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Abstract Reference conditions pertain to conditions without anthropogenic influence and serve to gauge the degree of river pollution and identify the best attainable water quality. Here we show estimates of the global human footprint of nitrogen and phosphorus concentrations and potential for related nuisance or harmful algal growth in rivers. We use statistical models based on 1.2 million stream nutrient measurements (from 2005 to 2013) and find global human enrichment of river total nitrogen and total phosphorus is 35% and 14% respectively. The greatest enrichment is in Europe (86 and 30% respectively) and the least in Oceania (9 and 2% respectively). The levels of enrichment translated into an almost doubling of the catchment areas with rivers predicted to have anthropogenically elevated levels of potentially harmful or nuisance algae, affecting ~40% of the world’s population. Focusing management on the difference between current and reference conditions can help protect good water quality while avoiding unrealistic goals where nitrogen and phosphorus are naturally high.

Abstract Background Declining gait performance is seen in aging individuals, due to neural and systemic factors. Plasma biomarkers provide an accessible way to assess evolving brain changes; non-specific neurodegeneration (NfL, GFAP) or evolving Alzheimer’s disease (Aβ 42/40 ratio, P-Tau181). Methods In a population-based cohort of older adults, we evaluate the hypothesis that plasma biomarkers of neurodegeneration and Alzheimer’s Disease pathology are associated with worse gait performance. A sample of 2641 Mayo Clinic Study of Aging participants with measurements of plasma biomarkers and gait parameters was analyzed in this cross-sectional study. Linear regression models using plasma biomarkers as predictors of gait parameters and adjusted for age, sex, BMI, Charlson Comorbidity Index, and cognitive diagnosis were evaluated. Results In this study multiple statistically significant relationships are observed for GFAP, NfL, and P-Tau181 with gait parameters. Each standard deviation increase in GFAP, NfL, and P-Tau181 is associated with a reduction in velocity of 2.100 (95% CI: −3.004, −1.196; p = 5.4 × 10−6), 4.400 (−5.292, -3.507; p = 9.5 × 10−22), and 2.617 (−3.414, −1.819; p = 1.5 × 10−10) cm/sec, respectively. Overall, NfL has the strongest associations with poor gait performance. Models with age interactions show that the strength of associations between the plasma biomarkers and the gait parameters became stronger with increasing age. There are no specific gait parameters that associate with individual plasma biomarkers. Conclusion Plasma biomarkers of neurodegeneration and Alzheimer’s Disease pathology are not only markers of cognitive decline but also indicate motor decline in the aging population.

Abstract Background Anxiety disorders (ADs) are a complex group of mental disorders and majorly contribute to the global health-related burden. Symptoms and clinical management differ widely depending on the specific diagnosis. There is a need for new, more effective pharmacological treatments for these patients as many patients do not respond to treatment and treatment is not available for several types of AD. The increased interest in the potential effects of cannabidiol (CBD) on symptoms of AD has led to several preclinical and clinical studies that suggest that CBD may be effective in some patients with AD. However, it remains unclear whether and how CBD can be used in the clinical management of ADs due to a lack of sufficiently robust clinical evidence. Comparative evaluation This narrative review provides a critical analysis of the current state of the art for ADs and summarizes six recently completed and 22 currently ongoing clinical trials investigating the effects of CBD on ADs or anxiety. The aim was to examine whether the ongoing trials are likely to provide the necessary solid evidence, or whether new studies with more robust design parameters can help to overcome the prevailing lack of solid clinical data for this CBD indication. Most of the trials reviewed are considered exploratory and do not focus on specific types of clinical anxiety or ADs as the primary condition studied. Participant numbers, CBD dose, treatment duration, and CBD formulation vary widely among the studies, and all but two are single-center studies. Conclusion For an effective clinical management of ADs using CBD, there is a need for sufficiently powered and appropriately designed clinical trials (RCT, multicenter, defined doses and exposure monitoring, robust primary outcomes) investigating the effect of CBD in specific ADs, such as social anxiety disorder and panic disorder, or in post-traumatic stress disorder.

ABSTRACT Ondansetron is an anti‐emetic 5‐HT3 receptor antagonist being investigated for treating neonatal opioid withdrawal syndrome (NOWS). Sparse PK data were analyzed from a multicenter, double‐blind clinical trial with 98 mother/neonate dyads. Pregnant women with opioid use disorder were randomized to receive either placebo or ondansetron 8 mg intravenously within 4 h of delivery. Neonates born to mothers who were randomized to ondansetron received 0.07 mg/kg orally once every 24 h for up to five doses. Using current PK data, model parameters from a two‐compartmental structural model from the literature (i.e., a priori model) were updated with the Metropolis‐Hastings Markov‐chain Monte Carlo estimation algorithm in NONMEM. The updated Bayesian model indicated a slower absorption rate (KA) but no differences in model parameters (CL, V, V2, Q) after including body weight and postmenstrual age. Sensitivity analyses on CL prior revealed statistical improvement favoring larger body weights, but not changes in postmenstrual age. However, further model development using larger body weights did not illustrate superior performance through visual inspection of diagnostic plots. Overall, a cumulative AUC of at least 1000 ng*h/mL appears to be the threshold for reductions in symptom severity. Exposure‐response analyses suggest the total number of doses to be the primary driver for efficacy with respect to AUC, which reasonably aligns with the literature. Overall, it is suggested that at least three doses of the current oral ondansetron regimen are required to reduce symptom severity in neonates.

