Predicting emergent animal biodiversity patterns across multiple scales.

Restoring biodiversity-based resilience and ecosystem multi-functionality needs to be informed by more accurate predictions of animal biodiversity responses to environmental change. Ecological models make a substantial contribution to this understanding, especially when they encode the biological mechanisms and processes that give rise to emergent patterns (population, community, ecosystem properties and dynamics). Here, a distinction between 'mechanistic' and 'process-based' ecological models is established to review existing approaches. Mechanistic and process-based ecological models have made key advances to understanding the structure, function and dynamics of animal biodiversity, but are typically designed to account for specific levels of biological organisation and spatiotemporal scales. Cross-scale ecological models, which predict emergent co-occurring biodiversity patterns at interacting scales of space, time and biological organisation, is a critical next step in predictive ecology. A way forward is to first capitalise on existing models to systematically evaluate the ability of scale-explicit mechanisms and processes to predict emergent patterns at alternative scales. Such model intercomparisons will reveal mechanism to process transitions across fine to broad scales, overcome approach-specific barriers to model realism or tractability and identify gaps which necessitate the development of new fundamental principles. Key challenges surrounding model complexity and uncertainty would need to be addressed, and while opportunities from big data can streamline the integration of multiple scale-explicit biodiversity patterns, ambitious cross-scale field studies are also needed. Crucially, overcoming cross-scale ecological modelling challenges would unite disparate fields of ecology with the common goal of improving the evidence-base to safeguard biodiversity and ecosystems under novel environmental change.

Revolution in diet therapy for inflammatory bowel disease.

Until recently, diet as a therapeutic tool to treat inflammatory bowel disease (IBD) has not been proven effective. Nearly a century in the making we are in the grips of a revolution in diet therapies for IBD, driven by emerging data revealing diet as a key environmental factor associated with IBD susceptibility, and observational studies suggesting that dietary intake may play a role in the disease course of established IBD. This review summarizes the current evidence for diets trialed as induction and maintenance therapy for IBD. For Crohn's disease, exclusive enteral nutrition and the Crohn's disease exclusion diet with partial enteral nutrition are supported by emerging high-quality evidence as induction therapy, but are short-term approaches that are not feasible for prolonged use. Data on diet as maintenance therapy for Crohn's disease are conflicting, with some studies supporting fortification, and others suppression, of certain food components. For ulcerative colitis, data are not as robust for diet as induction and maintenance therapy; however, consistent themes are emerging, suggesting benefits for diets that are plant-based, high in fiber and low in animal protein. Further studies for both Crohn's disease and ulcerative colitis are eagerly awaited, which will allow specific recommendations to be made. Until this time, recommendations default to population based healthy eating guidelines.

A Primary Telangiectatic Mandibular Osteosarcoma With Germ-Line Malignancy-Associated DNA Damage Repair Gene Polymorphisms: A Case Report.

Primary mandibular telangiectatic osteosarcomas are very rare lesions, with only nine cases reported. Histologically, these lesions show multiple cystic blood-filled cavities traversed by neoplastic bone in septa lined by high-grade malignant cells. Here, we report an 81-year-old woman who presented with a mandibular mass, which was surgically resected and analyzed by histologic examination and whole exome DNA sequencing. A diagnosis of telangiectatic osteosarcoma was given. Comparative sequencing data analysis of paired benign and tumor DNA revealed 1577 variants unique to the tumor DNA, which clustered into several gene families, including those regulating DNA repair and apoptosis. Comparison of benign and tumor DNA revealed many shared gene polymorphisms associated with an increased cancer risk. These included polymorphisms in the ATM, p53, BRCA1, and BRCA2 and many other genes. Interestingly, the patient's family history showed an unusually high cancer incidence, likely related to these cancer risk-associated polymorphisms. To our knowledge, this is the first-time sequencing applied to a mandibular telangiectatic osteosarcoma. Our findings may shed light on the molecular origins of these rare tumors and how they may relate to other tumors in related kindreds.

Applying a User-Centered Design Framework to Develop a Remote Research Assessment Protocol for a Randomized Clinical Trial for Toddlers with Early Autism Characteristics.

