The Foundation to Advance Brain Rehabilitation: Organization, History, and Collaborative Database.

OBJECTIVE: To describe the history, organization, goals, and data management procedures of the Foundation to Advance Brain Rehabilitation (FABR). SETTING: Postacute brain injury rehabilitation following acute inpatient care. KEY POINTS: FABR was incorporated in 2019 with a primary mission to advance brain rehabilitation through scientific and strategic analysis of industry-wide data. Contributing FABR member organizations include Bancroft NeuroRehab, Collage Rehabilitation Partners, On With Life, Pate NeuroRehabilitation, and Shepherd Center. These organizations contribute demographic, admission, discharge, and follow-up data on persons served in 5 types of intensive posthospital brain injury rehabilitation programs (neurobehavioral residential, neurorehabilitation residential, home and community neurorehabilitation, day treatment, and outpatient) and 3 types of supported living programs (neurobehavioral residential, residential, and community-based) to a collaborative database managed by Inventive Software Solutions. Inventive Software Solutions provides FABR researchers with a dataset that is de-identified both for participant and organizational identifying information.

Hip fracture projections up to the year 2060: an analysis based on data from the National Hip Fracture Database (NHFD) for England, Wales, and Northern Ireland.

INTRODUCTION: Hip fractures are common and cause a huge socioeconomic burden to patients, their carers, and healthcare services worldwide. Our aim was to examine how much hip fracture numbers would be expected to rise over coming decades, simply as a consequence of the ageing of the population. METHODS: We used data from the National Hip Fracture Database on the volume of hip fractures occurring in England, Wales and Northern Ireland in the year 2019 (n = 67,210). We projected future numbers of hip fractures by applying this number, assuming stable rates, to population growth forecast data provided by the Office for National Statistics up to the year 2060. RESULTS: By 2060, the number of hip fractures occurring in England, Wales and Northern Ireland are projected to increase by 107 % (n = 139,105). In males, there was an estimated increase of 130 % compared with 97 % in females. There was an estimated increase across all age ranges, however the oldest age groups demonstrated the largest relative increases. The estimated increase for those aged 90 years or over was as high as 348 % and 198 % for males and females, respectively. CONCLUSION: As a consequence of future ageing of the population, the demand on the health service posed by people with hip fracture is projected to more than double by the year 2060. Policymakers should be striving to mitigate against the huge public health impact of these projections by maximising fracture prevention strategies as far as possible and by improving the quality of hip fracture care.

Ileocolic intussusception secondary to Peutz-Jeghers polyp: the need for oncological resection surgery.

In this case report, we detail the management of a woman in her late 30s with ileocolic intussusception, emphasizing the high malignancy risk inherent in adult intussusception cases. Given the patient's acute symptoms and significant family history of ovarian and breast cancers, radical oncological resection was pursued. The surgical intervention comprised a right hemicolectomy and right ovarian cystectomy, with histopathological findings revealing a Peutz-Jeghers polyp and benign thyroid tissue, but no malignancy. This case underscores the imperative for a surgical approach that anticipates the potential for malignancy in adult intussusception, advocating for radical resection as a fundamental strategy, even in the absence of confirmed malignant histopathology, to ensure comprehensive management and alignment with oncological best practices.

Assessment of genetic diversity and population structure of U.S. Polypay sheep from breed origins to future genomic selection.

