis (CRS) is a common, yet underreported and understudied manifestation of upper respiratory disease in people with cystic fibrosis (CF). Recently developed standard of care guidelines for the management of CF CRS suggest treatment of upper airway disease may ameliorate lower airway disease. We sought to determine whether changes to sinus microbial community diversity and specific taxa known to cause CF lung disease are associated with increased respiratory disease and inflammation. We performed 16S rRNA gene sequencing, supplemented with cytokine analyses, microscopy, and bacterial culturing, on samples from the sinuses of 27 adults with CF CRS. At each study visit, participants underwent endoscopic paranasal sinus sampling and clinical evaluation. We identified key drivers of microbial community composition and evaluated relationships between diversity and taxa with disease outcomes and inflammation. Sinus community diversity was low, and the composition was unstable, with many participants exhibiting alternating dominance between Pseudomonas aeruginosa and staphylococci over time. Despite a tendency for dominance by these two taxa, communities were highly individualized and shifted composition during exacerbation of sinus disease symptoms. Exacerbations were also associated with communities dominated by Staphylococcus spp. Reduced microbial community diversity was linked to worse sinus disease and the inflammatory status of the sinuses (including increased interleukin-1β [IL-1β]). Increased IL-1β was also linked to worse sinus endoscopic appearance, and other cytokines were linked to microbial community dynamics. Our work revealed previously unknown instability of sinus microbial communities and a link between inflammation, lack of microbial community diversity, and worse sinus disease. IMPORTANCE Together with prior sinus microbiota studies of adults with CF chronic rhinosinusitis, our study underscores similarities between sinus and lower respiratory tract microbial community structures in CF. We show how community structure tracks with inflammation and several disease measures. This work strongly suggests that clinical management of CRS could be leveraged to improve overall respiratory health in CF. Our work implicates elevated IL-1β in reduced microbiota diversity and worse sinus disease in CF CRS, suggesting applications for existing therapies targeting IL-1β. Finally, the widespread use of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has led to less frequent availability of spontaneous expectorated sputum for microbiological surveillance of lung infections. A better understanding of CF sinus microbiology could provide a much-needed alternative site for monitoring respiratory infection status by important CF pathogens.

Global climate models are good tools for simulating transnational and interregional transport of pollutants such as PM _2.5 , which is of growing interest and importance, for example in human health and socio-economic development studies. However, reliable estimates of PM _2.5 are very challenging for such relatively coarse and simplified models, and even state of the art models fare poorly in matching satellite observations in many highly polluted, and some almost pristine environments. This work describes a novel bias correction method based on multiple linear regression (MLR) modelling. The target data we aim for is global satellite-based data and the PM _2.5 precursors simulated by the Community Earth System Model Version 1.2.2. The statistical method greatly reduced the simulation biases of PM _2.5 worldwide compared with satellite-derived PM _2.5 , especially in highly-polluted regions, such as northern China, the Indo-Gangetic plains, the Democratic Republic of Congo and northwestern Brazil. Root-mean-square differences (RMSD) between continental-averaged observations and simulations are reduced from 75% to 9%. The ensemble RMSD for 13 countries exemplified here is reduced from 116% to 3%. One virtue of the MLR method is that details of the classification of internal mixed modes of each aerosol and their spatial differences are not required. The MLR coefficients are designed to be highly aerosol- and country-dependent, so they provide new perspectives of relative importance of each aerosol to local PM _2.5 and offer clues on observational and simulation biases. The bias-correction method is easily applied for air pollutants simulated by global climate models due to its low computational cost.

Autologous haematopoietic stem cell transplantation (AHSCT) is a vital therapeutic option for patients with highly active multiple sclerosis (MS). Rates of remission suggest AHSCT is the most effective form of immunotherapy in controlling the disease. Despite an evolving understanding of the biology of immune reconstitution following AHSCT, the mechanism by which AHSCT enables sustained disease remission beyond the period of lymphopenia remains to be elucidated. Auto-reactive T cells are considered central to MS pathogenesis. Here, we analyse T cell reconstitution for 36 months following AHSCT in a cohort of highly active MS patients. Through longitudinal analysis of sorted naïve and memory T cell clones, we establish that AHSCT induces profound changes in the dominant T cell landscape of both CD4+ and CD8+ memory T cell clones. Lymphopenia induced homeostatic proliferation is followed by clonal attrition; with only 19% of dominant CD4 (p