COVID-19 required many research teams to shift from in-person to remote assessments, which posed both procedural and theoretical challenges. While research has explored the utility of remote assessments for autism diagnosis from the perspective of families and clinicians, less is known about their application in clinical trials. This paper describes the development of a remote research assessment protocol for a randomized clinical trial focusing on the implementation of reciprocal imitation teaching (RIT) with toddlers in Part C early intervention. This project spans two phases. For Phase 1, our team developed and documented a series of steps utilizing user-centered design (UCD) strategies (e.g., recruiting potential users, creating a prototype, engaging in iterative development) for the purpose of redesigning an assessment protocol for a remote environment. For Phase 2, we examined preliminary outcomes of the redesign process. Primary end users (assessors) rated post-redesign usability and acceptability, while acceptability was examined using attrition data from secondary end users (family participants). Preliminary fidelity of implementation was also examined. The iterative redesign process allowed the research team to refine aspects of the assessment that ultimately led to promising preliminary ratings of usability, acceptability, and feasibility, as well as high fidelity. Preliminary data suggest that the redesigned assessment appears to be an acceptable, feasible, and usable tool for autism clinical trial research and that assessors can use it with fidelity. Further research is needed to examine the reliability and validity of the assessment, as well as implementation characteristics on a larger scale.

Harnessing EHR data for health research.

With the increasing availability of rich, longitudinal, real-world clinical data recorded in electronic health records (EHRs) for millions of patients, there is a growing interest in leveraging these records to improve the understanding of human health and disease and translate these insights into clinical applications. However, there is also a need to consider the limitations of these data due to various biases and to understand the impact of missing information. Recognizing and addressing these limitations can inform the design and interpretation of EHR-based informatics studies that avoid confusing or incorrect conclusions, particularly when applied to population or precision medicine. Here we discuss key considerations in the design, implementation and interpretation of EHR-based informatics studies, drawing from examples in the literature across hypothesis generation, hypothesis testing and machine learning applications. We outline the growing opportunities for EHR-based informatics studies, including association studies and predictive modeling, enabled by evolving AI capabilities-while addressing limitations and potential pitfalls to avoid.

Identification of metabolites associated with preserved muscle volume after aneurysmal subarachnoid hemorrhage due to high protein supplementation and neuromuscular electrical stimulation.

The INSPIRE randomized clinical trial demonstrated that a high protein diet (HPRO) combined with neuromuscular electrical stimulation (NMES) attenuates muscle atrophy and may improve outcomes after aneurysmal subarachnoid hemorrhage We sought to identify specific metabolites mediating these effects. Blood samples were collected from subjects on admission prior to randomization to either standard of care (SOC; N = 12) or HPRO + NMES (N = 12) and at 7 days. Untargeted metabolomics were performed for each plasma sample. Sparse partial least squared discriminant analysis identified metabolites differentiating each group. Correlation coefficients were calculated between each metabolite and total protein per day and muscle volume. Multivariable models determined associations between metabolites and muscle volume. Unique metabolites (18) were identified differentiating SOC from HPRO + NMES. Of these, 9 had significant positive correlations with protein intake. In multivariable models, N-acetylleucine was significantly associated with preserved temporalis [OR 1.08 (95% CI 1.01, 1.16)] and quadricep [OR 1.08 (95% CI 1.02, 1.15)] muscle volume. Quinolinate was also significantly associated with preserved temporalis [OR 1.05 (95% CI 1.01, 1.09)] and quadricep [OR 1.04 (95% CI 1.00, 1.07)] muscle volume. N-acetylserine and ß-hydroxyisovaleroylcarnitine were associated with preserved temporalis or quadricep volume. Metabolites defining HPRO + NMES had strong correlations with protein intake and were associated with preserved muscle volume.

Divergent evolution of sleep in Drosophila species.

