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Abstract Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy. Using a genetic screening approach that detects antigen-reactive TCRs with high sensitivity and specificity based on T cell activation, we show that high complexity TCR libraries can be efficiently screened against multiplexed antigen libraries to identify both HLA class I and II restricted TCRs. Through the identification of neoantigen-specific TCRs directly from melanoma as well as low tumor mutational burden microsatellite-stable colorectal carcinoma samples, we demonstrate the pan-cancer potential of this platform.

Abstract Global nickel demand is projected to double by 2050 to support low-carbon technologies and renewable energy production. However, biomass carbon emissions from clearing vegetation for nickel mining are rarely included in corporate sustainability reports or considered in mineral sourcing decisions. Here, we compiled data for 481 nickel mines and undeveloped deposits to show that the footprint of nickel mining could be 4 to 500 times greater than previously reported (depending on the mine site), and thus the environmental impacts of nickel products, including batteries, have been underestimated to date. We found large variation in biomass losses among mines, and, in many cases, these unaccounted carbon emissions were significant relative to other Scope 1 and Scope 2 emissions from nickel extraction and processing. Reporting emissions from biomass losses from mining is key for strategic decision making on where to source nickel needed for effective climate action.

We aimed to test whether hearing speech in phonetic categories (as opposed to a continuous/gradient fashion) affords benefits to "cocktail party" speech perception. We measured speech perception performance (recognition, localization, and source monitoring) in a simulated 3D cocktail party environment. We manipulated task difficulty by varying the number of additional maskers presented at other spatial locations in the horizontal soundfield (1-4 talkers) and via forward vs. time-reversed maskers, the latter promoting a release from masking. In separate tasks, we measured isolated phoneme categorization using two-alternative forced choice (2AFC) and visual analog scaling (VAS) tasks designed to promote more/less categorical hearing and thus test putative links between categorization and real-world speech-in-noise skills. We first show cocktail party speech recognition accuracy and speed decline with additional competing talkers and amidst forward compared to reverse maskers. Dividing listeners into "discrete" vs. "continuous" categorizers based on their VAS labeling (i.e., whether responses were binary or continuous judgments), we then show the degree of release from masking experienced at the cocktail party is predicted by their degree of categoricity in phoneme labeling and not high-frequency audiometric thresholds; more discrete listeners make less effective use of time-reversal and show less release from masking than their gradient responding peers. Our results suggest a link between speech categorization skills and cocktail party processing, with a gradient (rather than discrete) listening strategy benefiting degraded speech perception. These findings suggest that less flexibility in binning sounds into categories may be one factor that contributes to figure-ground deficits.

Wildlife management can generate social conflict when stakeholder perceptions of the target species are not considered. Introduced Ring-necked Parakeets (RNP) are established in the UK and have been added to the ‘general licence’ of birds that can be killed to prevent serious economic damage. We aimed to better understand perceptions of RNPs on a nationwide scale to inform mitigation actions for potential future conflict over RNP management. We surveyed 3,947 UK residents to understand awareness of, knowledge of and attitudes towards the RNP across the UK. We found that most respondents (90.2%) were aware of the RNP. Almost half of respondents (45.9%) held negative opinions, particularly against the RNP in rural areas (64.7%), suggesting landscape contexts influence attitudes. Respondent preference for the RNP was low in local neighbourhoods (7.80%) although the species was considered aesthetically pleasing by most (83.0%). Many respondents knew the species’ name (54.9%), but underestimated current population numbers in the UK (82.6%) and few knew its full native range (10.0%). We identified respondents’ ecological interest, age, education, preference for, awareness of and knowledge of the RNP as significant factors associated with perceptions. Our findings suggest that the RNP presents a complex socio-environmental challenge, with respondent awareness, knowledge and attitudes each forming an important component of perceptions towards this species. We recommend that wildlife managers utilise our findings and cohesive approach to enhance future RNP perception research in the UK and abroad and towards the success of any proposed management initiatives under the UK general licence.

Understanding the challenges faced by second language (L2) learners in lexical tone perception is crucial for effective language acquisition. This study investigates the impact of exaggerated acoustic properties on facilitating Mandarin tone learning for English speakers. Using synthesized tone stimuli, we systematically manipulated pitch contours through three key modifications: expanding the fundamental frequency (F0), increasing F0 (female voice), and extending the overall duration. Our objectives were to assess the influence of F0 expansion, higher F0, longer duration, and varied syllables on Mandarin tone learning and generalization. Participants engaged in a non-adaptive trial-by-trial tone identification task. Mixed-effects logistic regression modeling was used to analyze accuracy across learning phases, acoustic factors, and tones. Findings reveal improvements in accuracy from training to testing and generalization phases, indicating the effectiveness of perceptual training to tone perception for adult English speakers. Tone 1 emerged as the easiest to perceive, while Tone 3 posed the most challenge, consistent with established hierarchies of tonal acquisition difficulty. Analysis of acoustic factors highlighted tone-specific effects. Expanded F0 was beneficial for the identification of Tone 2 and Tone 3 but posed challenges for Tone 1 and Tone 4. Additionally, longer durations also exhibited varied effects across tones, aiding in the identification of Tone 3 and Tone 4 but hindering Tone 1 identification. The higher F0 was advantageous for Tone 2 but disadvantageous for Tone 3. Furthermore, the syllable ma facilitated the identification of Tone 1 and Tone 2 but not for Tone 3 and Tone 4. These findings enhance our understanding of the role of acoustic properties in L2 tone perception and have implications for the design of effective training programs for second language acquisition.

Abstract Ireland and Britain are two islands located at Europe's westernmost edge, both of which act as the final breeding outposts for many bird species within their European ranges. Despite their similar geographic locations and geological histories, Ireland and Britain host different breeding avifauna assemblages. Diversity profiles, which can serve as more robust alternatives to classic diversity indices, were employed in this study to explore disparities in the two islands' breeding avifauna assemblages. Variations in assemblages were explored, along with their potential drivers, through analyses at three levels: island‐scale breeding bird assemblage compositions, island‐scale diversity profiles considering 49 common breeding species, and habitat‐specific diversity profiles considering assemblages in east/central Irish farmland and East Anglian farmland. Analysis of the two islands' breeding avifauna assemblages revealed that the Irish assemblage is a complete subset of the British assemblage. Analyses of Irish and British assemblages at both an island scale and a habitat scale revealed patterns linking land use to trends within the two islands' avifauna assemblages. Irish assemblages contained greater proportions of insectivorous farmland species by abundance, while British assemblages contained greater proportions of seed‐eating farmland species; both trends appeared to be related to structural differences in agricultural land use on the two islands. The British and East Anglian assemblages exhibited higher diversity across all analyses, which appeared to be driven by the assemblages' higher relative abundances of species that were most genetically distinct. This study highlights the ability of diversity profiles to impart more information than classic diversity indices by incorporating species similarity data.

The frequency-following response (FFR) is an evoked potential that provides a neural index of complex sound encoding in the brain. FFRs have been widely used to characterize speech and music processing, experience-dependent neuroplasticity (e.g., learning and musicianship), and biomarkers for hearing and language-based disorders that distort receptive communication abilities. It is widely assumed that FFRs stem from a mixture of phase-locked neurogenic activity from the brainstem and cortical structures along the hearing neuraxis. In this study, we challenge this prevailing view by demonstrating that upwards of ~50% of the FFR can originate from an unexpected myogenic source: contamination from the postauricular muscle (PAM) vestigial startle reflex. We measured PAM, transient auditory brainstem responses (ABRs), and sustained frequency-following response (FFR) potentials reflecting myogenic (PAM) and neurogenic (ABR/FFR) responses in young, normal-hearing listeners with varying degrees of musical training. We first establish that PAM artifact is present in all ears, varies with electrode proximity to the muscle, and can be experimentally manipulated by directing listeners' eye gaze toward the ear of sound stimulation. We then show this muscular noise easily confounds auditory FFRs, spuriously amplifying responses 3–4-fold with tandem PAM contraction and even explaining putative FFR enhancements observed in highly skilled musicians. Our findings expose a new and unrecognized myogenic source to the FFR that drives its large inter-subject variability and cast doubt on whether changes in the response typically attributed to neuroplasticity/pathology are solely of brain origin.