Abstract Accurate snow albedo simulation is a prerequisite for climate models to produce reliable climate prediction. Climate models would benefit from schemes of snowpack radiative transfer that are responsive to changing atmospheric conditions. However, the uncertainties in the narrowband snow optical parameters used by these schemes have not been evaluated. Conventional methods typically compute these narrowband parameters as irradiance‐weighted averages of the spectral snow optical parameters, with the single scattering albedo being additionally weighted by the optically thick snowpack albedo. We first evaluate the effectiveness of the conventional methods as adopted by the widely used Community Land Model (CLM). Snow albedo calculations using the CLM narrowband optical parameters are relatively accurate for very thin snow (e.g., a bias of 0.01 for a 2‐cm snowpack). The error, however, becomes larger as snowpack thickens (with biases of up to 0.05 for semi‐infinite snowpack), because the snow radiative transfer is highly nonlinear and is most significant at wavelengths

The nephrons in the kidney transport ions and organic molecules, but may not work effectively in patients with kidney disease. Here, a synthetic nephron is created, based on activated wafer electrodeionization, and shown to enable the transport of several physiologically relevant ions.

Goal: The aim of the study herein reported was to review mobile health (mHealth) technologies and explore their use to monitor and mitigate the effects of the COVID-19 pandemic. Methods: A Task Force was assembled by recruiting individuals with expertise in electronic Patient-Reported Outcomes (ePRO), wearable sensors, and digital contact tracing technologies. Its members collected and discussed available information and summarized it in a series of reports. Results: The Task Force identified technologies that could be deployed in response to the COVID-19 pandemic and would likely be suitable for future pandemics. Criteria for their evaluation were agreed upon and applied to these systems. Conclusions: mHealth technologies are viable options to monitor COVID-19 patients and be used to predict symptom escalation for earlier intervention. These technologies could also be utilized to monitor individuals who are presumed non-infected and enable prediction of exposure to SARS-CoV-2, thus facilitating the prioritization of diagnostic testing.

Summary: Pseudomonas aeruginosa notoriously adapts to the airways of people with cystic fibrosis (CF), yet how infection-site biogeography and associated evolutionary processes vary as lifelong infections progress remains unclear. Here we test the hypothesis that early adaptations promoting aggregation influence evolutionary-genetic trajectories by examining longitudinal P. aeruginosa from the sinuses of six adults with CF. Highly host-adapted lineages harbored mutator genotypes displaying signatures of early genome degradation associated with recent host restriction. Using an advanced imaging technique (MiPACT-HCR [microbial identification after passive clarity technique]), we find population structure tracks with genome degradation, with the most host-adapted, genome-degraded P. aeruginosa (the mutators) residing in small, sparse aggregates. We propose that following initial adaptive evolution in larger populations under strong selection for aggregation, P. aeruginosa persists in small, fragmented populations that experience stronger effects of genetic drift. These conditions enrich for mutators and promote degenerative genome evolution. Our findings underscore the importance of infection-site biogeography to pathogen evolution.

Cardiac catheterization associated with central vein cannulation can involve potential thrombotic and infectious complications due to multiple cannulation trials or improper placement. To minimize the risks, medical simulators are used for training. Simulators are also employed to test medical devices such as catheters before performing animal tests because they are more cost-effective and still reveal necessary improvements. However, commercial simulators are expensive, simplified for their purpose, and provide limited access sites. Inexpensive and anatomical cardiovascular simulators with central venous access for cannulation are sparse. Here, we developed an anatomically and physiologically accurate cardiovascular flow simulator to help train medical professionals and test medical devices. Our simulator includes an anatomical right atrium/ventricle, femoral and radial access sites, and considers the variability of arm position. It simulates physiological pulsatile blood flow with a setting for constant flow from 3 to 6 L/min and mimics physiological temperature (37°C). We demonstrated simulation by inserting a catheter into the system at radial/femoral access sites, passing it through the vasculature, and advancing it into the heart. We expect that our simulator can be used as an educational tool for cardiac catheterization as well as a testing tool that will allow for design iteration before moving to animal trials.