Living organisms synchronize their biological activities with the earth's rotation through the circadian clock, a molecular mechanism that regulates biology and behavior daily. This synchronization factually maximizes positive activities (e.g., social interactions, feeding) during safe periods, and minimizes exposure to dangers (e.g., predation, darkness) typically at night. Beyond basic circadian regulation, some behaviors like sleep have an additional layer of homeostatic control, ensuring those essential activities are fulfilled. While sleep is predominantly governed by the circadian clock, a secondary homeostatic regulator, though not well-understood, ensures adherence to necessary sleep amounts and hints at a fundamental biological function of sleep beyond simple energy conservation and safety. Here we explore sleep regulation across seven Drosophila species with diverse ecological niches, revealing that while circadian-driven sleep aspects are consistent, homeostatic regulation varies significantly. The findings suggest that in Drosophilids, sleep evolved primarily for circadian purposes. The more complex, homeostatically regulated functions of sleep appear to have evolved independently in a species-specific manner, and are not universally conserved. This laboratory model may reproduce and recapitulate primordial sleep evolution.

Sustained IL-6 and sTNF-αR1 levels after hip fracture predict 5-year mortality: A prospective cohort study from the Baltimore Hip Studies.

BACKGROUND: Persistent inflammation is associated with adverse health outcomes, but its impact on mortality has not been investigated previously among hip fracture patients. This article aims to investigate the influence of changes in levels of cytokines in the 2 months after a hip fracture repair on 5-year mortality. METHODS: This is a prospective cohort study from the Baltimore Hip Studies (BHS) with 191 community-dwelling older men and women (≥65 years) who had recently undergone surgical repair of an acute hip fracture, with recruitment from May 2006 to June 2011. Plasma interleukin-6 (IL-6), soluble tumor necrosis factor alpha receptor1 (sTNFα-R1), and interleukin-1 receptor agonist (IL-1RA) were obtained within 22 days of admission and at 2 months. All-cause mortality over 5 years was determined. Logistic regression analysis tested the associations between the cytokines' trajectories and mortality over 5 years, adjusted for covariates (age, sex, education, body mass index, lower extremity physical activities of daily living, and Charlson comorbidity index). RESULTS: High levels of IL-6 and sTNFα-R1 at baseline with small or no decline at 2 months were associated with higher odds of 5-year mortality compared with those with lower levels at baseline and greater decline at 2 months after adjustment for age, and other potential confounders (OR = 4.71, p = 0.01 for IL-6; OR = 15.03, p = 0.002 for sTNFα-R1). Similar results that failed to reach significance were found for IL-1RA (OR = 2.40, p = 0.18). Those with higher levels of cytokines at baseline with greater decline did not have significantly greater mortality than the reference group, those with lower levels at baseline and greater decline. CONCLUSION: Persistent elevation of plasma IL-6 and sTNFα-R1 levels within the first 2 months after hospital admission in patients with hip fracture is associated with higher 5-year mortality. These patients may benefit from enhanced care and earlier intensive interventions to reduce the risk of death.

Equipping Nurse Practitioner Students With Social Determinants of Health Competencies.

BACKGROUND: Social determinants of health (SDOH) cause significant burden on individuals living with acute and chronic disease. There are meaningful data to support screening for social needs, yet implementation limitations exist in the clinical setting. Incorporating SDOH education into nurse practitioner (NP) curriculum provides a framework for bringing these concepts into clinical practice. As NP education transitions from concept-based to competency-based instruction, NP programs across the nation are tasked with ensuring socially competent, practice-ready NPs. METHOD: To help students understand the impact of SDOH in an applied way, a multisemester clinical and didactic dyad approach to SDOH competency was implemented. RESULTS: NP students (N = 521) in three separate cohorts completed the SDOH project between 2019 and 2021. Statistically significant results (p > .001) demonstrated increased knowledge related to SDOH in the clinical setting. CONCLUSION: Equipping NP students with SDOH competencies empowers them to optimize health, improve patient outcomes, and promote health equity. [J Nurs Educ. 2024;63(X):XXX-XXX.].

Inhibition of aberrantly overexpressed Polo-like kinase 4 is a potential effective treatment for DNA damage repair-deficient uterine leiomyosarcoma.