Summary: SARM1 is a Toll-IL-1 receptor (TIR) domain-containing protein with roles in innate immunity and neuronal death in diverse organisms. Unlike other innate immune TIR proteins that function as adaptors for Toll-like receptors (TLRs), SARM1 has NADase activity, and this activity regulates murine neuronal cell death. However, whether human SARM1, and its NADase activity, are involved in innate immune regulation remains unclear. Here, we show that human SARM1 regulates proinflammatory cytokine expression in both an NADase-dependent and -independent manner in monocytes. SARM1 negatively regulated TLR4-dependent TNF mRNA induction independently of its NADase activity. In contrast, SARM1 inhibited IL-1β secretion through both NADase-dependent inhibition of pro-IL-1β expression, and NADase-independent suppression of the NLRP3 inflammasome and hence processing of pro-IL-1β to mature IL-1β. Our study reveals multiple mechanisms whereby SARM1 regulates pro-inflammatory cytokines in human monocytes and shows, compared to other mammalian TIR proteins, a distinct NADase-dependent role for SARM1 in innate immunity.

Abstract Dominance hierarchies often form between species, especially at common feeding locations. Yet, relative to work focused on the factors that maintain stable dominance hierarchies within species, large-scale analyses of interspecific dominance hierarchies have been comparatively rare. Given that interspecific behavioral interference mediates access to resources, these dominance hierarchies likely play an important and understudied role in community assembly and behavioral evolution. To test alternative hypotheses about the formation and maintenance of interspecific dominance hierarchies, we employ an large, participatory science generated dataset of displacements observed at feeders in North America in the non-breeding season. Consistent with the hypothesis that agonistic interference can be an adaptive response to exploitative competition, we find that species with similar niches are more likely to engage in costly aggression over resources. Among interacting species, we find broad support for the hypothesis that familiarity (measured as fine-scale habitat overlap) predicts adherence to the structure of the dominance hierarchy and reduces aggression between species. Our findings suggest that the previously documented agonistic hierarchy in North American birds emerges from species-level adaptations and learned behaviors that result in the avoidance of costly aggression.

Abstract Purpose The present study aimed at assessing the prevalences of post-traumatic stress disorder (PTSD) (main objective), anxiety, depression, and burnout syndrome (BOS) and their associated factors in intensive care unit (ICU) staff workers in the second year of the COVID-19 pandemic. Materials and methods An international cross-sectional multicenter ICU-based online survey was carried out among the ICU staff workers in 20 ICUs across 3 continents. ICUs staff workers (both caregivers and non-caregivers) were invited to complete PCL-5, HADS, and MBI questionnaires for assessing PTSD, anxiety, depression, and the different components of BOS, respectively. A personal questionnaire was used to isolate independent associated factors with these disorders. Results PCL-5, HADS, and MBI questionnaires were completed by 585, 570, and 539 responders, respectively (525 completed all questionnaires). PTSD was diagnosed in 98/585 responders (16.8%). Changing familial environment, being a non-caregiver staff worker, having not being involved in a COVID-19 patient admission, having not been provided with COVID-19-related information were associated with PTSD. Anxiety was reported in 130/570 responders (22.8%). Working in a public hospital, being a woman, being financially impacted, being a non-clinical healthcare staff member, having no theoretical or practical training on individual preventive measures, and fear of managing COVID-19 patients were associated with anxiety. Depression was reported in 50/570 responders (8.8%). Comorbidity at risk of severe COVID-19, working in a public hospital, looking after a child, being a non-caregiver staff member, having no information, and a request for moving from the unit were associated with depression. Having received no information and no adequate training for COVID-19 patient management were associated with all 3 dimensions of BOS. Conclusion The present study confirmed that ICU staff workers, whether they treated COVID-19 patients or not, have a substantial prevalence of psychological disorders.

Background: Many studies have demonstrated the benefits of long-term music training (i.e., musicianship) on the neural processing of sound, including simple tones and speech. However, the effects of musicianship on the encoding of simultaneously presented pitches, in the form of complex musical chords, is less well established. Presumably, musicians’ stronger familiarity and active experience with tonal music might enhance harmonic pitch representations, perhaps in an attention-dependent manner. Additionally, attention might influence chordal encoding differently across the auditory system. To this end, we explored the effects of long-term music training and attention on the processing of musical chords at the brainstem and cortical levels. Method: Young adult participants were separated into musician and nonmusician groups based on the extent of formal music training. While recording EEG, listeners heard isolated musical triads that differed only in the chordal third: major, minor, and detuned (4% sharper third from major). Participants were asked to correctly identify chords via key press during active stimulus blocks and watched a silent movie during passive blocks. We logged behavioral identification accuracy and reaction times and calculated information transfer based on the behavioral chord confusion patterns. EEG data were analyzed separately to distinguish between cortical (event-related potential, ERP) and subcortical (frequency-following response, FFR) evoked responses. Results: We found musicians were (expectedly) more accurate, though not faster, than nonmusicians in chordal identification. For subcortical FFRs, responses showed stimulus chord effects but no group differences. However, for cortical ERPs, whereas musicians displayed P2 (~150 ms) responses that were invariant to attention, nonmusicians displayed reduced P2 during passive listening. Listeners’ degree of behavioral information transfer (i.e., success in distinguishing chords) was also better in musicians and correlated with their neural differentiation of chords in the ERPs (but not high-frequency FFRs). Conclusions: Our preliminary results suggest long-term music training strengthens even the passive cortical processing of musical sounds, supporting more automated brain processing of musical chords with less reliance on attention. Our results also suggest that the degree to which listeners can behaviorally distinguish chordal triads is directly related to their neural specificity to musical sounds primarily at cortical rather than subcortical levels. FFR attention effects were likely not observed due to the use of high-frequency stimuli (>220 Hz), which restrict FFRs to brainstem sources.

Abstract Background Decisions about life-sustaining therapy (LST) in the intensive care unit (ICU) depend on predictions of survival as well as the expected functional capacity and self-perceived quality of life after discharge, especially in very old patients. However, prognostication for individual patients in this cohort is hampered by substantial uncertainty which can lead to a large variability of opinions and, eventually, decisions about LST. Moreover, decision-making processes are often embedded in a framework of ethical and legal recommendations which may vary between countries resulting in divergent management strategies. Methods Based on a vignette scenario of a multi-morbid 87-year-old patient, this article illustrates the spectrum of opinions about LST among intensivsts with a special interest in very old patients, from ten countries/regions, representing diverse cultures and healthcare systems. Results This survey of expert opinions and national recommendations demonstrates shared principles in the management of very old ICU patients. Some guidelines also acknowledge cultural differences between population groups. Although consensus with families should be sought, shared decision-making is not formally required or practised in all countries. Conclusions This article shows similarities and differences in the decision-making for LST in very old ICU patients and recommends strategies to deal with prognostic uncertainty. Conflicts should be anticipated in situations where stakeholders have different cultural beliefs. There is a need for more collaborative research and training in this field.