Abstract Background and Aims Physical activity (PA) is associated with higher gait speed. We aimed to examine the associations between PA and change in spatial and temporal gait measures as well as fall risk in community‐dwelling individuals free of dementia. Methods Longitudinal study among 4173 individuals aged ≥50 years (mean age 71 years; 2078 males; median follow‐up 4 years) enrolled in the Mayo Clinic Study of Aging. Self‐reported late‐life PA was used to calculate overall PA and moderate‐vigorous PA (MVPA) scores. Gait was assessed using GAITRite® and Zeno™ systems. Incident falls information was based on diagnostic codes retrieved from medical records. We ran linear mixed effects models to examine associations between z‐scored PA variables and longitudinal gait parameters, adjusted for age, sex, education, body mass index (BMI), medical comorbidities, and including interactions between PA and time since baseline. In secondary analyses, we calculated Cox Proportional hazard models with age as time scale predicting incident falls by PA, adjusting for sex, education, BMI, medical comorbidities, and falls history. Results At baseline, higher PA was associated with higher velocity (overall PA: estimate 2.9935; MVPA: 2.2961; p

Objectives: The purpose of this study was to examine the effect of hawthorn extract drink in mildly hypertensive and/or hyperlipidaemic Chinese patients. Methods: We performed a randomized double-blind placebo-controlled crossover study. Subjects who were randomly divided into 2 groups and asked to consume either hawthorn fruit extract drink or placebo with the same sugar content for 8-weeks with crossover to the alternative drink separated by a 4-weeks washout period. Adverse effects, lipid profile, fasting plasma glucose and blood pressure were recorded. Results: In 61 participants, body weight increased by mean (95% CI) 0.42 kg (−0.85, 1.69 kg) with the hawthorn drink and 0.94 kg (0.52, 1.36 kg) with placebo ( P > .05). Systolic blood pressure and plasma total cholesterol increased significantly with both treatments and cholesterol sub-fractions showed no significant changes. Significant increases were seen in fasting plasma glucose with placebo. The increase in plasma glucose was reversed during the 4-week washout period. Conclusions: Although our results didn’t show significant effects of hawthorn drink compared to placebo, there was a trend toward fewer adverse metabolic effects. A longer study with hawthorn fruit extract without additional calories would be useful to determine if beneficial effects occur in patients with mild hyperlipidaemia or hypertension.

Abstract Background The primary components driving the current commercial fascination with cannabis products are phytocannabinoids, a diverse group of over 100 lipophilic secondary metabolites derived from the cannabis plant. Although numerous phytocannabinoids exhibit pharmacological effects, the foremost attention has been directed towards Δ9-tetrahydrocannabinol (THC) and cannabidiol, the two most abundant phytocannabinoids, for their potential human applications. Despite their structural similarity, THC and cannabidiol diverge in terms of their psychotropic effects, with THC inducing notable psychological alterations. There is a clear need for accurate and rapid THC measurement methods that offer dependable, readily accessible, and cost-effective analytical information. This review presents a comprehensive view of the present state of alternative technologies that could potentially facilitate the creation of portable devices suitable for on-site usage or as personal monitors, enabling non-intrusive THC measurements. Method A literature survey from 2017 to 2023 on the development of portable technologies and commercial products to detect THC in biofluids was performed using electronic databases such as PubMed, Scopus, and Google Scholar. A systematic review of available literature was conducted using Preferred Reporting Items for Systematic. Reviews and Meta-analysis (PRISMA) guidelines. Results Eighty-nine studies met the selection criteria. Fifty-seven peer-reviewed studies were related to the detection of THC by conventional separation techniques used in analytical laboratories that are still considered the gold standard. Studies using optical (n = 12) and electrochemical (n = 13) portable sensors and biosensors were also identified as well as commercially available devices (n = 7). Discussion The landscape of THC detection technology is predominantly shaped by immunoassay tests, owing to their established reliability. However, these methods have distinct drawbacks, particularly for quantitative analysis. Electrochemical sensing technology holds great potential to overcome the challenges of quantification and present a multitude of advantages, encompassing the possibility of miniaturization and diverse modifications to amplify sensitivity and selectivity. Nevertheless, these sensors have considerable limitations, including non-specific interactions and the potential interference of compounds and substances existing in biofluids. Conclusion The foremost challenge in THC detection involves creating electrochemical sensors that are both stable and long-lasting while exhibiting exceptional selectivity, minimal non-specific interactions, and decreased susceptibility to matrix interferences. These aspects need to be resolved before these sensors can be successfully introduced to the market.

Erick E Rocher,1 Rishima Mukherjee,1 James Pitingolo,1 Eli Levenshus,1 Gwyneth Alexander,1 Minyoung Park,1 Rupsa Acharya,1 Sarah Khan,1 Jordan Shuff,1 Andres Aguirre,1 Shababa Matin,2 Keith Walter,3 Allen O Eghrari4 1Center for Bioengineering Innovation and Design, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; 2Rice 360 Institute for Global Health Technologies, Rice University, Houston, TX, USA; 3Department of Ophthalmology, Wake Forest Baptist Health, Winston-Salem, NC, USA; 4Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USACorrespondence: Allen O Eghrari, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Smith 5013, Baltimore, MD, 21231, USA, Email allen@jhmi.eduPurpose: Intraocular lens (IOL) unfurling can be a rate-limiting step in cataract surgery, limiting operative efficiency. Furthermore, inefficient unfurling has important implications for clinical outcomes. We examine the effects of solution temperature on IOL unfurling time using three in vitro models of the ocular environment.Methods: IOLs were injected into a 6-well plate filled with balanced salt solution (BSS), dispersive ophthalmic viscoelastic device (OVD), or cohesive OVD. Experiments were also performed in a plastic eye filled with dispersive or cohesive OVD. IOL unfurling time was recorded against the temperature of the respective solution.Results: IOL unfurling time decayed exponentially as solution temperature increased in all experiments, including the BSS-filled 6-well plate, the OVD-filled 6-well plate, and the OVD-filled plastic eye. IOLs failed to unfurl within 10 min at 10°C, below the glass transition temperature of the tested IOLs. Increasing solution temperature from 20°C to 30°C decreases IOL unfurling by greater than 2 min. Further heating to 40°C did not significantly decrease IOL unfurling time.Conclusion: Increased solution temperature rapidly decreases IOL unfurling time in vitro. IOLs do not unfurl within a clinically acceptable timeframe at or below their glass transition temperature. Increased BSS and/or OVD temperature may be a potential method to decrease IOL unfurling time in cataract surgery. However, future research is needed to elucidate potential consequences of warmed BSS and/or OVD on post-operative outcomes. This study demonstrates the potential for temperature regulation to decrease cataract surgery operative time and provides preliminary evidence to justify future clinical validation of this relationship.Plain Language Summary: During cataract surgery, a prosthetic intraocular lens (IOL) is inserted into the eye once the clouded lens is removed. The IOL must then unfurl before the procedure can proceed. When IOLs fail to unfurl or unfurl slowly, this can delay the operation and may even cause post-operative complications. Thus, we studied the effect temperature may have on IOL unfurling time to optimize this segment of the operation.We injected IOLs into solutions of saline (balanced salt solution) or ophthalmic viscoelastic device (OVD), two fluids injected into the eye during surgery. In both a well plate and a plastic eye, we found that increasing the temperature of the solution significantly affected IOL unfurling time. Specifically, heating the solution from refrigeration to room temperature decreased unfurling time from over 10 min to less than four. Heating to physiological temperature further decreased unfurling time to less than a minute.Our results show promise for potentially utilizing heated BSS and/or OVD to accelerate IOL unfurling and decrease cataract surgery operative time.Keywords: cataract surgery, balanced salt solution, ophthalmic viscoelastic device

