The evolution of pulmonary function in childhood onset Mucopolysaccharidosis type I.

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.

Success of pacemaker remote monitoring using app-based technology: Does patient age matter?

BACKGROUND: Remote monitoring (RM) improves patient outcomes. App-based RM is a novel technology that enables transmission of implantable device data using smart devices. Limited data exist on the impact of age and sex on the use of app-based RM. OBJECTIVE: To examine the impact of age and sex on the proportion of pacemaker patients who activated app-based RM, time from order to activation, and patient follow-up transmission adherence per guidelines. METHODS: A retrospective analysis was performed using deidentified data from U.S. pacemaker patients enrolled in the Medtronic CareLink database with an app-based monitor (MyCareLink Smart™). Activation was defined as first RM transmission and was considered early if it occurred < 90 days from order. Adherence analysis was limited to patients with ≥12 months' follow-up from activation and excluded transmissions < 90 days from activation. RESULTS: Of 48,016 patients assigned app-based RM, 40,511 (84.4%) activated their device; of these, 31,640 (65.9%) activated their device early. Among 14,232 activated patients (with 12 months' follow-up), 12,743 (89.5%) were considered adherent to guidelines by transmitting at least once more within 3-12 months following their activation transmission. While there were statistical differences in activation, early activation, and adherence among age and sex groups due to large sample sizes, the differences were not clinically significant and the majority of older patients were able to successfully use app-based RM. CONCLUSIONS: Most patients in this large and first-of-its kind reported cohort used smart devices to successfully activate app-based RM technology and remained adherent per guidelines irrespective of age or sex.

Assessing Coastal Plain Risk Indices for Subsurface Phosphorus Loss.

Phosphorus (P) Index evaluations are critical to advancing nutrient management planning in the United States. However, most assessments until now have focused on the risks of P losses in surface runoff. In artificially drained agroecosystems of the Atlantic Coastal Plain, subsurface flow is the predominant mode of P transport, but its representation in most P Indices is often inadequate. We explored methods to evaluate the subsurface P risk routines of five P Indices from Delaware, Maryland (two), Virginia, and North Carolina using available water quality and soils datasets. Relationships between subsurface P risk scores and published dissolved P loads in leachate (Delaware, Maryland, and North Carolina) and ditch drainage (Maryland) were directionally correct and often statistically significant, yet the brevity of the observation periods (weeks to several years) and the limited number of sampling locations precluded a more robust assessment of each P Index. Given the paucity of measured P loss data, we then showed that soil water extractable P concentrations at depths corresponding with the seasonal high water table (WEP) could serve as a realistic proxy for subsurface P losses in ditch drainage. The associations between WEP and subsurface P risk ratings reasonably mirrored those obtained with sparser water quality data. As such, WEP is seen as a valuable metric that offers interim insight into the directionality of subsurface P risk scores when water quality data are inaccessible. In the long term, improved monitoring and modeling of subsurface P losses clearly should enhance the rigor of future P Index appraisals.

Phosphorus Leaching in Soils Amended with Animal Manures Generated from Modified Diets.

New dietary modifications for dairy (reducing P content in feed) and poultry (addition of feed additives such as phytase) aim to reduce P excretion in manures. Our objective was to investigate if dietary changes were effective at reducing P leaching loss on land application of manures. We used 54 undisturbed lysimeters (30 cm diameter, 50 cm deep) collected from three typical mid-Atlantic soils. Lysimeters received 85 kg total P ha from fertilizer (superphosphate), dairy manures generated from low- or high-P diets, or broiler litters generated from normal diet or reduced P- and phytase-amended diets. Lysimeters were irrigated with 50 mm of water each week for 9 wk. The major forms of P in the leachate were dissolved (dissolved unreactive > dissolved reactive P [DRP]) rather than particulate (total particulate P). The higher P solubility (100%) in superphosphate resulted in greater leaching of DRP, whereas the lower P solubility (<30%) in dairy manures or broiler litters resulted in lower DRP leaching from soils. Preferential flow in two soils caused greater DRP leaching; this effect was more pronounced in the superphosphate-amended than in the manure/litter-amended lysimeters. The dairy and poultry dietary modification was effective at reducing the amount of P in manures and litters. However, the application of treatments at similar P rate (85 kg ha) resulted in the addition of a higher amount of manure (54-66%) in lysimeters that received low-P dairy manure-amended and phytase-amended broiler litter, which then controlled P leaching from soils.