Abstract Birds are useful indicators of overall biodiversity, which continues to decline globally, despite targets to reduce its loss. The aim of this paper is to understand the importance of different spatial drivers for modelling bird distributions. Specifically, it assesses the importance of satellite‐derived measures of habitat productivity, heterogeneity and landscape structure for modelling bird diversity across Great Britain. Random forest (RF) regression is used to assess the extent to which a combination of satellite‐derived covariates explain woodland and farmland bird diversity and richness. Feature contribution analysis is then applied to assess the relationships between the response variable and the covariates in the final RF models. We show that much of the variation in farmland and woodland bird distributions is explained (R2 0.64–0.77) using monthly habitat‐specific productivity values and landscape structure (FRAGSTATS) metrics. The analysis highlights important spatial drivers of bird species richness and diversity, including high productivity grassland during spring for farmland birds and woodland patch edge length for woodland birds. The feature contribution provides insight into the form of the relationship between the spatial drivers and bird richness and diversity, including when a particular spatial driver affects bird richness positively or negatively. For example, for woodland bird diversity, the May 80th percentile Normalized Difference Vegetation Index (NDVI) for broadleaved woodland has a strong positive effect on bird richness when NDVI is >0.7 and a strong negative effect below. If relationships such as these are stable over time, they offer a useful analytical tool for understanding and comparing the influence of different spatial drivers.

Abstract Membrane proteins play critical roles in disease and in the disposition of many pharmaceuticals. A prime example is P-glycoprotein (Pgp) which moves a diverse range of drugs across membranes and out of the cell before a therapeutic payload can be delivered. Conventional structural biology methods have provided a valuable framework for comprehending the complex conformational changes underlying Pgp function, which also includes ATPase activity, but the lack of real-time information hinders understanding. Atomic force microscopy (AFM) is a single-molecule technique that is well-suited for studying active membrane proteins in bilayers and is poised to advance the field beyond static snapshots. After verifying Pgp activity in surface-support bilayers, we used kymograph analysis in conjunction with AFM imaging and simulations to study structural transitions at the 100 ms timescale. Though kymographs are frequently employed to boost temporal resolution, the limitations of the method have not been well characterized, especially for sparse non-crystalline distributions of pharmaceutically relevant membrane proteins like Pgp. Common experimental challenges are analyzed, including protein orientation, instrument noise, and drift. Surprisingly, a lateral drift of 75% of the protein dimension leads to only a 12% probability of erroneous state transition detection; average dwell time error achieves a maximum value of 6%. Rotational drift of proteins like Pgp, with azimuthally-dependent maximum heights, can lead to artifactual transitions. Torsional constraints can alleviate this potential pitfall. Confidence in detected transitions can be increased by adding conformation-altering ligands such as non-hydrolysable analogs. Overall, the data indicate that AFM kymographs are a viable method to access conformational dynamics for Pgp, but generalizations of the method should be made with caution.

Abstract Given that metals, minerals and energy resources extracted through mining are fundamental to human society, it follows that accurate data describing mine production are equally important. Although there are often national statistical sources, this typically includes data for metals (e.g., gold), minerals (e.g., iron ore) or energy resources (e.g., coal). No such study has ever compiled a national mine production data set which includes basic mining data such as ore processed, grades, extracted products (e.g., metals, concentrates, saleable ore) and waste rock. These data are crucial for geological assessments of mineable resources, environmental impacts, material flows (including losses during mining, smelting-refining, use and disposal or recycling) as well as facilitating more quantitative assessments of critical mineral potential (including possible extraction from tailings and/or waste rock left by mining). This data set achieves these needs for Australia, providing a world-first and comprehensive review of a national mining industry and an exemplar of what can be achieved for other countries with mining industry sectors.

ABSTRACTColonization with multidrug-resistant Escherichia coli strains causes a substantial health burden in hospitalized patients. We performed a longitudinal genomics study to investigate the colonization of resistant E. coli strains in critically ill patients and to identify evolutionary changes and strain replacement events within patients. Patients were admitted to the intensive care unit and hematology wards at a major hospital in Lebanon. Perianal swabs were collected from participants on admission and during hospitalization, which were screened for extended-spectrum beta-lactamases and carbapenem-resistant Enterobacterales. We performed whole-genome sequencing and analysis on E. coli strains isolated from patients at multiple time points. The E. coli isolates were genetically diverse, with 11 sequence types (STs) identified among 22 isolates sequenced. Five patients were colonized by E. coli sequence type 131 (ST131)-encoding CTX-M-27, an emerging clone not previously observed in clinical samples from Lebanon. Among the eight patients whose resident E. coli strains were tracked over time, five harbored the same E. coli strain with relatively few mutations over the 5 to 10 days of hospitalization. The other three patients were colonized by different E. coli strains over time. Our study provides evidence of strain diversity within patients during their hospitalization. While strains varied in their antimicrobial resistance profiles, the number of resistance genes did not increase over time. We also show that ST131-encoding CTX-M-27, which appears to be emerging as a globally important multidrug-resistant E. coli strain, is also prevalent among critical care patients and deserves further monitoring.IMPORTANCEUnderstanding the evolution of bacteria over time in hospitalized patients is of utmost significance in the field of infectious diseases. While numerous studies have surveyed genetic diversity and resistance mechanisms in nosocomial infections, time series of within-patient dynamics are rare, and high-income countries are over-represented, leaving low- and middle-income countries understudied. Our study aims to bridge these research gaps by conducting a longitudinal survey of critically ill patients in Lebanon. This allowed us to track Escherichia coli evolution and strain replacements within individual patients over extended periods. Through whole-genome sequencing, we found extensive strain diversity, including the first evidence of the emerging E. coli sequence type 131 clone encoding the CTX-M-27 beta-lactamase in a clinical sample from Lebanon, as well as likely strain replacement events during hospitalization.

Osteosarcoma is a rare type of bone cancer, and half of the cases affect children and adolescents younger than 20 years of age. Despite intensive efforts to improve both chemotherapeutics and surgical management, the clinical outcome for metastatic osteosarcoma remains poor. Transforming growth factor β (TGF-β) is one of the most abundant growth factors in bones. The TGF-β signaling pathway has complex and contradictory roles in the pathogenesis of human cancers. TGF-β is primarily a tumor suppressor that inhibits proliferation and induces apoptosis of premalignant epithelial cells. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking antitumor immune responses, increasing tumor-associated fibrosis, and enhancing angiogenesis. In contrast with the dual effects of TGF-β on carcinoma (epithelial origin) progression, TGF-β seems to mainly have a pro-tumoral effect on sarcomas including osteosarcoma (mesenchymal origin). Many drugs that target TGF-β signaling have been developed: neutralizing antibodies that prevent TGF-β binding to receptor complexes; ligand trap employing recombinant Fc-fusion proteins containing the soluble ectodomain of either type II (TβRII) or the type III receptor ((TβRIII), preventing TGF-β from binding to its receptors; antisense nucleotides that reduce TGF-β expression at the transcriptional/translational level; small molecule inhibitors of serine/threonine kinases of the type I receptor (TβRI) preventing downstream signaling; and vaccines that contain cell lines transfected with TβRII antisense genes, or target furin convertase, resulting in reduced TGF-β signaling.TGF-β antagonists have been shown to have effects on osteosarcoma in vitro and in vivo. One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. Several phase 1/2/3 clinical trials have shown TGF-β antagonists are safe and well tolerated. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.

Summary: Perception of bistable stimuli is influenced by prior context. In some cases, the interpretation matches with how the preceding stimulus was perceived; in others, it tends to be the opposite of the previous stimulus percept. We measured high-density electroencephalography (EEG) while participants were presented with a sequence of vowels that varied in formant transition, promoting the perception of one or two auditory streams followed by an ambiguous bistable sequence. For the bistable sequence, participants were more likely to report hearing the opposite percept of the one heard immediately before. This auditory contrast effect coincided with changes in alpha power localized in the left angular gyrus and left sensorimotor and right sensorimotor/supramarginal areas. The latter correlated with participants’ perception. These results suggest that the contrast effect for a bistable sequence of vowels may be related to neural adaptation in posterior auditory areas, which influences participants’ perceptual construal level of ambiguous stimuli.