Knowledge of past and present genetic diversity within a breed is critical for the design and optimization of breeding programs as well as the development of strategies for the conservation of genetic resources. The Polypay sheep breed was developed at the U.S. Sheep Experiment Station (USSES) in 1968 with the goal of improving productivity in Western U.S. range flocks. It has since flourished in the more intensively managed production systems throughout the U.S. The genetic diversity of the breed has yet to be documented. Therefore, the primary objective of this study was to perform a comprehensive evaluation of the genetic diversity and population structure of U.S. Polypay sheep using both pedigree- and genomic-based methods. Pedigree data from 193 Polypay flocks participating in the National Sheep Improvement Program (NSIP) were combined with pedigree records from USSES (n = 162,997), tracing back to the breed's origin. A subset of these pedigreed sheep from 32 flocks born from 2011 to 2023 were genotyped with the GGP Ovine 50K BeadChip containing 51,867 single nucleotide polymorphisms (SNPs). Four subgroups were used for the pedigree-based analyses: 1) the current generation of animals born in 2020-2022 (n = 20,701), 2) the current generation with a minimum of four generations of known ancestors (n = 12,685), 3) only genotyped animals (n = 1,856), and 4) the sires of the current generation (n = 509). Pedigree-based inbreeding for the full population was 2.2%, with a rate of inbreeding of 0.22% per generation. Pedigree-based inbreeding, Wright's inbreeding, and genomic inbreeding based on runs of homozygosity were 2.9%, 1.3%, and 5.1%, respectively, for the genotyped population. The effective population size ranged from 41 to 249 for the pedigree-based methods and 118 for the genomic-based estimate. Expected and observed heterozygosity levels were 0.409 and 0.403, respectively. Population substructure was evident based on the fixation index (FST), principal component analysis, and model-based population structure. These analyses provided evidence of differentiation from the foundation flock (USSES). Overall, the Polypay breed exhibited substantial genetic diversity and the presence of a population substructure that provides a basis for the implementation of genomic selection in the breed.

A Qualitative Analysis of a Primary Care Medical-Legal Partnership: Impact, Barriers, and Facilitators.

BACKGROUND: Certain health-related risk factors require legal interventions. Medical-legal partnerships (MLPs) are collaborations between clinics and lawyers that address these health-harming legal needs (HHLNs) and have been shown to improve health and reduce utilization. OBJECTIVE: The objective of this study is to explore the impact, barriers, and facilitators of MLP implementation in primary care clinics. METHODS: A qualitative design using a semistructured interview assessed the perceived impact, barriers, and facilitators of an MLP, among clinicians, clinic and MLP staff, and clinic patients. Open AI software (otter.ai) was used to transcribe interviews, and NVivo was used to code the data. Braun & Clarke's framework was used to identify themes and subthemes. RESULTS: Sixteen (n = 16) participants were included in this study. Most respondents were women (81%) and white (56%). Four respondents were clinic staff, and 4 were MLP staff while 8 were clinic patients. Several primary themes emerged including: Patients experienced legal issues that were pernicious, pervasive, and complex; through trusting relationships, the MLP was able to improve health and resolve legal issues, for some; mistrust, communication gaps, and inconsistent staffing limited the impact of the MLP; and, the MLP identified coordination and communication strategies to enhance trust and amplify its impact. CONCLUSION: HHLNs can have a significant, negative impact on the physical and mental health of patients. Respondents perceived that MLPs improved health and resolved these needs, for some. Despite perceived successes, integration between the clinical and legal organizations was elusive.

Early Implementation and Outcomes Among People with HIV Who Accessed Long-Acting Injectable Cabotegravir/Rilpivirine at Two Ryan White Clinics in the U.S. South.