PURPOSE: Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibit DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment. EXPERIMENTAL DESIGN: Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) were tested in vitro on gynecological sarcoma cell lines SK-UT-1, and SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2 knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay. RESULTS: Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining (NHEJ) DNA repair. Compared to wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and NHEJ repairs were impaired. CONCLUSIONS: Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacological inhibition of ATM enhanced the efficacy of PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.

Genetic and phenotypic characterization of Parkinson's disease at the clinic-wide level.

Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale. All PD patients with clinical visits at the UPenn PD Center between 9/2018 and 12/2022 were eligible. Blood or saliva were collected, and a clinical questionnaire administered. Genotyping at 14 GBA1 and 8 LRRK2 variants was performed. PD symptoms were compared by sex and gene groups. 2063 patients were approached and 1,689 (82%) were enrolled, with 374 (18%) declining to participate. 608 (36%) females were enrolled, 159 (9%) carried a GBA1 variant, and 44 (3%) carried a LRRK2 variant. Compared with males, females across gene groups more frequently reported dystonia (53% vs 46%, p = 0.01) and anxiety (64% vs 55%, p < 0.01), but less frequently reported cognitive impairment (10% vs 49%, p < 0.01) and vivid dreaming (53% vs 60%, p = 0.01). GBA1 variant carriers more frequently reported anxiety (67% vs 57%, p = 0.04) and depression (62% vs 46%, p < 0.01) than non-carriers; LRRK2 variant carriers did not differ from non-carriers. We report feasibility for near-clinic-wide enrollment and characterization of individuals with PD during clinical visits at a high-volume academic center. Clinical symptoms differ by sex and GBA1, but not LRRK2, status.

Driving delivery and uptake of catch-up vaccination among adolescent and adult migrants in UK general practice: a mixed methods pilot study.

BACKGROUND: Migrants in the UK and Europe face vulnerability to vaccine-preventable diseases (VPDs) due to missed childhood vaccines and doses and marginalisation from health systems. Ensuring migrants receive catch-up vaccinations, including MMR, Td/IPV, MenACWY, and HPV, is essential to align them with UK and European vaccination schedules and ultimately reduce morbidity and mortality. However, recent evidence highlights poor awareness and implementation of catch-up vaccination guidelines by UK primary care staff, requiring novel approaches to strengthen the primary care pathway. METHODS: The 'Vacc on Track' study (May 2021-September 2022) aimed to measure under-vaccination rates among migrants in UK primary care and establish new referral pathways for catch-up vaccination. Participants included migrants aged 16 or older, born outside of Western Europe, North America, Australia, or New Zealand, in two London boroughs. Quantitative data on vaccination history, referral, uptake, and sociodemographic factors were collected, with practice nurses prompted to deliver catch-up vaccinations following UK guidelines. Focus group discussions and in-depth interviews with staff and migrants explored views on delivering catch-up vaccination, including barriers, facilitators, and opportunities. Data were analysed using STATA12 and NVivo 12. RESULTS: Results from 57 migrants presenting to study sites from 18 countries (mean age 41 [SD 7.2] years; 62% female; mean 11.3 [SD 9.1] years in UK) over a minimum of 6 months of follow-up revealed significant catch-up vaccination needs, particularly for MMR (49 [86%] required catch-up vaccination) and Td/IPV (50 [88%]). Fifty-three (93%) participants were referred for any catch-up vaccination, but completion of courses was low (6 [12%] for Td/IPV and 33 [64%] for MMR), suggesting individual and systemic barriers. Qualitative in-depth interviews (n = 39) with adult migrants highlighted the lack of systems currently in place in the UK to offer catch-up vaccination to migrants on arrival and the need for health-care provider skills and knowledge of catch-up vaccination to be improved. Focus group discussions and interviews with practice staff (n = 32) identified limited appointment/follow-up time, staff knowledge gaps, inadequate engagement routes, and low incentivisation as challenges that will need to be addressed. However, they underscored the potential of staff champions, trust-building mechanisms, and community-based approaches to strengthen catch-up vaccination uptake among migrants. CONCLUSIONS: Given the significant catch-up vaccination needs of migrants in our sample, and the current barriers to driving uptake identified, our findings suggest it will be important to explore this public health issue further, potentially through a larger study or trial. Strengthening existing pathways, staff capacity and knowledge in primary care, alongside implementing new strategies centred on cultural competence and building trust with migrant communities will be important focus areas.