Abstract Transgender women may have concerns of drug interactions between feminizing hormone therapy (FHT) and antiretrovirals, leading to nonadherence. This randomized, three‐period crossover, open‐label, phase I trial assessed the effects of doravirine (DOR) and tenofovir disoproxil fumarate (TDF) on the pharmacokinetics (PKs) of estradiol, spironolactone, and total testosterone and vice versa in healthy transgender women. Volunteers were randomized 1:1 into two sequences containing three treatment groups (DOR, lamivudine [3TC], and TDF alone; estradiol, spironolactone, and placebo; and DOR/3TC/TDF, estradiol, and spironolactone). Eight subjects enrolled in the study and six had completed all study periods. The geometric mean ratios for DOR area under the concentration‐time curve from zero to last measured concentration (AUC0‐last), maximum concentration (Cmax), and concentration at 24 h (C24) were similar. However, tenofovir (TFV) AUC0‐last, Cmax, and C24 moderately increased by 14%–38%. Last, estradiol AUC0‐last, Cmax, and C24 were increased by 10%–13%. Whereas most 90% confidence intervals did not meet the bioequivalence bounds of 80%–125%, the point estimates fell within the intervals. Log‐transformed DOR, TFV, and estradiol PK parameters computed with and without co‐administration were not statistically different (p > 0.05). There were no serious adverse events. There is not a clinically significant impact of FHT on DOR/TFV PKs. Similarly, there is no observed impact on estradiol PKs and total testosterone following use of DOR/3TC/TDF.

Objective To examine interactions between Neuropsychiatric symptoms (NPS) with Pittsburgh Compound B (PiB) and fluorodeoxyglucose positron emission tomography (FDG‐PET) in predicting cognitive trajectories. Methods We conducted a longitudinal study in the setting of the population‐based Mayo Clinic Study of Aging in Olmsted County, MN, involving 1581 cognitively unimpaired (CU) persons aged ≥50 years (median age 71.83 years, 54.0% males, 27.5% APOE ɛ4 carriers). NPS at baseline were assessed using the Neuropsychiatric Inventory Questionnaire (NPI‐Q). Brain glucose hypometabolism was defined as a SUVR ≤ 1.47 (measured by FDG‐PET) in regions typically affected in Alzheimer's disease. Abnormal cortical amyloid deposition was measured using PiB‐PET (SUVR ≥ 1.48). Neuropsychological testing was done approximately every 15 months, and we calculated global and domain‐specific (memory, language, attention, and visuospatial skills) cognitive z‐scores. We ran linear mixed‐effect models to examine the associations and interactions between NPS at baseline and z‐scored PiB‐ and FDG‐PET SUVRs in predicting cognitive z‐scores adjusted for age, sex, education, and previous cognitive testing. Results Individuals at the average PiB and without NPS at baseline declined over time on cognitive z‐scores. Those with increased PiB at baseline declined faster (two‐way interaction), and those with increased PiB and NPS declined even faster (three‐way interaction). We observed interactions between time, increased PiB and anxiety or irritability indicating accelerated decline on global z‐scores, and between time, increased PiB and several NPS (e.g., agitation) showing faster domain‐specific decline, especially on the attention domain. Conclusions NPS and increased brain amyloid deposition synergistically interact in accelerating global and domain‐specific cognitive decline among CU persons at baseline.

The resurgence of cannabis (Cannabis sativa L.) has been propelled by changes in the legal framework governing its cultivation and use, increased demand for hemp-derived products, and studies recognizing the industrial and health benefits of hemp. This has led to the creation of novel high-cannabidiol, low-Δ9-tetrahydrocannabinol varieties, enabling hemp crop expansion worldwide. This review elucidates the recent implications for hemp cultivation in Europe, with a focus on the legislative impacts on the cultivation practices, prospective breeding efforts, and dynamic scientific landscape surrounding this crop. We also review the current cultivars’ cannabinoid composition of the European hemp market and its major differences with that of the United States.

Abstract Purpose The goal of this study is to determine if certain aspects of endophthalmitis prophylaxis strategies are superior to others. Design This investigation is a systematic review and meta-analysis. Methods All studies specifying a type of prophylaxis strategy and resulting rates of endophthalmitis were included. Time course, method of administration, and antibiotic regimen, and confounding factors were collected and included for meta-regression. Results Time courses greater than 24 h did not significantly improve outcomes. Likewise, intraocular and/or intravenous antibiotic administration methods did not significantly outperform oral administration. No antibiotic regimens performed differently from vancomycin/ ≥ 3rd generation cephalosporin except for ciprofloxacin monotherapy which yielded significantly worse outcomes. Conclusions Future antibiotic strategies should strongly consider the risks of antibiotic treatment > 24 h and administration methods other than the oral antibiotic forms. In addition, providers should be wary of using ciprofloxacin monotherapy for endophthalmitis prophylaxis when treating open globe injuries.