Tedera is a drought-tolerant perennial forage legume introduced in Australia in 2006. In October 2018, T15-1218 Lanza®, the world’s first tedera variety, was released by the Department of Primary Industries and Regional Development and Meat & Livestock Australia for commercial use. A key agronomic practise for the successful establishment and adoption of tedera is to have a robust herbicide package to control a range of grass and broadleaf weeds well tolerated by tedera. A total of 9 pre-emergent and 44 post-emergent herbicide treatments were evaluated in eight experiments from 2017 to 2021. To control grasses such as annual ryegrass (Lolium rigidum Gaud.), propyzamide and carbetamide can be recommended for pre- or post-emergent applications and butroxydim, clethodim, and haloxyfop for post-emergent applications. The broadleaf pre-emergent herbicides recommended are clopyralid to control emerged capeweed (Arctotheca calendula (L.) Levyns), fomesafen to control pre-emergent wild radish (Raphanus raphanistrum L.), and the double mix of fomesafen + diuron, flumetsulam + diuron, and the triple mix of fomesafen + diuron + flumetsulam to control pre-emergent capeweed, pre- and post-emergent wild radish, and other broadleaf weeds. The most consistently well tolerated post-emergent herbicides by tedera seedlings and adult plants were diflufenican, diuron, flumetsulam, fomesafen, and their two- or three-way mixes that will provide good control of capeweed and wild radish. Desiccants such as paraquat or diquat were also well tolerated by 1-year-old tedera plants that recovered after being desiccated.

Three-dimensional ultrasound mosaicing can increase image quality and expand the field of view. However, limited work has been done applying these compounded approaches for cardiac procedures focused on the mitral valve. For procedures targeting the mitral valve, transesophageal echocardiography (TEE) is the primary imaging modality used as it provides clear 3D images of the valve and surrounding tissues. However, TEE suffers from image artefacts and signal dropout, particularly for structures lying below the valve, including chordae tendineae, making it necessary to acquire alternative echo views to visualize these structures. Due to the limited field of view obtainable, the entire ventricle cannot be directly visualized in sufficient detail from a single image acquisition in 3D. We propose applying an image compounding technique to TEE volumes acquired from a mid-esophageal position and several transgastric positions in order to reconstruct a high-detail volume of the mitral valve and sub-valvular structures. This compounding technique utilizes both fully and semi-simultaneous group-wise registration to align the multiple 3D volumes, followed by a weighted intensity compounding step based on the monogenic signal. This compounding technique is validated using images acquired from two excised porcine mitral valve units and three patient data sets. We demonstrate that this compounding technique accurately captures the physical structures present, including the mitral valve, chordae tendineae and papillary muscles. The chordae length measurement error between the compounded ultrasound and ground-truth CT for two porcine valves is reported as 0.7 ± 0.6 mm and 0.6 ± 0.6 mm.

2020 Editors' and President's Report

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The City of Detroit filed a petition for bankruptcy on July 18, 2013. At the time, it represented the largest municipal bankruptcy in American history. On November 12, 2014 a complex settlement agreement was accepted by the United States Bankruptcy Court. Causes leading to Detroit’s bankruptcy traced back several decades. Yet, Detroit’s emergence from bankruptcy only took about five hundred days. The problems leading to the City’s financial crisis are not unique to Detroit. Technological change, demographic shifts, faulty financial decisions and other variables that plagued Detroit are present in other American public entities. It is inevitable that there will be larger public bankruptcies in the future. The value of Detroit’s story, however, is the example of how its financial crisis was resolved through the creative resolution process that involved the Court, the City and the wide circle of its financial stakeholders. Detroit’s bankruptcy creates a valuable historical benchmark and its lessons can greatly impact how future public bankruptcies in the United States are resolved.