Three Halloween genes from the Varroa mite, Varroa destructor (Anderson & Trueman) and their expression during reproduction.

The ecdysteroid biosynthetic pathway involves sequential enzymatic hydroxylations by a group of enzymes collectively known as Halloween gene proteins. Complete sequences for three Halloween genes, spook (Vdspo), disembodied (Vddib) and shade (Vdshd), were identified in varroa mites and sequenced. Phylogenetic analyses of predicted amino acid sequences for Halloween orthologues showed that the acarine orthologues were distantly associated with insect and crustacean clades indicating that acarine genes had more ancestral characters. The lack of orthologues or pseudogenes for remaining genes suggests these pathway elements had not evolved in ancestral arthropods. Vdspo transcript levels were highest in gut tissues, while Vddib transcript levels were highest in ovary-lyrate organs. In contrast, Vdshd transcript levels were lower overall but present in both gut and ovary-lyrate organs. All three transcripts were present in eggs removed from gravid female mites. A brood cell invasion assay was developed for acquiring synchronously staged mites. Mites within 4 h of entering a brood cell had transcript levels of all three that were not significantly different from mites on adult bees. These analyses suggest that varroa mites may be capable of modifying 7-dehydro-cholesterol precursor and hydroxylations of other steroid precursors, but whether the mites directly produce ecdysteroid precursors and products remains undetermined.

Perampanel, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models.

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 µM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 µM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.

Role of screening for uveitis in subjects with sarcoidosis.

BACKGROUND AND OBJECTIVES: Ocular involvement is common in sarcoidosis. Our study aimed to evaluate the role of screening for uveitis in subjects with sarcoidosis. METHODS: Retrospective case series of 88 subjects with a pre-existing diagnosis of sarcoidosis, with no previous diagnosis of uveitis, reviewed by Ophthalmology at Auckland District Health Board between January 2016 and May 2022. RESULTS: Among those undergoing a screening examination, uveitis was observed in 27.8% (15 out of 54 subjects). In those presenting with acute eye symptoms, uveitis was observed in 94.1% (32 out of 34 subjects). Sarcoid uveitis was diagnosed in a total of 50 out of 88 subjects (56.8%). 45 subjects required ocular treatment. Sarcoid uveitis was observed in 6 out of 27 subjects (22.2%) who were entirely asymptomatic at screening. On multivariate analysis, blurring of vision (OR 26.2 p < 0.001), eye pain (OR 7.3 p = 0.014) and respiratory disease (OR 7.1 p = 0.044) were associated with increased risk of sarcoid uveitis. In the 41 subjects with no uveitis at initial examination, 3 subjects (7.3%) subsequently developed uveitis. CONCLUSION: Our study highlights the importance of ophthalmic screening of all patients with systemic sarcoidosis, even in asymptomatic patients. With a high correlation of ocular symptoms in diagnosis of sarcoid uveitis, ophthalmologists should educate patients to look out for the development of symptoms of ocular inflammation, and clinicians who continue follow up for systemic sarcoidosis should remind patients to watch carefully for these symptoms to facilitate timely diagnosis and intervention.

Safety Profile of a Cognitively Unimpaired Older Population with Elevated Cerebral Amyloid in a 4.5-Year Clinical Trial.

BACKGROUND: Preclinical Alzheimer's disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer's disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities. OBJECTIVES: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial. DESIGN: Phase 3, 4.5-year, multicenter, placebo-controlled trial. SETTING: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. PARTICIPANTS: Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography. MEASUREMENTS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging). RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001). CONCLUSION: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer's disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer's disease.

Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer's Disease.

BACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool. OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals. SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study. INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention. MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL. RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)). CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.

Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer's Disease Randomized Controlled Trial.

BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study. DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers). SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic. PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants. MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM. RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout. CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.

Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies.

BACKGROUND: Converging evidence suggests that markers of Alzheimer's disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aß+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aß-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aß+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aß+ underwent tau PET imaging in A4 (n=350). Aß- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aß- and A4 Aß+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

Assessing potential impacts of a wastewater rapid infiltration basin system on groundwater quality: a delaware case study.

Rapid infiltration basin systems (RIBS) are receiving increased interest for domestic wastewater disposal in rural areas. They rely on natural treatment processes to filter pollutants and use extremely high effluent loading rates, much greater than natural precipitation, applied to a small geographic area instead of disposal to surface water. Concerns exist today that adopting RIBS in areas with shallow groundwater and sandy soils may increase ground and surface water pollution. We conducted a field study of RIBS effects on N and P concentrations in soils and groundwater at Cape Henlopen State Park, Delaware, where a RIBS designed and operated following USEPA guidance has been used for >25 yr. Site and wastewater characteristics (water table of 8 m, Fe- and Al-oxide coatings on soils, organic-rich effluent) were favorable for denitrification and P sorption; however, we found high P saturation, reduced soil P sorption capacity, and significant total P accumulation at depths >1.5 m, factors that could lead to dissolved P leaching. Very low soil inorganic N levels suggest that wastewater N was converted rapidly to NO-N and leached from the RIBS. Extensive groundwater monitoring supported these concerns and showed rapid offsite transport of N and P at concentrations similar to the effluent. Results suggest that high hydraulic loads and preferential flow led to flow velocities that were too large, and contact times between effluent and soils that were too short, for effective N and P attenuation processes. These findings indicate the need for better site characterization and facility designs to reduce and monitor contaminant loss from RIBS in similar settings.

Advances and challenges for nutrient management in china in the 21st century.

Managing agricultural nutrients to provide a safe and secure food supply while protecting the environment remains one of the great challenges for the 21st century. The fourth International Nutrient Management Symposium (INMS), held in 2011 at the University of Delaware, addressed these issues via presentations, panel sessions, and field tours focused on latest technologies and policies available to increase nutrient use efficiency. Participants from the United States, Europe, Canada, and China discussed global trends and challenges, balancing food security and the environment in countries with struggling and emerging economics, nutrient management and transport at the catchment scale, new technologies for managing fertilizer and manure nutrients, and adaptive nutrient management practices for farm to watershed scales. A particular area of interest at the fourth INMS was nutrient management progress and challenges in China over the past 40 years. China's food security challenges and rapidly growing economy have led to major advances in agricultural production systems but also created severe nutrient pollution problems. This special collection of papers from the fourth INMS gives an overview of the remarkable progress China has made in nutrient management and highlights major challenges and changes in agri-environmental policies and practices needed today. Lessons learned in China are of value to both developing and developed countries facing the common task of providing adequate food for an expanding world population, while protecting air and water quality and restoring damaged ecosystems.

The driving forces for nitrogen and phosphorus flows in the food chain of china, 1980 to 2010.

Nitrogen (N) and phosphorus (P) use and losses in China's food chain have accelerated in the past three decades, driven by population growth, rapid urbanization, dietary transition, and changing nutrient management practice. There has been little detailed quantitative analysis of the relative magnitude of these driving forces throughout this period. Therefore, we analyzed changes in N and P flows and key drivers behind changes in the food (production and consumption) chain at the national scale from 1980 to 2010. Food (N and P) consumption increased by about fivefold in urban settings over this period but has decreased in rural settings since the 1990s. For urban settings, the integrated driving forces for increased food consumption were population growth, which accounted for ∼60%, and changing urban diets toward a greater emphasis on the consumption of animal products. Nutrient inputs and losses in crop and animal productions have continuously increased from 1980 to 2010, but the rates of decadal increase were greatly different. Increased total inputs and losses in crop production were primarily driven by increased crop production for food demand (68-96%) in the 1980s but were likely offset in the 2000s by improved nutrient management practices, as evidenced by decreased total inputs to and losses from cropland for harvesting per nutrient in crop. The contributions of animal production to total N and P losses to waters from the food chain increased by 34 and 60% from 1980 to 2010. These increases were caused mainly by decreased ratios of manure returned to cropland. Our study highlights a larger impact of changing nutrient management practice than population growth on elevated nutrient flows in China's food chain.