Abstract Background As primary care populations age, timely identification of palliative care need is becoming increasingly relevant. Previous studies have targeted particular patient populations with life-limiting disease, but few have focused on patients in a primary care setting. Toward this end, we propose a stepped-wedge pragmatic randomized trial whereby a machine learning algorithm identifies patients empaneled to primary care units at Mayo Clinic (Rochester, Minnesota, United States) with high likelihood of palliative care need. Methods 42 care team units in 9 clusters were randomized to 7 wedges, each lasting 42 days. For care teams in treatment wedges, palliative care specialists review identified patients, making recommendations to primary care providers when appropriate. Care teams in control wedges receive palliative care under the standard of care. Discussion This pragmatic trial therefore integrates machine learning into clinical decision making, instead of simply reporting theoretical predictive performance. Such integration has the possibility to decrease time to palliative care, improving patient quality of life and symptom burden. Trial registration Clinicaltrials.gov NCT04604457 , restrospectively registered 10/26/2020. Protocol v0.5, dated 9/23/2020

Objective: To estimate rates and identify factors associated with asymptomatic COVID-19 in the population of Olmsted County during the prevaccination era. Patients and Methods: We screened first responders (n=191) and Olmsted County employees (n=564) for antibodies to SARS-CoV-2 from November 1, 2020 to February 28, 2021 to estimate seroprevalence and asymptomatic infection. Second, we retrieved all polymerase chain reaction (PCR)-confirmed COVID-19 diagnoses in Olmsted County from March 2020 through January 2021, abstracted symptom information, estimated rates of asymptomatic infection and examined related factors. Results: Twenty (10.5%; 95% CI, 6.9%-15.6%) first responders and 38 (6.7%; 95% CI, 5.0%-9.1%) county employees had positive antibodies; an additional 5 (2.6%) and 10 (1.8%) had prior positive PCR tests per self-report or medical record, but no antibodies detected. Of persons with symptom information, 4 of 20 (20%; 95% CI, 3.0%-37.0%) first responders and 10 of 39 (26%; 95% CI, 12.6%-40.0%) county employees were asymptomatic. Of 6020 positive PCR tests in Olmsted County with symptom information between March 1, 2020, and January 31, 2021, 6% (n=385; 95% CI, 5.8%-7.1%) were asymptomatic. Factors associated with asymptomatic disease included age (0-18 years [odds ratio {OR}, 2.3; 95% CI, 1.7-3.1] and >65 years [OR, 1.40; 95% CI, 1.0-2.0] compared with ages 19-44 years), body mass index (overweight [OR, 0.58; 95% CI, 0.44-0.77] or obese [OR, 0.48; 95% CI, 0.57-0.62] compared with normal or underweight) and tests after November 20, 2020 ([OR, 1.35; 95% CI, 1.13-1.71] compared with prior dates). Conclusion: Asymptomatic rates in Olmsted County before COVID-19 vaccine rollout ranged from 6% to 25%, and younger age, normal weight, and later tests dates were associated with asymptomatic infection.

Summary: Background: Exercise can rapidly drop glucose in people with type 1 diabetes. Ubiquitous wearable fitness sensors are not integrated into automated insulin delivery (AID) systems. We hypothesised that an AID can automate insulin adjustments using real-time wearable fitness data to reduce hypoglycaemia during exercise and free-living conditions compared with an AID not automating use of fitness data. Methods: Our study population comprised of individuals (aged 21–50 years) with type 1 diabetes from from the Harold Schnitzer Diabetes Health Center clinic at Oregon Health and Science University, OR, USA, who were enrolled into a 76 h single-centre, two-arm randomised (4-block randomisation), non-blinded crossover study to use (1) an AID that detects exercise, prompts the user, and shuts off insulin during exercise using an exercise-aware adaptive proportional derivative (exAPD) algorithm or (2) an AID that automates insulin adjustments using fitness data in real-time through an exercise-aware model predictive control (exMPC) algorithm. Both algorithms ran on iPancreas comprising commercial glucose sensors, insulin pumps, and smartwatches. Participants executed 1 week run-in on usual therapy followed by exAPD or exMPC for one 12 h primary in-clinic session involving meals, exercise, and activities of daily living, and 2 free-living out-patient days. Primary outcome was time below range (

Abstract Background Up to 11% of critically ill patients with sepsis have an unknown source, where the pathogen and site of infection are unclear. The aim of this scoping review is to document currently reported diagnostic criteria of sepsis of unknown origin (SUO) and identify the types and breadth of existing evidence supporting diagnostic processes to identify the infection source in critically ill patients with suspected SUO. Methods A literature search of Embase, MEDLINE and PubMed for published studies from 1910 to August 19, 2021 addressing the topic of SUO was performed. Study type, country of origin according to World Bank classification, diagnostic criteria of sepsis of unknown origin, and investigative approaches were extracted from the studies. Results From an initial 722 studies, 89 unique publications fulfilled the inclusion and exclusion criteria and were included for full text review. The most common publication type was case report/series 45/89 (51%). Only 10/89 (11%) of studies provided a diagnostic criteria of SUO, but a universally accepted diagnostic criterion was not identified. The included studies discussed 30/89 (34%) history, 23/89 (26%) examination, 57/89 (64%) imaging, microbiology 39/89 (44%), and special tests 32/89 (36%) as part of the diagnostic processes in patients with SUO. Conclusions Universally accepted diagnostic criteria for SUO was not found. Prospective studies on investigative processes in critically ill patients managed as SUO across different healthcare settings are needed to understand the epidemiology and inform the diagnostic criteria required to diagnose SUO.

Abstract The influence of supplementary feeding of wildlife on disease transmission and its consequent impacts on population dynamics are underappreciated. In Great Britain, supplementary feeding is hypothesised to have enabled the spread of the protozoan parasite, Trichomonas gallinae, from columbids to finches, leading to epidemic finch trichomonosis and a rapid population decline of greenfinch (Chloris chloris). More recently, chaffinch (Fringilla coelebs), has also declined markedly from the second to fifth commonest bird in Britain. Using citizen science data, we show that both declines were driven primarily by reduced adult survival, with the greatest reductions occurring in peri-domestic habitats, where supplementary food provision is common. Post-mortem examinations showed a proportional increase in chaffinch trichomonosis cases, near-contemporaneous with its population decline. Like greenfinches, chaffinches often use supplementary food, but are less associated with human habitation. Our results support the hypothesis that supplementary feeding can increase parasite transmission frequency within and between common species. However, the dynamics behind resultant population change can vary markedly, highlighting the need for integrating disease surveillance with demographic monitoring. Other species susceptible to T. gallinae infection may also be at risk. Supplementary feeding guidelines for wildlife should include disease mitigation strategies to ensure that benefits to target species outweigh risks.

Summary: System-level analysis of single-cell data is rapidly transforming the field of immunometabolism. Given the competitive demand for nutrients in immune microenvironments, there is a need to understand how and when immune cells access these nutrients. Here, we describe a new approach for single-cell analysis of nutrient uptake where we use in-cell biorthogonal labeling of a functionalized amino acid after transport into the cell. In this manner, the bona fide active uptake of glutamine via SLC1A5/ASCT2 could be quantified. We used this assay to interrogate the transport capacity of complex immune subpopulations, both in vitro and in vivo. Taken together, our findings provide an easy sensitive single-cell assay to assess which cells support their function via SLC1A5-mediated uptake. This is a significant addition to the single-cell metabolic toolbox required to decode the metabolic landscape of complex immune microenvironments.