Abstract: Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [

Computational models are employed to study and respond to pressing environmental issues such as groundwater contamination. This use of computational models, which often involves algorithms and uncertainty that are hidden to the public, has implications for environmental science literacy. This study applies a design-based research approach to explore how technology-infused science instruction can scaffold secondary students in developing proficiency with computational modeling of groundwater contamination as a facet of environmental science literacy. Descriptions of research-based, technology-infused learning experiences situated within a groundwater contamination issue-based context are shared, and evidence of students' subsequent learning is presented. Findings suggest that student learning may be supported by enacting instructional experiences that scaffold students in (a) developing first concrete then increasingly abstract understanding of groundwater system structure, function, and dynamics; (b) building conceptual connections between multiple types of models and representations of a system; and (c) explicitly engaging with and judging uncertainties associated with system models, model outputs, and associated arguments. Insights are shared concerning how instructional technologies including physical models, two-dimensional representations (e.g., maps and cross-sections), and computational models may be employed in science teaching to support students in developing computational modeling competencies needed for participating in debates and discussions about socioenvironmental problems like groundwater contamination.

Abstract Due to compromised homologous recombination (HR) repair, BRCA1‐ and BRCA2‐mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2‐deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2‐deficient cells, including olaparib‐resistant and cisplatin‐resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2‐deficient xenografts and inhibits growth of olaparib‐resistant patient‐derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication‐associated DNA double‐strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2‐compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA‐deficient tumours.

Los palos flamencos suelen dividirse en dos categorías: los palos a compás y los palos libres. La mayoría de los palos libres pertenece a la familia de los fandangos, que derivan de palos folklóricos rítmicos. Los palos libres surgieron a finales del siglo XIX y principios del XX, cuando cantaores profesionales ampliaron el repertorio flamenco transformando los palos rítmicos en obras libres. Entre estas últimas se encuentran los fandangos personales, asociados con el movimiento de la “ópera flamenca”. Este ensayo estudia dos posibles formas de compás en los fandangos personales: la de Pepe Marchena y la de Manolo Caracol. Propongo aquí que existe una amplia gama de expresiones rítmicas que incluye estructuras rítmicas claramente definidas, así como estructuras de cante libre. Sin embargo, siempre quedan vestigios de compás incluso en los ejemplos más libres del cante libre.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

To maximize utilization of our forest resources, detailed knowledge of wood property variation and the impacts this has on end-product performance is required at multiple scales (within and among trees, regionally). As many wood properties are difficult and time-consuming to measure our knowledge regarding their variation is often inadequate as is our understanding of their responses to genetic and silvicultural manipulation. The emergence of many non-destructive evaluation (NDE) methodologies offers the potential to greatly enhance our understanding of the forest resource; however, it is critical to recognize that any technique has its limitations and it is important to select the appropriate technique for a given application. In this review, we will discuss the following technologies for assessing wood properties both in the field: acoustics, Pilodyn, Resistograph and Rigidimeter and the lab: computer tomography (CT) scanning, DiscBot, near infrared (NIR) spectroscopy, radial sample acoustics and SilviScan. We will discuss these techniques, explore their utilization, and list applications that best suit each methodology. As an end goal, NDE technologies will help researchers worldwide characterize wood properties, develop accurate models for prediction, and utilize field equipment that can validate the predictions. The continued advancement of NDE technologies will also allow researchers to better understand the impact on wood properties on product performance.

Two isotopic ice core records from western Svalbard are calibrated to reconstruct more than 1000 years of past winter surface air temperature variations in Longyearbyen, Svalbard, and Vardø, northern Norway. Analysis of the derived reconstructions suggests that the climate evolution of the last millennium in these study areas comprises three major sub-periods. The cooling stage in Svalbard (ca. 800–1800) is characterized by a progressive winter cooling of approximately 0.9 °C century−1 (0.3 °C century−1 for Vardø) and a lack of distinct signs of abrupt climate transitions. This makes it difficult to associate the onset of the Little Ice Age in Svalbard with any particular time period. During the 1800s, which according to our results was the coldest century in Svalbard, the winter cooling associated with the Little Ice Age was on the order of 4 °C (1.3 °C for Vardø) compared to the 1900s. The rapid warming that commenced at the beginning of the 20th century was accompanied by a parallel decline in sea-ice extent in the study area. However, both the reconstructed winter temperatures as well as indirect indicators of summer temperatures suggest the Medieval period before the 1200s was at least as warm as at the end of the 1990s in Svalbard.