Diel variations in the isotopic composition of dissolved oxygen in river water reveal high rates of gross primary production and respiration rates in 14 rivers across three biomes, suggesting that the microbial loop in rivers may cycle carbon more rapidly than thought.

The Spheroid Reservoir Bioartificial Liver (SRBAL) is an innovative treatment option for acute liver failure (ALF). This extracorporeal support device, which provides detoxification and other liver functions using high-density culture of porcine hepatocyte spheroids, has been reported in three randomized large animal studies. A meta-analysis of these three preclinical studies was performed to establish efficacy of SRBAL treatment in terms of survival benefit and neuroprotective effect. The studies included two hepatotoxic drug models of ALF (D-galactosamine, α-amanitin/lipopolysaccharide) or a liver resection model (85% hepatectomy) in pigs or monkeys. The SRBAL treatment was started in three different settings starting at 12 h, 24 h or 48 h after induction of ALF; comparisons were made with two similar control groups in each model. SRBAL therapy was associated with significant survival and neuroprotective benefits in all three animal models of ALF. The benefits of therapy were dose dependent with the most effective configuration of SRBAL being continuous treatment of 24 h duration and dose of 200 g of porcine hepatic spheroids. Future clinical testing of SRBAL in patients with ALF appears warranted.

Objective To determine if the introduction of value-based healthcare (VBHC) in fertility care can help to create realistic expectations in patients resulting in increased patient value, by demonstrating the relevance of defining outcome measures that truly matter to subfertile patients.Design Retrospective cohort study.Setting Tertiary fertility centre.Results Time to pregnancy (TTP) and ongoing pregnancy rate (OPR), as a proxy for the live birth rate, for the full cycle of fertility care, regardless of which and how many treatment cycles performed, were identified as the most relevant medical outcome measures. Outcome measures were incorporated into a digital dashboard by using anonymised and validated patient data from the electronic patient file. We were able to present the TTP and OPR for the population as a whole as well as stratified for age, diagnosis, gravidity and type of gamete source used thereby resulting in a virtual ‘patient like me’ resembling the individual patient in the consultation room.Conclusion We have shown that, by applying VBHC principles, relevant outcome measures can be generated and stratified for different patient characteristics, in order to develop a virtual ‘patient like me’. This virtual ‘patient like me’ can be used in the consulting room in the form of a digital dashboard, attributing to create realistic patient expectations. This facilitates healthcare providers and patients in shared decision-making.

It is now widely known that research brain MRI, CT, and PET images may potentially be re-identified using face recognition, and this potential can be reduced by applying face-deidentification (“de-facing”) software. However, for research MRI sequences beyond T1-weighted (T1-w) and T2-FLAIR structural images, the potential for re-identification and quantitative effects of de-facing are both unknown, and the effects of de-facing T2-FLAIR are also unknown. In this work we examine these questions (where applicable) for T1-w, T2-w, T2*-w, T2-FLAIR, diffusion MRI (dMRI), functional MRI (fMRI), and arterial spin labelling (ASL) sequences. Among current-generation, vendor-product research-grade sequences, we found that 3D T1-w, T2-w, and T2-FLAIR were highly re-identifiable (96–98%). 2D T2-FLAIR and 3D multi-echo GRE (ME-GRE) were also moderately re-identifiable (44–45%), and our derived T2* from ME-GRE (comparable to a typical 2D T2*) matched at only 10%. Finally, diffusion, functional and ASL images were each minimally re-identifiable (0–8%). Applying de-facing with mri_reface version 0.3 reduced successful re-identification to ≤8%, while differential effects on popular quantitative pipelines for cortical volumes and thickness, white matter hyperintensities (WMH), and quantitative susceptibility mapping (QSM) measurements were all either comparable with or smaller than scan-rescan estimates. Consequently, high-quality de-facing software can greatly reduce the risk of re-identification for identifiable MRI sequences with only negligible effects on automated intracranial measurements. The current-generation echo-planar and spiral sequences (dMRI, fMRI, and ASL) each had minimal match rates, suggesting that they have a low risk of re-identification and can be shared without de-facing, but this conclusion should be re-evaluated if they are acquired without fat suppression, with a full-face scan coverage, or if newer developments reduce the current levels of artifacts and distortion around the face.

Abstract INTRODUCTION We examined associations between plasma‐derived biomarkers of Alzheimer's disease (AD) and neuropsychiatric symptoms (NPS) in community‐dwelling older adults. METHODS Cross‐sectional study involving 1005 persons ≥50 years of age (mean 74 years, 564 male, 118 cognitively impaired), who completed plasma‐derived biomarker (amyloid beta 42 [Aβ42]/Aβ40, phosphorylated tau 181 [p‐tau181], p‐tau217, total tau [t‐tau], neurofilament light [NfL]), and NPS assessment. RESULTS P‐tau181 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.41–3.00, p