The use of long-acting injectable cabotegravir/rilpivirine (LAI-CAB/RPV) as maintenance therapy for persons with HIV (PWH), which may improve treatment access and outcomes, though real-world data on uptake are limited, was studied at two Ryan White clinics in Atlanta, Georgia. Among PWH referred from 4/1/2021 to 9/15/2022 to switch to LAI-CAB/RPV, characteristics were ascertained at time of referral; and disposition (initiated; ineligible; uninterested; pending) was recorded as of 9/15/2022. Among patients initiated on CAB/RPV, we assessed the drug procurement process and clinical outcomes through 6/1/2023. Among 149 PWH referred, 74/149 (50%) initiated CAB/RPV as of 9/15/2022, of whom, characteristics were median age 47 (Q1-Q3 36-55) years, 16% cisgender female, 72% Black race, median HIV duration 15 (Q1-Q3 9-19) years, and 64% had commercial health insurance. Of the 75 PWH not initiated, 35 were ineligible owing to a clinical concern (n = 16) or insurance issue (n = 19); 15 patients changed their mind about switching; and 25 were pending eligibility review or therapy initiation. Median time from CAB/RPV prescription to initiation was 46 (Q1-Q3 29-78) days. Of 731 total injections administered (median 11 injections/patient), 95% were given within 7 days of the target treatment date. Nearly all patients were virally suppressed upon referral and remained suppressed through follow-up. At two clinics in the U.S. South, half of the patients referred for LAI-CAB/RPV successfully accessed therapy nearly 2 years after U.S. drug approval. We identified barriers to uptake at the patient and structural levels, highlighting key areas to invest resource and personnel support to sustain and scale long-acting antiretroviral therapy programming.

The effect of a pre- and post- operative exercise program versus standard care on physical fitness of patients with oesophageal and gastric cancer undergoing neoadjuvant treatment prior to surgery (The PERIOP-OG Trial): a randomized controlled trial.

INTRODUCTION: Although the benefits of post-operative rehabilitation in cancer surgery are well established, the role of prehabilitation is less defined. Oesophagogastric cancers present a unique opportunity to study the impact of prehabilitation during the neoadjuvant window, whether with chemotherapy or chemoradiotherapy (NCT) in patients who are frequently nutritionally depleted. This trial examines the impact of a community-based exercise program on patient fitness during and after the neoadjuvant window. METHODS: A pragmatic, randomized controlled multi-centre trial was undertaken in three centres. Inclusion criteria were patients aged ≥ 18 years planned for NCT and esophagectomy or gastrectomy. Participants were randomized 1:1 to an exercise prehabilitation group (EX) or to usual care (UC). The primary endpoint was cardiorespiratory fitness between baseline and pre-surgery timepoint using the 6-min walk test. Secondary endpoints included hand dynamometer, 10-sec sit to stand, activity behaviour, body mass index, semi-structured interviews, questionnaires assessing quality of life, surgical fear, general self-efficacy and mastery. RESULTS: Between March 2019 and December 2020, 71 participants were recruited: EX (n=36) or UC (n=35). From baseline to pre-surgery, the difference-in-difference for EX showed a significant improvement in 6MWT of 50.7m (P=0.05) compared to UC [mean (SD): 522.1m (+/-104.3) to 582.1m (+/-108) vs. 497.5m (+/-106.3) to 506.0 m (+/-140.4). There was no statistically significant DID for secondary outcome measures. CONCLUSIONS: This community exercise prehabilitation program significantly improves physical fitness for surgery, is feasible and provides a standardized framework for prescription of exercise in esophagogastric cancer patients undergoing NCT.

Milk microbiome in the first month of lactation and at weaning from ewes supplemented with zinc pre- and postpartum.