Drought prone, arid and semi-arid ecosystems are challenging to restore once degraded due to low levels of natural recruitment and survival of reintroduced plants. This is evident in the restoration of degraded succulent thicket habitats in the Albany Subtropical Thicket Biome located in South Africa. The current restoration practice for this ecosystem focuses predominantly on reintroducing Portulacaria afra L. Jacq., which is naturally dominant in terms of cover and biomass, but largely absent in regions degraded by domestic livestock. This has been achieved by planting unrooted cuttings with limited consideration of soil water availability in a drought-prone ecosystem. This study tests the effects of the timing of water availability after planting on the root development of P. afra cuttings. Cuttings were harvested from seven individual plants and grown in a glasshouse setting. Eighty four cuttings were taken from each individual, twelve for each of the seven watering treatments per individual plant. The treatments represented a time-staggered initial watering after planting, including: on the day of planting, 4 days, 7 days, 14 days, 21 days, and 28 days after planting. After 32 days, all treatments were watered on a bi-weekly basis for two weeks; a control treatment with no watering throughout the experiment was included. The proportion of rooted cuttings per treatment and dry root mass were determined at the end of the experimental period (day 42). The early onset of watering was associated with a higher percentage of rooting (X2(5) = 11.352, p = 0.045) and had a weak, but non-significant, impact on the final dry root mass (F5,36 = 2.109, p = 0.0631). Importantly, no clear rooting window within 28 days was detected as the majority of cuttings exhibited root development (greater than 50% of cuttings rooted for each individual parent-plant); this suggests that watering at the time of planting P. afra cuttings in-field for restoration may not be necessary. An unexpected, but important, result was that parent-plant identity had a strong interaction with the accumulation of root mass (F36,460 = 5.026, p

A deviation in the soundness of cognitive health is known as mild cognitive impairment (MCI), and it is important to monitor it early to prevent complicated diseases such as dementia, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Traditionally, MCI severity is monitored with manual scoring using the Montreal Cognitive Assessment (MoCA). In this study, we propose a new MCI severity monitoring algorithm with regression analysis of extracted features of single-channel electro-encephalography (EEG) data by automatically generating severity scores equivalent to MoCA scores. We evaluated both multi-trial and single-trail analysis for the algorithm development. For multi-trial analysis, 590 features were extracted from the prominent event-related potential (ERP) points and corresponding time domain characteristics, and we utilized the lasso regression technique to select the best feature set. The 13 best features were used in the classical regression techniques: multivariate regression (MR), ensemble regression (ER), support vector regression (SVR), and ridge regression (RR). The best results were observed for ER with an RMSE of 1.6 and residual analysis. In single-trial analysis, we extracted a time–frequency plot image from each trial and fed it as an input to the constructed convolutional deep neural network (CNN). This deep CNN model resulted an RMSE of 2.76. To our knowledge, this is the first attempt to generate automated scores for MCI severity equivalent to MoCA from single-channel EEG data with multi-trial and single data.

Mostly produced as a by-product of zinc (Zn) mining, cadmium (Cd) is used in solar photovoltaic cells, battery storage, alloys, pigments, plating, and in nuclear reactors. However, it is also a regulated toxic substance with a long history of environmental and health impacts. As the mining of both Zn and Cd will need to increase to support the global energy transition, the status of Cd as either a resource or a pollutant has major implications for global supply chains and environmental management. Here, we present a new global, site-specific database and analysis of Cd resources in Zn-bearing mineral deposits and mines. Our database, which exceeds past Cd studies in scope, transparency and replicability is made available in full to support future assessments of Cd and Zn resources, mine production and associated risks. It includes 927 sites subject to detailed geological data compilation and analysis. Collectively, these sites suggest a new global resource estimate of 3.3 Mt Cd (95% confidence interval: 2.7–6.1 Mt). A preliminary geospatial analysis of sites in our database and mine toxicity indicators was also conducted. It shows that: As ∼27% of Cd resources are in countries that do not refine it, our study highlights the need for further research exploring global Cd trade flows and associated emissions. Heavy metal pollution in mining and metal production regions is an ongoing challenge, and our global dataset refines our understanding of its magnitude and distribution.

Abstract Background Limitations of life-sustaining interventions in intensive care units (ICUs) exhibit substantial changes over time, and large, contemporary variation across world regions. We sought to determine whether a weighted end-of-life practice score can explain a large, contemporary, worldwide variation in limitation decisions. Methods The 2015–2016 (Ethicus-2) vs. 1999–2000 (Ethicus-1) comparison study was a two-period, prospective observational study assessing the frequency of limitation decisions in 4952 patients from 22 European ICUs. The worldwide Ethicus-2 study was a single-period prospective observational study assessing the frequency of limitation decisions in 12,200 patients from 199 ICUs situated in 8 world regions. Binary end-of-life practice variable data (1 = presence; 0 = absence) were collected post hoc (comparison study, 22/22 ICUs, n = 4592; worldwide study, 186/199 ICUs, n = 11,574) for family meetings, daily deliberation for appropriate level of care, end-of-life discussions during weekly meetings, written triggers for limitations, written ICU end-of-life guidelines and protocols, palliative care and ethics consultations, ICU-staff taking communication or bioethics courses, and national end-of-life guidelines and legislation. Regarding the comparison study, generalized estimating equations (GEE) analysis was used to determine associations between the 12 end-of-life practice variables and treatment limitations. The weighted end-of-life practice score was then calculated using GEE-derived coefficients of the end-of-life practice variables. Subsequently, the weighted end-of-life practice score was validated in GEE analysis using the worldwide study dataset. Results In comparison study GEE analyses, end-of-life discussions during weekly meetings [odds ratio (OR) 0.55, 95% confidence interval (CI) 0.30–0.99], end-of-life guidelines [OR 0.52, (0.31–0.87)] and protocols [OR 15.08, (3.88–58.59)], palliative care consultations [OR 2.63, (1.23–5.60)] and end-of-life legislation [OR 3.24, 1.60–6.55)] were significantly associated with limitation decisions (all P

The brain transforms continuous acoustic events into discrete category representations to downsample the speech signal for our perceptual-cognitive systems. Such phonetic categories are highly malleable, and their percepts can change depending on surrounding stimulus context. Previous work suggests these acoustic-phonetic mapping and perceptual warping of speech emerge in the brain no earlier than auditory cortex. Here, we examined whether these auditory-category phenomena inherent to speech perception occur even earlier in the human brain, at the level of auditory brainstem. We recorded speech-evoked frequency following responses (FFRs) during a task designed to induce more/less warping of listeners’ perceptual categories depending on stimulus presentation order of a speech continuum (random, forward, backward directions). We used a novel clustered stimulus paradigm to rapidly record the high trial counts needed for FFRs concurrent with active behavioral tasks. We found serial stimulus order caused perceptual shifts (hysteresis) near listeners’ category boundary confirming identical speech tokens are perceived differentially depending on stimulus context. Critically, we further show neural FFRs during active (but not passive) listening are enhanced for prototypical vs. category-ambiguous tokens and are biased in the direction of listeners’ phonetic label even for acoustically-identical speech stimuli. These findings were not observed in the stimulus acoustics nor model FFR responses generated via a computational model of cochlear and auditory nerve transduction, confirming a central origin to the effects. Our data reveal FFRs carry category-level information and suggest top-down processing actively shapes the neural encoding and categorization of speech at subcortical levels. These findings suggest the acoustic-phonetic mapping and perceptual warping in speech perception occur surprisingly early along the auditory neuroaxis, which might aid understanding by reducing ambiguity inherent to the speech signal.

IntroductionSpoken language comprehension requires listeners map continuous features of the speech signal to discrete category labels. Categories are however malleable to surrounding context and stimulus precedence; listeners’ percept can dynamically shift depending on the sequencing of adjacent stimuli resulting in a warping of the heard phonetic category. Here, we investigated whether such perceptual warping—which amplify categorical hearing—might alter speech processing in noise-degraded listening scenarios.MethodsWe measured continuous dynamics in perception and category judgments of an acoustic-phonetic vowel gradient via mouse tracking. Tokens were presented in serial vs. random orders to induce more/less perceptual warping while listeners categorized continua in clean and noise conditions.ResultsListeners’ responses were faster and their mouse trajectories closer to the ultimate behavioral selection (marked visually on the screen) in serial vs. random order, suggesting increased perceptual attraction to category exemplars. Interestingly, order effects emerged earlier and persisted later in the trial time course when categorizing speech in noise.DiscussionThese data describe interactions between perceptual warping in categorization and speech-in-noise perception: warping strengthens the behavioral attraction to relevant speech categories, making listeners more decisive (though not necessarily more accurate) in their decisions of both clean and noise-degraded speech.