Abstract Apixaban is frequently used off‐label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. We conducted an open‐label drug–drug interaction study to determine the pharmacokinetics of apixaban in lung and kidney transplant recipients who were taking a calcineurin inhibitor. A single dose of apixaban 10 mg was administered orally to kidney and lung transplant recipients maintained on either tacrolimus or cyclosporine, and pharmacokinetic parameters were compared to a reference cohort of 12 healthy subjects who used the same apixaban dose and pharmacokinetic blood sampling. Fourteen participants were enrolled (n = 6 kidney, n = 8 lung), with 10 maintained on tacrolimus and four on cyclosporine. Data from 13 participants was usable. Participants were taking triple therapy immunosuppression and had a mean (SD) of 12 (3) medications. Participants receiving tacrolimus and cyclosporine had area under the plasma concentration–time curve from time zero to infinity (AUC0‐inf) geometric least square means (90% confidence interval [CI]) of 4312 (95% CI 3682, 5049) and 5388 (95% CI 3277, 8858), respectively. Compared to healthy subjects, the associated geometric mean ratios (GMRs) for apixaban maximum plasma concentration (Cmax), AUC from time zero to the last quantifiable concentration (AUC0‐tlast) and AUC0‐inf were 197% (95% CI 153, 295), 244% (95% CI 184, 323), and 224% (95% CI 170, 295) for transplant recipients on tacrolimus. The GMR (90% CI) Cmax, AUC0‐tlast, and AUC0‐inf of apixaban for patients on cyclosporine were 256% (95% CI 184, 358), 287% (95% CI 198, 415), and 280% (95% CI 195, 401). Kidney and lung transplant recipients receiving tacrolimus had higher apixaban exposure. A similar trend was noted for patients receiving cyclosporine, but additional patients are needed to confirm this interaction. Future studies are needed before apixaban can be safely recommended in this population, and the impact of dose staggering should be investigated. This study highlights the importance of pharmacokinetic studies in actual patient populations.

Abstract It is unclear if the pharmacokinetics of vancomycin are the same during automated peritoneal dialysis (APD), where cycler exchanges may affect the systemic, peritoneal, and urinary disposition of drug. We conducted a prospective pharmacokinetic study evaluating the pharmacokinetics of vancomycin in plasma, dialysis fluid, and urine in peritonitis‐negative patients on APD. Patients underwent four drug‐free exchanges with 1.5% or 2.5% dextrose following the initial dwell period. Plasma, dialysis fluid, and urine was collected over the course of 7 days for pharmacokinetic analysis. Four patients completed the study with no adverse events. Following a median (range) dwell of 14.6 (14.2–17.6 h), the mean (±SD) observed maximum plasma concentration was 28.7 ± 4.9 mg/L with a mean bioavailability of 98.5 ± 1.4% prior to starting the cycler. The overall mean total plasma clearance estimated from study start to completion was 7.6 ± 1.2 ml/min. Mean total clearance during the dialytic exchange was 13.6 ± 4.9 ml/min. In patients with residual renal function, the mean vancomycin renal clearance was 3.1 ± 1.5 ml/min, representing 21.4%–58.9% of the overall total plasma clearance during the study period. Despite the small sample size, this pilot study suggests that the dwell time has important implications for systemic vancomycin exposure, time to therapeutic plasma concentration, and dosing. Dose is driven by dwell time, whereas the cycler determines the dosing interval. Rapid exchanges from APD will determine the frequency of dosing rather than the adequacy of absorption when vancomycin is given in the peritoneum.

ABSTRACT Many CAAX proteins, such as Ras GTPase, undergo a series of posttranslational modifications at their carboxyl terminus (i.e., cysteine prenylation, endoproteolysis of AAX, and carboxylmethylation). Some CAAX proteins, however, undergo prenylation-only modification, such as Saccharomyces cerevisiae Hsp40 Ydj1. We previously observed that altering the CAAX motif of Ydj1 from prenylation-only to canonical resulted in altered Ydj1 function and localization. Here, we investigated the effects of a reciprocal change that altered the well-characterized canonical CAAX motif of S. cerevisiae Ras2 to prenylation-only. We observed that the type of CAAX motif impacted Ras2 protein levels, localization, and function. Moreover, we observed that using a prenylation-only sequence to stage hyperactive Ras2-G19V as a farnesylated and nonproteolyzed intermediate resulted in a different phenotype relative to staging by a genetic RCE1 deletion strategy that simultaneously affected many CAAX proteins. These findings suggested that a prenylation-only CAAX motif is useful for probing the specific impact of CAAX proteolysis on Ras2 under conditions where other CAAX proteins are normally modified. We propose that our strategy could be easily applied to a wide range of CAAX proteins for examining the specific impact of CAAX proteolysis on their functions. IMPORTANCE CAAX proteins are subject to multiple posttranslational modifications: cysteine prenylation, CAAX proteolysis, and carboxylmethylation. For investigations of CAAX proteolysis, this study took the novel approach of using a proteolysis-resistant CAAX sequence to stage Saccharomyces cerevisiae Ras2 GTPase in a farnesylated and nonproteolyzed state. Our approach specifically limited the effects of disrupting CAAX proteolysis to Ras2. This represented an improvement over previous methods where CAAX proteolysis was inhibited by gene knockout, small interfering RNA knockdown, or biochemical inhibition of the Rce1 CAAX protease, which can lead to pleiotropic and unclear attribution of effects due to the action of Rce1 on multiple CAAX proteins. Our approach yielded results that demonstrated specific impacts of CAAX proteolysis on the function, localization, and other properties of Ras2, highlighting the utility of this approach for investigating the impact of CAAX proteolysis in other protein contexts.

Brain imaging research studies increasingly use “de-facing” software to remove or replace facial imagery before public data sharing. Several works have studied the effects of de-facing software on brain imaging biomarkers by directly comparing automated measurements from unmodified vs de-faced images, but most research brain images are used in analyses of correlations with cognitive measurements or clinical statuses, and the effects of de-facing on these types of imaging-to-cognition correlations has not been measured. In this work, we focused on brain imaging measures of amyloid (A), tau (T), neurodegeneration (N), and vascular (V) measures used in Alzheimer’s Disease (AD) research. We created a retrospective sample of participants from three age- and sex-matched clinical groups (cognitively unimpaired, mild cognitive impairment, and AD dementia, and we performed region- and voxel-wise analyses of: hippocampal volume (N), white matter hyperintensity volume (V), amyloid PET (A), and tau PET (T) measures, each from multiple software pipelines, on their ability to separate cognitively defined groups and their degrees of correlation with age and Clinical Dementia Rating (CDR)–Sum of Boxes (CDR-SB). We performed each of these analyses twice: once with unmodified images and once with images de-faced with leading de-facing software mri_reface, and we directly compared the findings and their statistical strengths between the original vs. the de-faced images. Analyses with original and with de-faced images had very high agreement. There were no significant differences between any voxel-wise comparisons. Among region-wise comparisons, only three out of 55 correlations were significantly different between original and de-faced images, and these were not significant after correction for multiple comparisons. Overall, the statistical power of the imaging data for AD biomarkers was almost identical between unmodified and de-faced images, and their analyses results were extremely consistent.