Mastitis is an important disease with economic and welfare implications in both clinical and subclinical states. The aim of this research was to sequence the hypervariable V4 region of the 16S rRNA gene to describe the microbial diversity and taxonomy of milk from clinically healthy ewes (Rambouillet, WF = 9; Hampshire, BF = 5). Experimental ewes represented a subset of a larger study assessing the impacts of divergent dietary zinc (Zn) concentrations [1 × National Academics of Sciences, Engineering, and Medicine (NASEM) recommendations = CON or 3 × NASEM recommendations = ZnTRT] throughout late gestation and lactation. Milk was collected at four periods during early lactation (18 to 24 h, 7 d, 14 d, and 21 d postpartum) and at weaning (84 ±â€…14 d postpartum). Somatic cell counts (SCC) were quantified, averaged, and classed (low: < 500 × 103; medium: 500 × 103 - 100 × 104; high: > 100 × 104 cells/mL). Milk samples (n = 67) were sequenced to identify bacteria and archaea; the most abundant phyla were Actinobacteria, Bacteroidetes, Cyanobacteria, Euryarchaeota, Firmicutes, Fusobacteria, Lentisphaerae, Proteobacteria, Spirochaetes, Tenericutes, Saccharibacteria TM7, and Verrucomicrobia. Mastitis pathogens were among the most relatively abundant genera, including Staphylococcus, Mannheimia, Corynebacterium, and Pseudomonas. Effects of breed, dietary Zn concentration, SCC class, and their two-way interactions on milk microbiome diversity and taxonomy were assessed within early lactation (using a repeated measures model) and weaning samples. Alpha-diversity metrics included Pielou's evenness, Faith's phylogenetic diversity, and Shannon's entropy indices. The main and interactive effects between Zn treatment, breed, SCC class, and period were variable in early lactation and not evident in weaning samples. Milk from BF ewes had increased Faith's phylogenetic diversity and Shannon's entropy, and differed in unweighted UniFrac composition (P ≤ 0.10). Milk from CON ewes had a reduced rate of composition change through early lactation (P = 0.02) indicating greater microbiome stability than ZnTRT ewe milk. These results support that milk is not sterile, and breed, dietary Zn concentration, and SCC class variably affect the milk microbiome. Findings from the current study provide important foundational insights into the effects of increased dietary Zn supplementation on longitudinal changes in the milk microbiome and associations with mammary gland health and mastitis.

Mastitis is an important disease with economic and welfare implications in both clinical and subclinical states. This research described the microbial diversity and taxonomy of milk collected from clinically healthy Rambouillet (WF; n = 9) and Hampshire (BF; n = 5) primiparous ewes in a longitudinal study involving differing dietary zinc concentrations [1 × National Academics of Sciences, Engineering, and Medicine (NASEM) recommendations, CON; 3 × NASEM recommendations, ZnTRT]. Milk was collected weekly during the first 3 wk of lactation and at weaning, and somatic cell counts (SCC) were classed (low, medium, high). Mastitis pathogens were among the most relatively abundant via amplicon sequencing, including Staphylococcus, Mannheimia, Corynebacterium, and Pseudomonas. Breed, zinc treatment, and SCC class effects on milk microbiome α-diversity and ß-diversity changes and taxonomy were assessed. These effects and their two-way interactions were limited but variable in early lactation samples and not evident in weaning samples. Notably, BF ewe milk samples had increased Faith's phylogenetic diversity and increased Shannon's entropy during early lactation, and CON ewe milk samples had a reduced rate of compositional change than ZnTRT samples. These results support the existence of a milk microbiome that is variably affected by breed, increased dietary zinc concentrations, and SCC class.

Measuring practice preference variation for quality improvement in neonatal respiratory care.

OBJECTIVES: The authors sought to measure and compare practice preference variation in neonatal respiratory care within and between neonatal intensive care units (NICUs) using the Neonatology Survey of Interdisciplinary Groups in Healthcare Tool (NSIGHT). STUDY DESIGN: Eleven NICUs completed the NSIGHT between 2019 and 2021. Net preference was measured by mean response; agreement was ranked by standard distribution of response values. Heat maps showed comparisons between NICUs and disciplines. RESULTS: NICUs and individuals agreed most often on use of pressure support with mandatory ventilation and on use of non-invasive positive pressure ventilation for apnea. High preference variation surrounded decisions for invasive ventilation versus continuous positive airway pressure for extremely low birth weight infants. Preference difference was most frequent between neonatologists and nurses. CONCLUSIONS: Patterns of practice preference variation in neonatal respiratory care are specific to clinical scenario. Measuring preference variation may inform psychology of change and strengthen quality improvement efforts.

Theory of four wave mixing-based parametric amplification of spin-orbit modes.