The microbiome, an influential factor affecting plant health and growth, is attracting increasing interest with respect to wine grape production. The purpose of this study was to characterize the microbiome (fungi and bacteria) of the soil, cover crop roots, and grape (Vitis spp.) roots across rootstock and depth in a cool-climate, organic vineyard. The cover crop consisted of a fescue (Festuca sp.) grass, while grape roots were sampled from New York Muscat, a cool-climate hybrid, across three root types (ungrafted, 3309C and Riparia Gloire) at three root depths (0 to 15, 15 to 30, and 30 to 50 cm). The grape root microbiome was more specialized, with fewer observed amplicon sequence variants for both bacteria (16S) and fungi (internal transcribe spacer) than found in the cover crop and the surrounding soil. Grape roots were dominated by bacterial genera Pseudomonas, Niastella, and Rhizobium; most prominent fungal genera were Plectosphaerella, Trichosporon, and Ilyonectria. Although no correlations were found between α-diversity metrics and soil parameters, Pseudaleuria relative abundance was correlated with Mn, Fe, and Na levels. Soil depth explained a small portion of bacterial but not fungal variance and taxonomic composition. Rootstock type explained a portion of both bacterial and fungal variance and taxonomic composition, substantiating the role of host plant genetics in the development of the grape root microbiome. This is the first characterization of the grape root microbiome in a cool-climate Canadian vineyard.

Many microbiome differential abundance methods are available, but it lacks systematic comparison among them. Here, the authors compare the performance of 14 differential abundance testing methods on 38 16S rRNA gene datasets with two sample groups, and show ALDEx2 and ANCOM-II produce the most consistent results.

IntroductionReal time modulation of brainstem frequency-following responses (FFRs) by online changes in cortical arousal state via the corticofugal (top-down) pathway has been demonstrated previously in young adults and is more prominent in the presence of background noise. FFRs during high cortical arousal states also have a stronger relationship with speech perception. Aging is associated with increased auditory brain responses, which might reflect degraded inhibitory processing within the peripheral and ascending pathways, or changes in attentional control regulation via descending auditory pathways. Here, we tested the hypothesis that online corticofugal interplay is impacted by age-related hearing loss.MethodsWe measured EEG in older adults with normal-hearing (NH) and mild to moderate hearing-loss (HL) while they performed speech identification tasks in different noise backgrounds. We measured α power to index online cortical arousal states during task engagement. Subsequently, we split brainstem speech-FFRs, on a trial-by-trial basis, according to fluctuations in concomitant cortical α power into low or high α FFRs to index cortical-brainstem modulation.ResultsWe found cortical α power was smaller in the HL than the NH group. In NH listeners, α-FFRs modulation for clear speech (i.e., without noise) also resembled that previously observed in younger adults for speech in noise. Cortical-brainstem modulation was further diminished in HL older adults in the clear condition and by noise in NH older adults. Machine learning classification showed low α FFR frequency spectra yielded higher accuracy for classifying listeners’ perceptual performance in both NH and HL participants. Moreover, low α FFRs decreased with increased hearing thresholds at 0.5–2 kHz for clear speech but noise generally reduced low α FFRs in the HL group.DiscussionCollectively, our study reveals cortical arousal state actively shapes brainstem speech representations and provides a potential new mechanism for older listeners’ difficulties perceiving speech in cocktail party-like listening situations in the form of a miss-coordination between cortical and subcortical levels of auditory processing.

Urbanisation and population growth are concentrated on the coast with approximately 40% of the human population living within 100 km of the ocean. The freshwater systems on which coastal urban areas rely are vulnerable to bidirectional pressures including coastal processes such as sea-level rise and coastal erosion coupled with land use changes and pollution occurring in inland catchment areas. These threats are likely to be amplified in the future under climate change conditions and more frequent and severe drought periods are expected to jeopardise already constrained water supply systems. Groundwater is used as a freshwater resource globally and is especially important as a conjunctive supply during drought periods due to perceived buffer capabilities. However, several threats impact coastal aquifers due to over-abstraction, such as salinisation, land subsidence and groundwater flooding and often these subterranean resources are “out of sight and out of mind” when it comes to management strategies. Here, we present an assessment of current issues and management options relevant to coastal aquifers using recent literature. These insights provide knowledge on global issues relevant to groundwater resources, especially regarding water use during droughts. This is exemplified using a South African case study of two metropolitan municipalities that have experienced or are experiencing severe multi-year droughts. Both municipalities have grappled with the depletion of surface water resources, which constitutes the bulk of the local water supply systems. Consequently, groundwater resources have been explored as an augmentation strategy. Although groundwater resources may be useful in alleviating drought effects, it is crucial that a local understanding of the aquifers is developed through baseline hydrological studies and long-term monitoring. Furthermore, unregistered groundwater use needs to be quantified. Finally, a holistic groundwater management view, and the communication thereof, is required to ensure the sustainable management of coastal aquifers.

Background Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors.Methods Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed.Results No DLTs occurred in parts A (n=18) or B (n=85). Grade 3–5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35).Conclusions Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy.Trial registration number NCT02043665.

OBJECTIVES:. To summarize the most impactful articles relevant to the pharmacotherapy of critically ill adult patients published in 2021. DATA SOURCE:. PubMed/MEDLINE. STUDY SELECTION:. Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critical care patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2021, and December 31, 2021. DATA EXTRACTION:. Candidate articles were organized by clinical domain based on the emerging themes from all studies. A modified Delphi process was applied to obtain consensus on the most impactful publication within each clinical domain based on overall contribution to scientific knowledge and novelty to the literature. DATA SYNTHESIS:. The search revealed 830 articles, of which 766 were excluded leaving 64 candidate articles for the Delphi process. These 64 articles were organized by clinical domain including: emergency/neurology, cardiopulmonary, nephrology/fluids, infectious diseases, metabolic, immunomodulation, and nutrition/gastroenterology. Each domain required the a priori defined three Delphi rounds. The resultant most impactful articles from each domain included five randomized controlled trials and two systematic review/meta-analyses. Topics studied included sedation during mechanical ventilation, anticoagulation in COVID-19, extended infusion beta-lactams, interleukin-6 antagonists in COVID-19, balanced crystalloid resuscitation, vitamin C/thiamine/hydrocortisone in sepsis, and promotility agents during enteral feeding. CONCLUSIONS:. This synoptic review provides a summary and perspective of the most impactful articles relevant to the pharmacotherapy of critically ill adults published in 2021.

Experimental evidence in animals demonstrates cortical neurons innervate subcortex bilaterally to tune brainstem auditory coding. Yet, the role of the descending (corticofugal) auditory system in modulating earlier sound processing in humans during speech perception remains unclear. Here, we measured EEG activity as listeners performed speech identification tasks in different noise backgrounds designed to tax perceptual and attentional processing. We hypothesized brainstem speech coding might be tied to attention and arousal states (indexed by cortical α power) that actively modulate the interplay of brainstem-cortical signal processing. When speech-evoked brainstem frequency-following responses (FFRs) were categorized according to cortical α states, we found low α FFRs in noise were weaker, correlated positively with behavioral response times, and were more ”decodable” via neural classifiers. Our data provide new evidence for online corticofugal interplay in humans and establish that brainstem sensory representations are continuously yoked to (i.e., modulated by) the ebb and flow of cortical states to dynamically update perceptual processing.