Objective: To assess the impact of standardized pretransplant alcohol abstinence and treatment guidelines on liver transplant outcomes. Methods: This study assessed the posttransplant relapse and survival associated with a pretransplant guideline mandating alcohol abstinence, addiction treatment, and Alcoholics Anonymous (AA) attendance. This retrospective cohort study included liver recipients with alcohol-induced liver disease transplanted between January 1, 2000, and December 31, 2012, at a Midwest transplant center. Cox regression models tested for associations between pretransplant treatment, demographic and clinical characteristics, and outcome measures. Results: Of 236 liver recipients (188 [79.7%] male; 210 [89%] white; mean follow-up, 88.6±55.0 months), 212 (90.2%) completed pretransplant treatment and 135 (57.2%) attended AA weekly. At 5 years, 16.3% and 8.2% had relapsed to any alcohol use and to high-dose drinking, respectively. Smoking during the 6 months before transplant was associated with any relapse (P=.0002) and high-dose relapse (P

Abstract To utilize noninvasive collection of amniotic fluid in the setting of preterm premature rupture of membranes (PPROMs) to report the time concentration profile of azithromycin in amniotic fluid over 7 days from a single dose, and evaluate the correlation between azithromycin concentration and inflammatory markers in amniotic fluid. Prospective cohort study of five pregnant patients admitted with PPROMs and treated with a single 1 g oral azithromycin dose. Amniotic fluid was collected from pads and used to quantify azithromycin concentration as well as TNFa, IL‐1a, IL‐1b, IL‐6, IL‐8, and IL‐10 concentrations. Primary outcome was time/concentration profile of azithromycin in amniotic fluid. Secondary outcome included correlation between azithromycin concentration and cytokine concentrations. Five patients were enrolled. Mean gestational age on admission with PPROM was 27.5 ± 2.3 weeks with a median latency of 7 days (interquartile range [IQR] = 4–13). A median of two samples/day (IQR = 1–3) were collected per participant. Azithromycin was quantified in duplicate; intra‐assay coefficient of variation was 17%. Azithromycin concentration was less than 60 ng/ml after day 3. Azithromycin concentration was positively correlated with IL‐8 (r = 0.38, p = 0.03), IL1a (r = 0.39, p = 0.03), and IL‐1b (r = 0.36, p = 0.04) in amniotic fluid. Azithromycin is detectable in amniotic fluid over 7 days from a single 1 g maternal dose, however, it is not sustained over the range of minimum inhibitory concentration for common genitourinary flora. Based on correlation with specific cytokines, azithromycin penetration in amniotic fluid may relate to maternal monocyte concentration in amniotic fluid in the setting of PPROM.

Abstract Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up‐titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up‐titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half‐maximal effective concentration (EC50) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model‐based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.

Background. Limited health literacy (HL) is associated with decreased kidney function and death in patients with chronic kidney disease. Less is known about the impact of HL on kidney transplant (KT) outcomes. The aim of this study was to examine the relationship between HL and KT outcomes, including rates of waitlisting, healthcare utilization, acute rejection, renal allograft function, renal allograft failure, and death. Methods. We performed a retrospective review of HL data previously collected at our center. HL was assessed in a convenience sample of consecutive, English-speaking patients age ≥18 y who were evaluated for KT at Mayo Clinic in Minnesota between June 2015 and March 2017 as part of a practice improvement feasibility project (n = 690). HL was assessed using the 4-item Brief Health Literacy Screening Tool modified for the outpatient KT evaluation process. The 4 items assess confidence completing forms, reading comprehension, and oral literacy. Results. Overall, 30.4% of patients had limited or marginal HL. Patients with limited or marginal HL were less likely than those with adequate HL to be waitlisted for KT (hazard ratio = 0.62 and 0.69, respectively), even after adjusting for age, marital status, body mass index, Charlson comorbidity index, or dialysis dependency. Patient HL was not associated with post-KT healthcare utilization, acute rejection, or renal allograft function. Patients with limited or marginal HL appeared to experience a higher risk of renal allograft failure and post-KT death, but the number of events was small, and the relationship was statistically significant only for marginal HL. Conclusions. Inadequate HL is common in KT candidates and independently associated with decreased waitlisting for KT. We observed no statistically significant relationship between HL and posttransplant outcomes in our cohort. Further efforts to improve communication in patients with inadequate HL may improve access to KT.

It is well known that de-identified research brain images from MRI and CT can potentially be re-identified using face recognition; however, this has not been examined for PET images. We generated face reconstruction images of 182 volunteers using amyloid, tau, and FDG PET scans, and we measured how accurately commercial face recognition software (Microsoft Azure's Face API) automatically matched them with the individual participants’ face photographs. We then compared this accuracy with the same experiments using participants’ CT and MRI. Face reconstructions from PET images from PET/CT scanners were correctly matched at rates of 42% (FDG), 35% (tau), and 32% (amyloid), while CT were matched at 78% and MRI at 97-98%. We propose that these recognition rates are high enough that research studies should consider using face de-identification (“de-facing”) software on PET images, in addition to CT and structural MRI, before data sharing. We also updated our mri_reface de-identification software with extended functionality to replace face imagery in PET and CT images. Rates of face recognition on de-faced images were reduced to 0-4% for PET, 5% for CT, and 8% for MRI. We measured the effects of de-facing on regional amyloid PET measurements from two different measurement pipelines (PETSurfer/FreeSurfer 6.0, and one in-house method based on SPM12 and ANTs), and these effects were small: ICC values between de-faced and original images were > 0.98, biases were

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood–derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.