We study the generation of spin-orbit (SO) modes via four-wave mixing (FWM)-based parametric amplification. SO modes carry quantized total angular momentum (TAM), and we show that FWM processes that generate new signals conserve TAM. This is a generalization of prior research which operated in a regime where FWM processes conserved spin and orbital angular momenta independently. We calculate the growth rates of new modes for both degenerate and nondegenerate pump configurations. Our theory is validated against numerical simulations for the cases where the generated signals are in the same SO mode(s) as the pump(s). We also calculate the growth rates of signals in SO modes other than the pumps.

Synaptic cell-adhesion molecule latrophilin-2 is differentially directed to dendritic domains of hippocampal neurons.

Hippocampal pyramidal cells possess elaborate dendritic arbors with distinct domains that are targeted with input-specific synaptic sites. This synaptic arrangement is facilitated by synaptic cell-adhesion molecules that act as recognition elements to connect presynaptic and postsynaptic neurons. In this study, we investigate the organization of the synaptic recognition molecule latrophilin-2 at the surface of pyramidal neurons classified by spatial positioning and action potential firing patterns. Surveying two hippocampal neurons that highly express latrophilin-2, late-bursting CA1 pyramidal cells and early-bursting subiculum pyramidal cells, we found the molecule to be differentially positioned on their respective dendritic compartments. Investigating this latrophilin-2 positioning at the synaptic level, we found that the molecule is not present within either the pre- or postsynaptic terminal but rather is tightly coupled to synapses at a perisynaptic location. Together these findings indicate that hippocampal latrophilin-2 distribution patterning is cell-type specific, and requires multiple postsynaptic neurons for its synaptic localization.

Combining camera trap surveys and IUCN range maps to improve knowledge of species distributions.

Reliable maps of species distributions are fundamental for biodiversity research and conservation. The International Union for Conservation of Nature (IUCN) range maps are widely recognized as authoritative representations of species' geographic limits, yet they might not always align with actual occurrence data. In recent area of habitat (AOH) maps, areas that are not habitat have been removed from IUCN ranges to reduce commission errors, but their concordance with actual species occurrence also remains untested. We tested concordance between occurrences recorded in camera trap surveys and predicted occurrences from the IUCN and AOH maps for 510 medium- to large-bodied mammalian species in 80 camera trap sampling areas. Across all areas, cameras detected only 39% of species expected to occur based on IUCN ranges and AOH maps; 85% of the IUCN only mismatches occurred within 200 km of range edges. Only 4% of species occurrences were detected by cameras outside IUCN ranges. The probability of mismatches between cameras and the IUCN range was significantly higher for smaller-bodied mammals and habitat specialists in the Neotropics and Indomalaya and in areas with shorter canopy forests. Our findings suggest that range and AOH maps rarely underrepresent areas where species occur, but they may more often overrepresent ranges by including areas where a species may be absent, particularly at range edges. We suggest that combining range maps with data from ground-based biodiversity sensors, such as camera traps, provides a richer knowledge base for conservation mapping and planning.

Combinación de censos con fototrampas y mapas de extensión de la UICN para incrementar el conocimiento sobre la distribución de las especies Resumen Los mapas confiables de la distribución de las especies son fundamentales para la investigación y conservación de la biodiversidad. Los mapas de distribución de la Unión Internacional para la Conservación de la Naturaleza (UICN) están reconocidos como representaciones de autoridad de los límites geográficos de las especies, aunque no siempre se alinean con los datos actuales de su presencia. En los mapas recientes de área de hábitat (ADH), las áreas que no son hábitat han sido eliminadas de la distribución de la UICN para reducir los errores de comisión, pero su concordancia con la presencia actual de las especies tampoco ha sido analizada. Analizamos la concordancia entre la presencia registrada por los censos de fototrampas y pronosticamos la presencia a partir de los mapas de la UICN y de ADH de 510 especies de mamíferos de talla mediana a grande en 80 áreas de muestreo de fototrampas. Las cámaras detectaron sólo el 39% de las especies esperadas con base en la distribución de la UICN y los mapas de ADH en todas las áreas; el 85% de las disparidades con la UICN ocurrieron dentro de los 200 km a partir del borde de la distribución. Sólo el 4% de la presencia de las especies fue detectada por las cámaras ubicadas fuera de la distribución de la UICN. La probabilidad de disparidad entre las cámaras y la UICN fue significativamente mayor para los mamíferos de talla pequeña y para los especialistas de hábitat en las regiones Neotropical e Indomalaya y en áreas con doseles forestales más bajos. Nuestros hallazgos sugieren que los mapas de distribución y ADH pocas veces subrepresentan las áreas con presencia de las especies, pero con frecuencia pueden sobrerrepresentar la distribución al incluir áreas en donde las especies pueden estar ausentes, en particular los bordes de la distribución. Sugerimos que la combinación de los mapas de distribución con los sensores de biodiversidad en tierra, como las fototrampas, proporciona una base más rica de conocimiento para el mapeo y la planeación de la conservación.