Abstract A spatially explicit eco‐evolutionary model assembles simulated meta‐communities which are subjected to species and community perturbation experiments to determine factors affecting the stability of the global ecosystem. Spatial structure and resource variety increase the persistence of the ensembles against the removal of an individual species, yet they remain vulnerable to re‐invasion by an existing member of the meta‐community if it is introduced to all patches with minimal population. Optimal reserve placement strategies are identified for maximally preserving global biodiversity from the effects of sequences of patch disruption, and targeted reserve placement that shields the most or the rarest biodiversity is usually effective. However, if disturbed populations are permitted to re‐settle in neighboring patches, then reserves should also be situated remotely to isolate their residents from invasion.

Candida albicans causes severe invasive candidiasis. C. albicans infection requires the virulence factor candidalysin (CL) which damages target cell membranes. However, the mechanism that CL uses to permeabilize membranes is unclear. We reveal that CL forms membrane pores using a unique mechanism. Unexpectedly, CL readily assembled into polymers in solution. We propose that the basic structural unit in polymer formation is a CL oligomer, which is sequentially added into a string configuration that can close into a loop. CL loops appear to spontaneously insert into the membrane to become pores. A CL mutation (G4W) inhibited the formation of polymers in solution and prevented pore formation in synthetic lipid systems. Epithelial cell studies showed that G4W CL failed to activate the danger response pathway, a hallmark of the pathogenic effect of CL. These results indicate that CL polymerization in solution is a necessary step for the damage of cellular membranes. Analysis of CL pores by atomic force microscopy revealed co-existence of simple depressions and more complex pores, which are likely formed by CL assembled in an alternate oligomer orientation. We propose that this structural rearrangement represents a maturation mechanism that stabilizes pore formation to achieve more robust cellular damage. To summarize, CL uses a previously unknown mechanism to damage membranes, whereby pre-assembly of CL loops in solution leads to formation of membrane pores. Our investigation not only unravels a new paradigm for the formation of membrane pores, but additionally identifies CL polymerization as a novel therapeutic target to treat candidiasis.

Background Lowering low‐density lipoprotein cholesterol (LDL‐C) levels decreases major cardiovascular events and is recommended for patients at elevated cardiovascular risk. However, appropriate doses of statin therapy are often insufficient to reduce LDL‐C in accordance with current guidelines. In such cases, treatment could be supplemented with nonstatin lipid‐lowering therapy. Methods and Results A systematic literature review and network meta‐analysis were conducted on randomized controlled trials of nonstatin lipid‐lowering therapy added to maximally tolerated statins, including statin‐intolerant patients. The primary objective was to assess relative efficacy of nonstatin lipid‐lowering therapy in reducing LDL‐C levels at week 12. Secondary objectives included the following: LDL‐C level reduction at week 24 and change in non–high‐density lipoprotein cholesterol and apolipoprotein B at week 12. There were 48 randomized controlled trials included in the primary network meta‐analysis. All nonstatin agents significantly reduced LDL‐C from baseline versus placebo, regardless of background therapy. At week 12, evolocumab, 140 mg every 2 weeks (Q2W)/420 mg once a month, and alirocumab, 150 mg Q2W, were the most efficacious regimens, followed by alirocumab, 75 mg Q2W, alirocumab, 300 mg once a month, inclisiran, bempedoic acid/ezetimibe fixed‐dose combination, and ezetimibe and bempedoic acid used as monotherapies. Primary end point results were generally consistent at week 24, and for other lipid end points at week 12. Conclusions Evolocumab, 140 mg Q2W/420 mg once a month, and alirocumab, 150 mg Q2W, were consistently the most efficacious nonstatin regimens when added to maximally tolerated statins to lower LDL‐C, non–high‐density lipoprotein cholesterol, and apolipoprotein B levels and facilitate attainment of guideline‐recommended risk‐stratified lipoprotein levels.

Geovisualization tools can supplement the statistical analyses of landscape-level wildfire behavior by enabling the discovery of nuanced information regarding the relationships between fire spread, topography, fuels, and weather. The objectives of this study were to develop and evaluate the effectiveness of geovisualization tools for analyzing wildfire behavior and specifically to apply those tools to study portions of the Thomas and Detwiler wildfire events that occurred in California in 2017. Fire features such as active fire fronts and rate of spread (ROS) vectors derived from repetitive airborne thermal infrared (ATIR) imagery sequences were incorporated into geovisualization tools hosted in a web geographic information systems application. This geovisualization application included ATIR imagery, fire features derived from ATIR imagery (rate of spread vectors and fire front delineations), growth form maps derived from NAIP imagery, and enhanced topographic rasters for visualizing changes in local topography. These tools aided in visualizing and analyzing landscape-level wildfire behavior for study portions of the Thomas and Detwiler fires. The primary components or processes of fire behavior analyzed in this study were ROS, spotting, fire spread impedance, and fire spread over multidirectional slopes. Professionals and researchers specializing in wildfire-related topics provided feedback on the effectiveness and utility of the geovisualization tools. The geovisualization tools were generally effective for visualizing and analyzing (1) fire spread over multidirectional slopes; (2) differences in spread magnitudes within and between sequences over time; and (3) the relative contributions of fuels, slope, and weather at any given point within the sequences. Survey respondents found the tools to be moderately effective, with an average effectiveness score of 6.6 (n = 5) for the visualization tools on a scale of 1 (ineffective) to 10 (effective) for postfire spread analysis and visualizing fire spread over multidirectional slopes. The results of the descriptive analysis indicate that medium- and fine-scale topographic features, roads, and riparian fuels coincided with cases of fire spread impedance and exerted control over fire behavior. Major topographic features such as ridges and valleys slowed, or halted, fire spread consistently between study areas. The relationships between spotting, fuels, and topography were inconclusive.

IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.

Introduction Lung cancer is the leading cause of cancer mortality, comprising the largest national cancer disease burden in Australia and New Zealand. Regional reports identify substantial evidence-practice gaps, unwarranted variation from best practice, and variation in processes and outcomes of care between treating centres. The Australia and New Zealand Lung Cancer Registry (ANZLCR) will be developed as a Clinical Quality Registry to monitor the safety, quality and effectiveness of lung cancer care in Australia and New Zealand.Methods and analysis Patient participants will include all adults >18 years of age with a new diagnosis of non-small-cell lung cancer (NSCLC), SCLC, thymoma or mesothelioma. The ANZLCR will register confirmed diagnoses using opt-out consent. Data will address key patient, disease, management processes and outcomes reported as clinical quality indicators. Electronic data collection facilitated by local data collectors and local, state and federal data linkage will enhance completeness and accuracy. Data will be stored and maintained in a secure web-based data platform overseen by registry management. Central governance with binational representation from consumers, patients and carers, governance, administration, health department, health policy bodies, university research and healthcare workers will provide project oversight.Ethics and dissemination The ANZLCR has received national ethics approval under the National Mutual Acceptance scheme. Data will be routinely reported to participating sites describing performance against measures of agreed best practice and nationally to stakeholders including federal, state and territory departments of health. Local, regional and (bi)national benchmarks, augmented with online dashboard indicator reporting will enable local targeting of quality improvement efforts.

A magnetically separable palladium nanocatalyst has been synthesized through the immobilization of palladium onto 3-aminopropylphenanthroline Schiff based functionalized silica coated superparamagnetic Fe3O4 nanoparticles. The nanocatalyst (Fe3O4@SiNSB-Pd) was fully characterized using several spectroscopic techniques, such as FT-IR, HR-SEM, TEM, XRD, ICP, and XPS. The microscopic image of Fe3O4 showed spherical shape morphology and had an average size of 150 nm. The Pd-nanoparticles exhibited an average size 3.5 ± 0.6 nm. The successful functionalization of Fe3O4@SiNSB-Pd was identified by FT-IR spectroscopy and the appearance of palladium species in Fe3O4@SiNSB-Pd was confirmed by XRD analysis. While XPS has been utilized for the determination of the chemical oxidation state of palladium species in Fe3O4@SiNSB-Pd. Several activated and deactivated arene halides and olefines were employed for Mizoroki-Heck cross-coupling reactions in the presence of Fe3O4@SiNSB-Pd, each of which produced the respective cross-coupling products with excellent yields. The Fe3O4@SiNSB-Pd shows good reactivity and reusability for up to seven consecutive cycles.