Historians have long examined the causes of the American Civil War. Frequently, they identify three explanatory factors: slavery, states’ rights and tariffs. This paper assesses the Tariffs of 1841 and 1842, asserting that arguments attributing the tariff as a causal factor of the Civil War are exaggerated and deserve reconsideration. Upon close examination, these tariff debates represent a continuation of a long-standing discourse as to whether American foreign trade policy should embrace free trade or protectionist characteristics. Consequently, these debates, which occurred only nineteen years before Fort Sumter, are more closely aligned with late 18th century debates over political economy than they are as a prelude cause to Civil War.

With conifer plantations having an increasingly important role in meeting the fiber needs of society, an understanding of the effect of silvicultural practices on wood quality is critical. The perception of wood quality varies, making it hard to define in a single statement; however, possibly the most succinct definition is “a measure of the aptness of wood for a given use”. In general, properties that have a positive influence on a specific product assist in defining changes in wood quality. Since wood properties exhibit large variability within annual rings, within trees, and among trees in a stand, and have both genetic and environmental components (i.e., vary with different physiographical regions), it is imperative to have an understanding of wood properties at multiple levels. In this paper, we review the typical variation patterns in wood properties of conifers, with specific emphasis on loblolly pine (Pinus taeda L.), and radiata pine (Pinus radiata D.Don), two of the most common conifer plantation species globally. We also describe the impact of conventional silvicultural treatments on wood quality. Modeling efforts to predict variation in wood properties within trees, and in response to silvicultural treatments are also summarized.

Background Autologous hematopoietic stem cell transplantation has been used since 1996 for the treatment of severe autoimmune diseases refractory to approved therapies. We evaluated the long-term outcomes of these transplants and aimed to identify potential prognostic factors.Design and Methods In this observational study we analyzed all first autologous hematopoietic stem cell transplants for autoimmune diseases reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1996–2007. The primary end-points for analysis were overall survival, progression-free survival and transplant-related mortality at 100 days.Results Nine hundred patients with autoimmune diseases (64% female; median age, 35 years) who underwent a first autologous hematopoietic stem cell transplant were included. The main diseases were multiple sclerosis (n=345), systemic sclerosis (n=175), systemic lupus erythematosus (n=85), rheumatoid arthritis (n=89), juvenile arthritis (n=65), and hematologic immune cytopenia (n=37). Among all patients, the 5-year survival was 85% and the progression-free survival 43%, although the rates varied widely according to the type of autoimmune disease. By multivariate analysis, the 100-day transplant-related mortality was associated with the transplant centers’ experience (P=0.003) and type of autoimmune disease (P=0.03). No significant influence of transplant technique was identified. Age less than 35 years (P=0.004), transplantation after 2000 (P=0.0015) and diagnosis (P=0.0007) were associated with progression-free survival.Conclusions This largest cohort studied worldwide shows that autologous hematopoietic stem cell transplantation can induce sustained remissions for more than 5 years in patients with severe autoimmune diseases refractory to conventional therapy. The type of autoimmune disease, rather than transplant technique, was the most relevant determinant of outcome. Results improved with time and were associated with the transplant centers’ experience. These data support ongoing and planned phase III trials to evaluate the place of autologous hematopoietic stem cell transplantation in the treatment strategy for severe autoimmune diseases.

My original intention had been to consider the roles being developed in British academic libraries to assist users in making full use of cartographic material that is available for their requirements - an almost predictable report on the blending of the old with the new and, again hopefully, coming to a slightly more positive vision of the future for the academic map library in the United Kingdom. That was before I received an e-mail from David Medyckyj-Scott, Research and Geo-Data Services Manager at the EDINA National Data Centre in Edinburgh and one of the key figures behind the implementation and development of the Digimap service to the UK Higher and Further Education sectors. Launched in 2000, Digimap delivers Ordnance Survey map data to subscribing institutions and allows staff and students to produce map extracts at set scales, to generate their own maps online or download map data to use with appropriate application software such as CAD or GIS. I do not think it is an overstatement to suggest that the advent of the Digimap service has been the most important and influential event in British academic map libraries in, at least, the last thirty years - and I say this as someone who was critically cautious of the service at the outset.