Ultraprocessed Food Intake during the Transition to Adulthood Varies According to Sociodemographic Characteristics and Maternal Intake in Cebu, Philippines.

BACKGROUND: Ultraprocessed foods (UPFs) are associated with elevated risk of noncommunicable disease, but little is known about UPF intake and the individual-, household-, and community-level factors associated with it among adolescents in low- or middle-income countries. OBJECTIVES: We estimated the association of UPF intake across adolescence with sociodemographic characteristics and maternal UPF intake in a Filipino cohort. METHODS: Data were from 4 waves (1994-2005) of the Cebu Longitudinal Health and Nutrition Survey (n = 2068); participants were aged 11, 15, 18, and 21 y. Foods from 24-h recalls were classified using NOVA. We used two-part multilevel models to estimate time-varying associations of the odds and amount (percentage daily kilocalories) of UPF intake with sociodemographic characteristics and maternal UPF intake (none, below median among UPF-consuming mothers ["low"], at or above median ["high"]). RESULTS: Median UPF intake (interquartile range [IQR]) among adolescents was 7.3% (IQR: 0, 17.2%) of daily kilocalories at age 11 y and 10.6% (IQR: 3.6, 19.6%) at 21 y. The odds and amount of adolescent UPF intake were positively associated with female sex, years of schooling, and household wealth and inversely associated with household size. The odds-but not amount-of adolescent UPF intake was positively associated with maternal education and urbanicity and inversely associated with the distance from a household's primary store/market. The association between odds of adolescent UPF intake and school enrollment was positive in adolescence but disappeared in early adulthood. Compared with offspring whose mothers did not consume UPFs, the odds of UPF intake among those whose mothers had low or high UPF intake was greater in adolescence, but there was no association once offspring became adults. At all ages, maternal UPF intake was positively associated with the amount of offspring intake. CONCLUSIONS: Adolescent UPF intake varied across sociodemographic characteristics and was positively associated with maternal UPF intake, but not after adolescents entered adulthood.

Cyclic Formula Feeding Among Infants Participating in the Special Supplemental Nutrition Program for Women, Infants, and Children.

BACKGROUND: Low-income households often experience a cyclic pattern in food availability, with acute food shortages at month end. Variations in the monthly feeding of infant formula are understudied. OBJECTIVES: This study aimed to compare the amount and frequency of formula consumed at the beginning and end of the monthly Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) assistance cycle and test associations with total energy intake and other feeding practices among infants aged 7-11 mo. METHODS: This study was conducted between May 2020 and April 2021 in the southeastern United States and involved mothers of infants participating in WIC's fully formula package. Mothers were interviewed and 24-h feeding recalls were conducted at the beginning and end of the month. We defined month beginning as 5 d following the first WIC formula purchase and month end as 5 d before the next monthly cycle. Fifty mother-infant dyads participated in single or multiple monthly cycles, totaling 98 monthly cycles. Generalized linear mixed-effects modeling was used to test differences in formula feeding at month beginning and end. RESULTS: Most participants (84%) were African American or Latino and >90% purchased all formula within 2-3 d of the WIC issuance. The energy intake from formula at month beginning was significantly higher than at month end (67.63% and 57.85%, respectively; P = 0.002), with no differences in total energy intake. The odds of infants being fed cow milk and fruit juices/drinks increased from month beginning to end (P < 0.05). CONCLUSIONS: Infants in low-income households are at risk of experiencing a cyclic feeding pattern characterized by higher formula feeding at month beginning and an increase in feeding of nonrecommended drinks at month end. The WIC program policy could review educational and distribution options to reduce cyclic formula feeding and clarify caregivers' understanding of infants' formula needs. Household-level investigations into formula management and determinants of cyclic feeding are warranted.