Emerging evidence suggests transcranial direct current stimulation (tDCS) can improve cognitive performance in older adults. Similarly, music listening may improve arousal and stimulate subsequent performance on memory-related tasks. We examined the synergistic effects of tDCS paired with music listening on auditory neurobehavioral measures to investigate causal evidence of short-term plasticity in speech processing among older adults. In a randomized sham-controlled crossover study, we measured how combined anodal tDCS over dorsolateral prefrontal cortex (DLPFC) paired with listening to autobiographically salient music alters neural speech processing in older adults compared to either music listening (sham stimulation) or tDCS alone. EEG assays included both frequency-following responses (FFRs) and auditory event-related potentials (ERPs) to trace neuromodulation-related changes at brainstem and cortical levels. Relative to music without tDCS (sham), we found tDCS alone (without music) modulates the early cortical neural encoding of speech in the time frame of ∼100–150 ms. Whereas tDCS by itself appeared to largely produce suppressive effects (i.e., reducing ERP amplitude), concurrent music with tDCS restored responses to those of the music+sham levels. However, the interpretation of this effect is somewhat ambiguous as this neural modulation could be attributable to a true effect of tDCS or presence/absence music. Still, the combined benefit of tDCS+music (above tDCS alone) was correlated with listeners’ education level suggesting the benefit of neurostimulation paired with music might depend on listener demographics. tDCS changes in speech-FFRs were not observed with DLPFC stimulation. Improvements in working memory pre to post session were also associated with better speech-in-noise listening skills. Our findings provide new causal evidence that combined tDCS+music relative to tDCS-alone (i) modulates the early (100–150 ms) cortical encoding of speech and (ii) improves working memory, a cognitive skill which may indirectly bolster noise-degraded speech perception in older listeners.

Categorizing sounds into meaningful groups helps listeners more efficiently process the auditory scene and is a foundational skill for speech perception and language development. Yet, how auditory categories develop in the brain through learning, particularly for non-speech sounds (e.g., music), is not well understood. Here, we asked musically naïve listeners to complete a brief (∼20 min) training session where they learned to identify sounds from a musical interval continuum (minor-major 3rds). We used multichannel EEG to track behaviorally relevant neuroplastic changes in the auditory event-related potentials (ERPs) pre- to post-training. To rule out mere exposure-induced changes, neural effects were evaluated against a control group of 14 non-musicians who did not undergo training. We also compared individual categorization performance with structural volumetrics of bilateral Heschl’s gyrus (HG) from MRI to evaluate neuroanatomical substrates of learning. Behavioral performance revealed steeper (i.e., more categorical) identification functions in the posttest that correlated with better training accuracy. At the neural level, improvement in learners’ behavioral identification was characterized by smaller P2 amplitudes at posttest, particularly over right hemisphere. Critically, learning-related changes in the ERPs were not observed in control listeners, ruling out mere exposure effects. Learners also showed smaller and thinner HG bilaterally, indicating superior categorization was associated with structural differences in primary auditory brain regions. Collectively, our data suggest successful auditory categorical learning of music sounds is characterized by short-term functional changes (i.e., greater post-training efficiency) in sensory coding processes superimposed on preexisting structural differences in bilateral auditory cortex.

Territory quality shapes population dynamics and has conservation implications for territorial species. Yet, quantifying territory quality using different measures can yield conflicting results, particularly if territory selection is non-ideal, thus challenging the understanding of territory quality. We used a 25-year population study of spotted owls (Strix occidentalis) occupying 72 territories to evaluate five commonly used demographic- and occupancy-based measures of territory quality: occupancy rate, annual apparent survival rate, territory fitness, mean annual reproductive rate, and total reproductive output. To do so, we evaluated pairwise relationships between measures of territory quality and assessed the extent to which spotted owls selected territories based on their potential to promote fitness. Measures of territory quality were generally positively correlated. Notably, however, territory occupancy explained less than half of the variation (R2 = 0.37) in territory fitness (the expected fitness of territory holders). Non-ideal patterns in territory occupancy were the result of weak linkages between the likelihood of vacant territories becoming colonized and their fitness potential, particularly their capacity to promote reproduction. Imperfect territory colonization was likely the product of the spotted owl’s strong site fidelity to even low-fitness territories and constraints on the ability of dispersing individuals to locate high quality territories. Mismatches emerging from non-ideal colonization have important conservation implications because populations may benefit more from habitat restoration at low fitness-high occupancy territories and more from conspecific attraction measures at high fitness-low occupancy territories. Our findings for spotted owls were reasonably consistent with broad patterns observed for other species in previous studies, but the strength of associations between pairs of territory quality measures often varied considerably, suggesting that species-specific assessments of patterns in territory quality are important. Finally, when practical, examination of the ecological processes shaping multiple measures of territory quality will benefit the study and conservation of territorial species.

Background: Since changes in the national guidance in 2011, prophylactic antibiotics for women undergoing caesarean section are recommended prior to skin incision, rather than after the baby’s umbilical cord has been clamped. Evidence from randomised controlled trials conducted outside the UK has shown that this reduces maternal infectious morbidity; however, the prophylactic antibiotics also cross the placenta, meaning that babies are exposed to them around the time of birth. Antibiotics are known to affect the gut microbiota of the babies, but the long-term effects of exposure to high-dose broad-spectrum antibiotics around the time of birth on allergy and immune-related diseases are unknown. Objectives: We aimed to examine whether or not in-utero exposure to antibiotics immediately prior to birth compared with no pre-incisional antibiotic exposure increases the risk of (1) asthma and (2) eczema in children born by caesarean section. Design: This was a controlled interrupted time series study. Setting: The study took place in primary and secondary care. Participants: Children born in the UK during 2006–18 delivered by caesarean section were compared with a control cohort delivered vaginally. Interventions: In-utero exposure to antibiotics immediately prior to birth. Main outcome measures: Asthma and eczema in children in the first 5 years of life. Additional secondary outcomes, including other allergy-related conditions, autoimmune diseases, infections, other immune system-related diseases and neurodevelopmental conditions, were also assessed. Data sources: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) primary care databases and the Hospital Episode Statistics (HES) database. Previously published linkage strategies were adapted to link anonymised data on mothers and babies in these databases. Duplicate practices contributing to both THIN and the CPRD databases were removed to create a THIN–CPRD data set. Results: In the THIN–CPRD and HES data sets, records of 515,945 and 3,945,351 mother–baby pairs were analysed, respectively. The risk of asthma was not significantly higher in children born by caesarean section exposed to pre-incision antibiotics than in children whose mothers received post-cord clamping antibiotics, with an incidence rate ratio of 0.91 (95% confidence interval 0.78 to 1.05) for diagnosis of asthma in primary care and an incidence rate ratio of 1.05 (95% confidence interval 0.99 to 1.11) for asthma resulting in a hospital admission. We also did not find an increased risk of eczema, with an incidence rate ratio of 0.98 (95% confidence interval 0.94 to1.03) and an incidence rate ratio of 0.96 (95% confidence interval 0.71 to 1.29) for diagnosis in primary care and hospital admissions, respectively. Limitations: It was not possible to ascertain the exposure to pre-incision antibiotics at an individual level. The maximum follow-up of children was 5 years. Conclusions: There was no evidence that the policy change from post-cord clamping to pre-incision prophylactic antibiotics for caesarean sections during 2006–18 had an impact on the incidence of asthma and eczema in early childhood in the UK. Future work: There is a need for further research to investigate if pre-incision antibiotics have any impact on developing asthma and other allergy and immune-related conditions in older children. Study registration: This study is registered as researchregistry3736. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 30. See the NIHR Journals Library website for further project information.