Strong transient magnetic fields induced by THz-driven plasmons in graphene disks.

Strong circularly polarized excitation opens up the possibility to generate and control effective magnetic fields in solid state systems, e.g., via the optical inverse Faraday effect or the phonon inverse Faraday effect. While these effects rely on material properties that can be tailored only to a limited degree, plasmonic resonances can be fully controlled by choosing proper dimensions and carrier concentrations. Plasmon resonances provide new degrees of freedom that can be used to tune or enhance the light-induced magnetic field in engineered metamaterials. Here we employ graphene disks to demonstrate light-induced transient magnetic fields from a plasmonic circular current with extremely high efficiency. The effective magnetic field at the plasmon resonance frequency of the graphene disks (3.5 THz) is evidenced by a strong ( ~ 1°) ultrafast Faraday rotation ( ~ 20 ps). In accordance with reference measurements and simulations, we estimated the strength of the induced magnetic field to be on the order of 0.7 T under a moderate pump fluence of about 440 nJ cm-2.

An extreme model of fertility in sheep demonstrates the basis of controversies surrounding antral follicle count and circulating concentrations of anti-Müllerian hormone as predictors of fertility in ruminants.

Ovarian ultrasonography and measurement of circulating concentrations of anti-Müllerian hormone (AMH) have been used to estimate follicle number and predict fertility in mammalian females, but no study has evaluated follicle number and circulating concentrations of AMH in ewes known to differ in fertility. We tested the hypothesis that ewes that had failed to lamb (BARREN) in four consecutive annual breeding seasons of 21-35 d have fewer follicles and diminished circulating concentrations of AMH compared to closely matched ewes that consistently produced lambs (FERTILE) under the same breeding protocols. Once identified, BARREN ewes (n = 19) were paired by breed and sire to a FERTILE control ewe (n = 19) and reproductive tracts were recovered at necropsy. Visible antral follicles in both ovaries were counted and a representative cross section of one ovary was embedded for histological evaluation of pre-antral follicle numbers. Paired t-tests indicated that BARREN ewes had fewer antral follicles, fewer primordial follicles, and decreased circulating concentrations of AMH compared to FERTILE ewes (P ≤ 0.01), but there were ewes in each fertility classification that had ovarian phenotypes like the opposite fertility classification. The best technologies we have currently for estimating follicle numbers are ultrasonography and measurement of circulating concentrations of AMH, but no single technique is perfect for predicting fertility. A better understanding of the under-lying biological mechanisms linking AMH, folliculogenesis, and fertility is required to improve the use of measurements of follicle number for predicting fertility in livestock.

The influence of pre-operative Computed Tomography (CT) on surgical approach and fixation for fractures of the tibial plateau.