Disposition of desfuroylceftiofur acetamide in serum, placental tissue, fetal fluids, and fetal tissues after administration of ceftiofur crystalline free acid (CCFA) to pony mares with placentitis.

The objective of this study was to determine the pharmacokinetics of CCFA in mares with placentitis and evaluate the disposition of the drug in fetal fluids, fetal membranes, colostrum, and serum of foals. A secondary objective was to obtain pilot data regarding the efficacy of CCFA for improving foal survival in mares with placentitis. Twelve pregnant pony mares were enrolled in the study, inoculated with Streptococcus zooepidemicus, intracervically and assigned to one of three groups: CEFT (n = 3; administered CCFA only; 6.6 mg/kg, i.m., q96h); COMBO (n = 6; administered combination therapy of CCFA, altrenogest, and pentoxifylline); UNTREAT (n = 3, no treatment). Treatment was initiated at the onset of clinical signs. Concentrations of desfuroylceftiofur acetamide (DCA), the acetamide derivative of ceftiofur and desfuroylceftiofur metabolites, were measured using high-performance liquid chromatography. Maximum and minimum serum concentrations of DCA at steady state in treated mares were 2.40±0.40 µg/mL and 1.06±0.29 µg/mL, respectively. Concentration of DCA in colostrum was 1.51±0.60 µg/mL. DCA concentrations in placenta and fetal tissues were very low (median = 0.03 µg/mL) and below the minimum inhibitory concentration of relevant pathogens. DCA was not detected in amniotic fluid or foal serum. Treatment did not appear to improve foal survival (CEFT: 0/3; COMBO: 2/6; UNTREAT: 2/3). Bacteria were recovered from the uterus of most mares postpartum and from blood cultures of most foals regardless of treatment.

Predictors of glaucoma in patients with uveitis and scleritis.

BACKGROUND: To examine risk factors for development of glaucoma in a large cohort of subjects with uveitis and scleritis. METHODS: Retrospective review of subjects diagnosed with uveitis or scleritis between 2006 and 2019 at Auckland District Health Board. Subjects were excluded if they had glaucoma due to another cause. Main outcome measure was development of glaucoma. Data for local steroid use was not available. RESULTS: 3462 eyes of 2414 subjects were included in the study. Mean follow-up was 5.7 years (total follow-up time 19,897 eye years). Median age was 44.3 years and 1189 (49.3%) were female. Glaucoma developed in 222 eyes (6.3%) during the follow-up. Five-year cumulative risk of glaucoma was 6.2% (CI 5.0-7.5%) for anterior uveitis, 5.4% (CI 3.2-9.0%) for intermediate uveitis, 1.6% (CI 0.4-6.7%) for posterior uveitis, 8.7% (CI 6.5-11.7%) for panuveitis, and 3.2% (CI 1.0-9.5%) for scleritis. Five-year cumulative risk of glaucoma was lowest in HLA-B27 uveitis at 0.9% (CI 0.4-2.1%) and highest in viral uveitis 15.1% (CI 10.1-22.3%), sarcoidosis 9.9% (CI 6.1-15.9%) and tuberculosis 9.7% (CI 5.4-17.0%). On multivariate analysis, risk factors for development of glaucoma were older age at presentation, higher presenting intraocular pressure, chronic inflammation, and cystoid macular oedema. CONCLUSIONS: Glaucoma is a common complication of uveitis and scleritis and was more frequent in older subjects, high presenting IOP, chronic inflammation and those with cystoid macular oedema. Local steroid therapy contributes to this, but is not quantifiable in this study. Targeted screening is required to avoid irreversible progression of glaucomatous optic neuropathy.