Atogepant is a potent, selective, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once‐daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double‐blind, placebo‐controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty‐four participants aged 23–55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well‐tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half‐life of ~ 11 hours, and no evidence of accumulation after once‐daily dosing. Overall, atogepant at a high oral dose is safe and well‐tolerated in healthy participants with no clinically meaningful elevations in ALT.

Ubrogepant is a novel, oral calcitonin gene‐related peptide (CGRP) receptor antagonist intended for the acute treatment of migraine attacks. Ubrogepant has a chemical structure distinct from previous small‐molecule CGRP receptor antagonists that were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report overall and hepatic safety data from two placebo‐controlled phase I trials of ubrogepant, spray‐dried oral compressed tablet (SD‐OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK) trial of single (100–400 mg) and multiple (40–400 mg) ascending doses. Trial B was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported. Ubrogepant was well‐tolerated in both trials, with a low incidence of adverse events that did not differ greatly from placebo. Changes in mean ALT levels were minimal and similar to placebo. Over 28 days of treatment, the mean percentage change in ALT from baseline was

Abstract Objective To examine the association of baseline elevated brain amyloid and neurodegeneration with changes in activities of daily living in participants without dementia (ND; i.e., cognitively unimpaired and participants with mild cognitive impairment) at baseline in the population‐based Mayo Clinic Study of Aging. Methods We included 1747 ND participants with 11C‐PiB PET and MR imaging in the study, with data on activities of daily living (as assessed by the Functional Activities Questionnaire (FAQ) and the Clinical Dementia Rating scale Sum of Boxes for functional domains (CDR‐SOB (functional)), with a median (range) of 4.3 (0.0–12.7) years of follow‐up. Abnormal (elevated; A+) 11C‐PiB‐PET retention ratio was defined as standardized uptake value ratio ≥ 1.48, and abnormal (reduced) AD signature cortical thickness as ≤ 2.68 mm (neurodegeneration; N+). Associations were examined with mixed effects models, adjusting for age, sex, education, apolipoprotein E ε4 allele carrier status, and global cognitive z‐score. Results Mean age (SD) was 71.4 years (10.1), 46.7% were females, 195 (11.2%) had A+N‐, 442 (25.3%) had A‐N+, and 339 (19.4%) had A+N+ biomarkers. The A+N+ group had the largest annualized change in the FAQ score from baseline (difference in annual change A+N+ vs. A‐N‐; ß (SE): 0.80 (0.07)); associations were substantially attenuated when a time‐varying global cognitive composite was included in the model (A+N+ vs. A‐N‐; ß (SE): 0.31 (0.05)). CDR‐SOB (functional) findings partly agreed with FAQ score findings. Interpretation The longitudinal increase in functional limitations is greater for individuals with abnormal neuroimaging biomarkers, especially for those with both elevated brain amyloid and neurodegeneration.

Iota-carrageenan (IC) nasal spray, a medical device approved for treating respiratory viral infections, has previously been shown to inhibit the ability of a variety of respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to enter and replicate in the cell by interfering with the virus binding to the cell surface. The aim of this study was to further investigate the efficacy and safety of IC in SARS-CoV-2 infection in advanced in vitro models of the human respiratory epithelium, the primary target and entry port for SARS-CoV-2. We extended the in vitro safety assessment of nebulized IC in a 3-dimensional model of reconstituted human bronchial epithelium, and we demonstrated the efficacy of IC in protecting reconstituted nasal epithelium against viral infection and replication of a patient-derived SARS-CoV-2 strain. The results obtained from these two advanced models of human respiratory tract epithelia confirm previous findings from in vitro SARS-CoV-2 infection assays and demonstrate that topically applied IC can effectively prevent SARS-CoV-2 infection and replication. Moreover, the absence of toxicity and functional and structural impairment of the mucociliary epithelium demonstrates that the nebulized IC is well tolerated.

Background. Improving both patient and graft survival after kidney transplantation are major unmet needs. The goal of this study was to assess risk factors for specific causes of graft loss to determine to what extent patients who develop either death with a functioning graft (DWFG) or graft failure (GF) have similar baseline risk factors for graft loss. Methods. We retrospectively studied all solitary renal transplants performed between January 1, 2006, and December 31, 2018, at 3 centers and determined the specific causes of DWFG and GF. We examined outcomes in different subgroups using competing risk estimates and cause-specific Cox models. Results. Of the 5752 kidney transplants, graft loss occurred in 21.6% (1244) patients, including 12.0% (691) DWFG and 9.6% (553) GF. DWFG was most commonly due to malignancy (20.0%), infection (19.7%), cardiac disease (12.6%) with risk factors of older age and pretransplant dialysis, and diabetes as the cause of renal failure. For GF, alloimmunity (38.7%), glomerular diseases (18.6%), and tubular injury (13.9%) were the major causes. Competing risk incidence models identified diabetes and older recipients with higher rates of both DWFG and nonalloimmune GF. Conclusions. These data suggest that at baseline, 2 distinct populations can be identified who are at high risk for renal allograft loss: a younger, nondiabetic patient group who develops GF due to alloimmunity and an older, more commonly diabetic population who develops DWFG and GF due to a mixture of causes—many nonalloimmune. Individualized management is needed to improve long-term renal allograft survival in the latter group.