Background: It is well known that a computed tomography (CT) scan improves the classification of tibial plateau fractures (TPF) compared with radiographs. However, it is less clear how this translates into clinical practice. The aim of this study is to establish to what extent a pre-operative CT scan alters the approach, setup and fixation choice in TPF compared to radiographs. Methods: 50 consecutive TPF with a preoperative CT and radiographic imaging available, were assessed by 4 consultant surgeons. First, anonymised radiographs were classifying according to the column classification and the planned setup, approach, and fixation technique documented. At a 1-month interval, randomised matched CT scans were assessed and the same data collected. A tibial plateau disruption score (TPDS) was derived for all 4 quadrants (no injury = 0, split = 1, split/depression = 2 and depression = 3). Radiograph and CT TPDS were assessed using an unpaired T-test. Results: 26 female and 24 male patients, mean age 50.3, were included. Mean TPDS on radiographs and CT scans were 2.77 and 3.17 respectively. A significantly higher CT TPDS, of 0.4 (95%CI 0.10-0.71)[P = 0.0093] was observed, demonstrating that radiographs underestimate the extent of injury. The surgical approach changed in 28.5% of cases, thus influencing a change in the patient setup in theatre in 27% of cases. Identification of fractures within a column changed in 34% of cases. A high intra-observer reliability was observed when surgeons were asked to repeat their assessment in a third round at a further one month interval. Conclusion: A pre-operative CT scan has a significant effect on the approach required to fix TPF. This therefore influences the setup of the patient and can justifiably be requested as part of pre-operative planning.

Evolution of the Xerocarpa clade (Opuntia; Opuntieae): Evidence for the Role of the Grand Canyon in the Biogeographic History of the Iconic Beavertail Cactus and Relatives.

The formation of the western North American drylands has led to the evolution of an astounding diversity of species well adapted for such communities. Complex historical patterns often underlie the modern distribution of the flora and fauna of these areas. We investigated the biogeography of a group of desert-adapted prickly pears, known as the Xerocarpa clade, from western North America. The Xerocarpa clade originated in the mid-late Pliocene, likely on the Colorado Plateau, and then moved south into the Mojave, Sonoran, and Chihuahuan deserts, and California montane regions, further diversifying, mostly into the Quaternary. The southward trajectory of the clade was likely greatly influenced by the formation of the Grand Canyon. The synapomorphy of dry fruit presumably impeded the long-distance dispersibility of the beavertail cactus, Opuntia basilaris, while dry, spiny fruit may have enabled O. polyacantha to substantially increase its distribution. Opuntia basilaris evolved a pubescent epidermis, allowing it to invade hotter, drier conditions, while the spine-clothed stems of O. polyacantha may have given it an advantage for increasing its northern range into colder environments. The Xerocarpa clade shows a cold desert origin, and changes in morphological characters have made these sister taxa well adapted for invading broadscale, but oftentimes contrasting habitats.

Small molecules restore azole activity against drug-tolerant and drug-resistant Candida isolates.

Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or patients in intensive care units. The limited antifungal arsenal and emerging multidrug-resistant species necessitate the development of new therapies. One strategy for combating drug-resistant pathogens is the administration of molecules that restore fungal susceptibility to approved drugs. Accordingly, we carried out a screen to identify small molecules that could restore the susceptibility of pathogenic Candida species to azole antifungals. This screening effort led to the discovery of novel 1,4-benzodiazepines that restore fluconazole susceptibility in resistant isolates of Candida albicans, as evidenced by 100-1,000-fold potentiation of fluconazole activity. This potentiation effect was also observed in azole-tolerant strains of C. albicans and in other pathogenic Candida species. The 1,4-benzodiazepines selectively potentiated different azoles, but not other approved antifungals. A remarkable feature of the potentiation was that the combination of the compounds with fluconazole was fungicidal, whereas fluconazole alone is fungistatic. Interestingly, the potentiators were not toxic to C. albicans in the absence of fluconazole, but inhibited virulence-associated filamentation of the fungus. We found that the combination of the potentiators and fluconazole significantly enhanced host survival in a Galleria mellonella model of systemic fungal infection. Taken together, these observations validate a strategy wherein small molecules can restore the activity of highly used anti-infectives that have lost potency. IMPORTANCE In the last decade, we have been witnessing a higher incidence of fungal infections, due to an expansion of the fungal species capable of causing disease (e.g., Candida auris), as well as increased antifungal drug resistance. Among human fungal pathogens, Candida species are a leading cause of invasive infections and are associated with high mortality rates. Infections by these pathogens are commonly treated with azole antifungals, yet the expansion of drug-resistant isolates has reduced their clinical utility. In this work, we describe the discovery and characterization of small molecules that potentiate fluconazole and restore the susceptibility of azole-resistant and azole-tolerant Candida isolates. Interestingly, the potentiating 1,4-benzodiazepines were not toxic to fungal cells but inhibited their virulence-associated filamentous growth. Furthermore, combinations of the potentiators and fluconazole decreased fungal burdens and enhanced host survival in a Galleria mellonella model of systemic fungal infections. Accordingly, we propose the use of novel antifungal potentiators as a powerful strategy for addressing the growing resistance of fungi to clinically approved drugs.