Identifying long-term survivors and those at higher or lower risk of relapse among patients with cytogenetically normal acute myeloid leukemia using a high-dimensional mixture cure model.

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) may harbor prognostically relevant gene mutations and thus be categorized into one of the three 2022 European LeukemiaNet (ELN) genetic-risk groups. Nevertheless, there remains heterogeneity with respect to relapse-free survival (RFS) within these genetic-risk groups. Our training set included 306 adults on Alliance for Clinical Trials in Oncology studies with de novo CN-AML aged < 60 years who achieved a complete remission and for whom centrally reviewed cytogenetics, RNA-sequencing, and gene mutation data from diagnostic samples were available (Alliance trial A152010). To overcome deficiencies of the Cox proportional hazards model when long-term survivors are present, we developed a penalized semi-parametric mixture cure model (MCM) to predict RFS where RNA-sequencing data comprised the predictor space. To validate model performance, we employed an independent test set from the German Acute Myeloid Leukemia Cooperative Group (AMLCG) consisting of 40 de novo CN-AML patients aged < 60 years who achieved a complete remission and had RNA-sequencing of their pre-treatment sample. For the training set, there was a significant non-zero cure fraction (p = 0.019) with 28.5% of patients estimated to be cured. Our MCM included 112 genes associated with cure, or long-term RFS, and 87 genes associated with latency, or shorter-term time-to-relapse. The area under the curve and C-statistic were respectively, 0.947 and 0.783 for our training set and 0.837 and 0.718 for our test set. We identified a novel, prognostically relevant molecular signature in CN-AML, which allows identification of patient subgroups independent of 2022 ELN genetic-risk groups.Trial registration Data from companion studies CALGB 8461, 9665 and 20202 (trials registered at www.clinicaltrials.gov as, respectively, NCT00048958, NCT00899223, and NCT00900224) were obtained from Alliance for Clinical Trials in Oncology under data sharing study A152010. Data from the AMLCG 2008 trial was registered at www.clinicaltrials.gov as NCT01382147.

Lipid A modification of colistin-resistant Klebsiella pneumoniae does not alter innate immune response in a mouse model of pneumonia.

Polymyxin resistance in carbapenem-resistant Klebsiella pneumoniae bacteria is associated with high morbidity and mortality in vulnerable populations throughout the world. Ineffective antimicrobial activity by these last resort therapeutics can occur by transfer of mcr-1, a plasmid-mediated resistance gene, causing modification of the lipid A portion of lipopolysaccharide (LPS) and disruption of the interactions between polymyxins and lipid A. Whether this modification alters the innate host immune response or carries a high fitness cost in the bacteria is not well established. To investigate this, we studied infection with K. pneumoniae (KP) ATCC 13883 harboring either the mcr-1 plasmid (pmcr-1) or the vector control (pBCSK) ATCC 13883. Bacterial fitness characteristics of mcr-1 acquisition were evaluated. Differentiated human monocytes (THP-1s) were stimulated with KP bacterial strains or purified LPS from both parent isolates and isolates harboring mcr-1. Cell culture supernatants were analyzed for cytokine production. A bacterial pneumonia model in WT C57/BL6J mice was used to monitor immune cell recruitment, cytokine induction, and bacterial clearance in the bronchoalveolar lavage fluid (BALF). Isolates harboring mcr-1 had increased colistin MIC compared to the parent isolates but did not alter bacterial fitness. Few differences in cytokines were observed with purified LPS from mcr-1 expressing bacteria in vitro. However, in a mouse pneumonia model, no bacterial clearance defect was observed between pmcr-1-harboring KP and parent isolates. Consistently, no differences in cytokine production or immune cell recruitment in the BALF were observed, suggesting that other mechanisms outweigh the effect of these lipid A mutations in LPS.

Aquivion-Based Spray Freeze-Dried Composite Materials for the Cascade Production of γ-Valerolactone.