Can We Use Blood Biomarkers as Entry Criteria and for Monitoring Drug Treatment Effects in Clinical Trials? A Report from the EU/US CTAD Task Force.

In randomized clinical trials (RCTs) for Alzheimer's Disease (AD), cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are currently used for the detection and monitoring of AD pathological features. The use of less resource-intensive plasma biomarkers could decrease the burden to study volunteers and limit costs and time for study enrollment. Blood-based markers (BBMs) could thus play an important role in improving the design and the conduct of RCTs on AD. It remains to be determined if the data available on BBMs are strong enough to replace CSF and PET biomarkers as entry criteria and monitoring tools in RCTs.

Therapeutic Targets for Alzheimer's Disease: Amyloid Vs. Non-Amyloid. Where Does Consensus Lie Today? An CTAD Task Force Report.

There was consensus that both amyloid and tau pathologies should be targeted in Alzheimer's disease, as well as additional pathophysiological mechanisms such as neuroinflammation. The selection of one or both of these targets may depend upon a personalized approach that takes into account the genetic and acquired factors that cause AD in any given person as well as their stage of disease as reflected in a biomarker profile. The validation of this therapeutic approach will be made possible by new methodologies for subdividing into predominant pathology, by efficient methods for identifying people in the earliest stages of disease, and by combination studies.

Amyloid-Related Imaging Abnormalities and Other MRI Findings in a Cognitively Unimpaired Population With and Without Cerebral Amyloid.

BACKGROUND: Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies provide a unique opportunity to compare magnetic resonance imaging (MRI) findings such as amyloid-related imaging abnormalities (ARIA) in cognitively unimpaired elderly with and without elevated cerebral amyloid. OBJECTIVES: To compare screening MRI findings, such as ARIA, in the cognitively unimpaired potential participants of a clinical trial with and without elevated cerebral amyloid. DESIGN: Cross-sectional analysis of structural MRI findings in screening data from the A4 and LEARN studies. SETTING: The A4 Study is a multi-center international clinical trial. The LEARN Study is a multi center observational study in the United States. PARTICIPANTS: Clinically normal older adults (65-85 years) with elevated cerebral amyloid (Aß+; n = 1250, A4) and without elevated cerebral amyloid (Aß-; n = 538, LEARN). MEASUREMENTS: Participants underwent florbetapir positron emission tomography for Aß+/- classification. A centrally read 3T MRI to assess for study eligibility was conducted on study qualified MRI scanners. RESULTS: No ARIA-effusions (ARIA-E) was detected on screening MRI in the Aß+ or Aß- cohorts. At least one ARIA-H (microhemorrhages [MCH] or superficial siderosis [SS]) was present in 18% of the Aß+ cohort compared with 8% in Aß- (P < 0.001). In the Aß+ cohort, approximately 2% of screening MRIs demonstrated MCH ≥4 compared with 0% in Aß-. The presence of two apolipoprotein E ε4 (APOEε4) alleles (vs no ε4 alleles) in the Aß+ cohort increased the odds for presence of MCH (odds ratio [OR] = 2.03; 95% CI, 1.23 to 3.27, P = 0.004). Cortical infarctions (4% vs 0%) and subcortical infarctions (10% vs 1%) were observed at statistically significantly higher prevalence in the Aß+ cohort compared with Aß- (P < 0.001). Females showed reduced odds of MCH in the Aß+ cohort by a factor of 0.63 (95% CI, 0.47 to 0.84, P = 0.002). CONCLUSIONS: ARIA-E is rare in cognitively unimpaired Aß+ and Aß- populations prior to anti-amyloid drug intervention. ARIA-H in Aß+ was greater than in Aß- populations.

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.