Accident proneness, laterality, and time estimation.

Cerebral laterality has been linked to accident proneness and time perception, but the possible role of time estimation abilities has received little attention. Accordingly, the present study focused on this under-explored question while also aiming to replicate past work examining the relationship between measures of laterality and injury proneness. Participants reported on the number of accidents they have had in their lifetime requiring medical care and the number of minor accidents they had in the past month as outcome variables. They also completed the Waterloo Handedness Questionnaire, a left bias visual task (Greyscales task), a right bias auditory verbal task (Fused Dichotic Words Task), and an objective measure of time perception. Extensive examination of statistical model fit showed that a model assuming a Poisson distribution provided the best fit for minor injuries and an additional negative binomial provided the best fit to the lifetime accidents. Results showed a negative relation between the degree of verbal laterality (absolute right bias) and injuries requiring medical care. Furthermore, the number of accidents requiring medical care was positively related to the precision of time estimation and the direction of verbal laterality on response time (raw right bias). Interpretations of these findings emphasize their implications for interhemispheric communication and motor control in the context of time estimation and auditory verbal laterality. These aspects seem to provide promising avenues for future research.

Cohort profile: POPPY II - a population-based cohort examining the patterns and outcomes of prescription opioid use in New South Wales, Australia.

PURPOSE: The POPPY II cohort is an Australian state-based cohort linking data for a population of individuals prescribed opioid medicines, constructed to allow a robust examination of the long-term patterns and outcomes of prescription opioid use. PARTICIPANTS: The cohort includes 3 569 433 adult New South Wales residents who initiated a subsidised prescription opioid medicine between 2003 and 2018, identified through pharmacy dispensing data (Australian Pharmaceutical Benefits Scheme) and linked to 10 national and state datasets and registries including rich sociodemographic and medical services data. FINDINGS TO DATE: Of the 3.57 million individuals included in the cohort, 52.7% were female and 1 in 4 people were aged ≥65 years at the time of cohort entry. Approximately 6% had evidence of cancer in the year prior to cohort entry. In the 3 months prior to cohort entry, 26.9% used a non-opioid analgesic and 20.5% used a psychotropic medicine. Overall, 1 in 5 individuals were initiated on a strong opioid (20.9%). The most commonly initiated opioid was paracetamol/codeine (61.3%), followed by oxycodone (16.3%). FUTURE PLANS: The POPPY II cohort will be updated periodically, both extending the follow-up duration of the existing cohort, and including new individuals initiating opioids. The POPPY II cohort will allow a range of aspects of opioid utilisation to be studied, including long-term trajectories of opioid use, development of a data-informed method to assess time-varying opioid exposure, and a range of outcomes including mortality, transition to opioid dependence, suicide and falls. The duration of the study period will allow examination of population-level impacts of changes to opioid monitoring and access, while the size of the cohort will also allow examination of important subpopulations such as people with cancer, musculoskeletal conditions or opioid use disorder.