The development of multifunctional catalysts is a necessary step to effectively carry out one-pot cascade reactions, such as that from furfural to γ-valerolactone. This research effort faces the challenge posed by the intrinsic limit of how many kinds of catalytic sites a single material can bear. In this work, the application of Spray-Freeze Drying (SFD) as a synthetic technique for the preparation of a wide range of innovative composite multi-functional catalysts is reported. Herein we show that by the proper combination of Aquivion as a highly active Brønsted acid catalyst and metal oxides as both support materials and Lewis acids (LAS) enable to achieve highly unique efficient and effective dual acid composite catalysts that are able to carry out the cascade reaction from furfural to γ-valerolactone. The dual catalytic system comprised of Aq/ZrO2 with 30 % polymer content prepared via spray-freeze drying exhibited GVL yields of 25 % after only 2 h at 180 °C and a remarkably high productivity of 4470 µmolGVL gCat -1 h-1, one of the highest reported results. Mechanistic studies based on experimental and advanced characterisation and spectroscopic techniques, such as, SEM, TEM, 15N MAS NMR and 19F MAS NMR indicate that activity arises from the proper tuning of BAS/LAS (Brønsted Acid Site/Lewis Acid Site) acidic properties.

Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

BACKGROUND: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander (NHPI) women. METHODS: Participants included 1734 Asian (785 cases, 949 controls), 266 NHPI (99 cases, 167 controls), 1149 Hispanic (505 cases, 644 controls), and 24,189 White (9,981 cases, 14,208 controls) women from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations by race and ethnicity. RESULTS: Heterogeneity in EOC risk associations by race and ethnicity (p ≤ 0.02) was observed for oral contraceptive (OC) use, parity, tubal ligation and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in NHPI and Asian women. The inverse association for tubal ligation with risk was most pronounced for NHPI participants (OR=0.25, 95% CI 0.13-0.48), versus Asian and White participants, respectively (OR=0.68, 95% CI 0.51-0.90; OR=0.78, 95% CI 0.73-0.85). CONCLUSIONS: Differences in EOC risk factor associations were observed across racial and ethnic groups, which could in part be due to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain ( e.g., in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated in vitro - termed Strain A and Strain B - and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinson's Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.

Ambulatory Cardiology or General Internal Medicine Assessment Prior to Scheduled Major Vascular Surgery is Associated with Improved Outcomes.

OBJECTIVE: To characterize the association between ambulatory cardiology or general internal medicine (GIM) assessment prior to surgery and outcomes following scheduled major vascular surgery. BACKGROUND: Cardiovascular risk assessment and management prior to high-risk surgery remains an evolving area of care. METHODS: This is population-based retrospective cohort study of all adults who underwent scheduled major vascular surgery in Ontario, Canada, April 1, 2004-March 31, 2019. Patients who had an ambulatory cardiology and/or GIM assessment within 6 months prior to surgery were compared to those who did not. The primary outcome was 30-day mortality. Secondary outcomes included: composite of 30-day mortality, myocardial infarction or stroke; 30-day cardiovascular death; 1-year mortality; composite of 1-year mortality, myocardial infarction or stroke; and 1-year cardiovascular death. Cox proportional hazard regression using inverse probability of treatment weighting (IPTW) was used to mitigate confounding by indication. RESULTS: Among 50,228 patients, 20,484 (40.8%) underwent an ambulatory assessment prior to surgery: 11,074 (54.1%) with cardiology, 8,071 (39.4%) with GIM and 1,339 (6.5%) with both. Compared to patients who did not, those who underwent an assessment had a higher Revised Cardiac Risk Index (N with Index over 2= 4,989[24.4%] vs. 4,587[15.4%], P<0.001) and more frequent pre-operative cardiac testing (N=7,772[37.9%] vs. 6,113[20.6%], P<0.001) but, lower 30-day mortality (N=551[2.7%] vs. 970[3.3%], P<0.001). After application of IPTW, cardiology or GIM assessment prior to surgery remained associated with a lower 30-day mortality (weighted Hazard Ratio [95%CI] = 0.73 [0.65-0.82]) and a lower rate of all secondary outcomes. CONCLUSIONS: Major vascular surgery patients assessed by a cardiology or GIM physician prior to surgery have better outcomes than those who are not. Further research is needed to better understand potential mechanisms of benefit.