Background. Nephrolithiasis in living kidney donors is concerning due to the potential impact on long-term postdonation kidney function. Methods. We performed a cohort study of living kidney donors from 2 centers with a baseline computed tomography scan and implantation renal biopsy. Donors (>5 y since donation) completed a follow-up survey or underwent chart review to assess eGFR and incident hypertension. Stone formers were classified as symptomatic if they had a past symptomatic episode or asymptomatic if only incidental radiographic kidney stones were identified during donor evaluation. We compared baseline clinical, imaging, and biopsy characteristics by stone former status including review of metabolic evaluations in stone formers. Long-term risks of renal complications (low eGFR and hypertension) by stone former status were evaluated. Results. There were 12 symptomatic and 76 asymptomatic stone formers among 866 donors. Overall, baseline clinical characteristics and implantation biopsy findings were similar between stone formers and non-stone formers. After a median follow-up of 10 y, stone former status was not associated with eGFR

Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids at the a1 and a2 positions, while quite flexible at the X position. Prenylation prediction methods often rely on these features despite emerging evidence that FTase has broader target specificity than previously considered. Using a machine learning approach and training sets based on canonical (prenylated, proteolyzed, and carboxymethylated) and recently identified shunted motifs (prenylation only), this study aims to improve prenylation predictions with the goal of determining the full scope of prenylation potential among the 8000 possible Cxxx sequence combinations. Further, this study aims to subdivide the prenylated sequences as either shunted (i.e., uncleaved) or cleaved (i.e., canonical). Predictions were determined for Saccharomyces cerevisiae FTase and compared to results derived using currently available prenylation prediction methods. In silico predictions were further evaluated using in vivo methods coupled to two yeast reporters, the yeast mating pheromone a-factor and Hsp40 Ydj1p, that represent proteins with canonical and shunted CaaX motifs, respectively. Our machine learning-based approach expands the repertoire of predicted FTase targets and provides a framework for functional classification.

Cigarette smoking causes major preventable diseases, morbidity, and mortality worldwide. Smoking cessation and prevention of smoking initiation are the preferred means for reducing these risks. Less harmful tobacco products, termed modified-risk tobacco products (MRTP), are being developed as a potential alternative for current adult smokers who would otherwise continue smoking. According to a regulatory framework issued by the US Food and Drug Administration, a manufacturer must provide comprehensive scientific evidence that the product significantly reduces harm and the risk of tobacco-related diseases, in order to obtain marketing authorization for a new MRTP. For new tobacco products similar to an already approved predicate product, the FDA has foreseen a simplified procedure for assessing “substantial equivalence”. In this article, we present a use case that bridges the nonclinical evidence from previous studies demonstrating the relatively reduced harm potential of two heat-not-burn products based on different tobacco heating principles. The nonclinical evidence was collected along a “causal chain of events leading to disease” (CELSD) to systematically follow the consequences of reduced exposure to toxicants (relative to cigarette smoke) through increasing levels of biological complexity up to disease manifestation in animal models of human disease. This approach leverages the principles of systems biology and toxicology as a basis for further extrapolation to human studies. The experimental results demonstrate a similarly reduced impact of both products on apical and molecular endpoints, no novel effects not seen with cigarette smoke exposure, and an effect of switching from cigarettes to either MRTP that is comparable to that of complete smoking cessation. Ideally, a subset of representative assays from the presented sequence along the CELSD could be sufficient for predicting similarity or substantial equivalence in the nonclinical impact of novel products; this would require further validation, for which the present use case could serve as a starting point.

Neonates experience dramatic changes in the disposition of drugs after birth as a result of enzyme maturation and environmental adjustment, challenging therapeutic decision making. In this research, we establish postnatal age, postmenstrual age, and body weight as physiologically reasonable predictors of morphine's clearance in neonates. By integrating knowledge of bilirubin, morphine, and other drugs metabolized by glucuronidation pathways from previously published studies, we hypothesize that uridine diphosphate glucuronic acid, a postnatal age–dependent sugar, plays an important role in the metabolism of morphine during the first week of life. This finding can be extended to other drugs metabolized by uridine diphosphate glucuronosyltransferase pathways in neonates and thus has important clinical implications for the use of drugs in this population.

Rationale & Objective: The number of glomeruli is often used to determine the adequacy of a kidney biopsy (eg, at least 10 glomeruli). It is often assumed that biopsy specimens with limited amounts of cortex are too imprecise for detection of focal pathology. Study Design: Clinical-pathologic correlation (cross-sectional). Setting & Participants: Living kidney donors who underwent a needle core biopsy of their kidney at the time of donation. Exposure: The amount of cortex biopsied as determined by either the number of glomeruli or area of cortex on histology. Outcome: The percentage of globally sclerotic glomeruli, density of interstitial fibrosis foci, and severity of arteriosclerosis were determined. Analytical approach: A beta-binomial model assessed how the mean percentage of globally sclerotic glomeruli and patient variability in percentage of globally sclerotic glomeruli differed with the number of glomeruli on the biopsy specimen. Additional models assessed the association of interstitial fibrosis and arteriosclerosis with number of glomeruli. Results: There were 2,915 kidney donors studied. Fewer glomeruli on the biopsy specimen associated with higher mean percentage of globally sclerotic glomeruli and higher patient variability in percentage of globally sclerotic glomeruli. Smaller cortical volume on imaging correlated with both less cortex on biopsy and higher percentage of globally sclerotic glomeruli. Based on a statistical simulation, the probability of patient percentage of globally sclerotic glomeruli ≥ 10% if the biopsy percentage of globally sclerotic glomeruli is ≥10% (positive predictive value) was 45% with 1 to 9 glomeruli versus 31% with 10 or more glomeruli; the negative predictive value was 91% versus 98%. Fewer glomeruli also associated with more interstitial fibrosis and arteriosclerosis. Limitations: The study was limited to living kidney donors. Patient variability in percentage of globally sclerotic glomeruli was based on a statistical model because multiple biopsy specimens per patient were not available. Conclusions: The amount of cortex on a needle core biopsy is not completely random. Chronic changes from loss of cortex contribute to low amounts of cortex on a kidney biopsy specimen. Index Words: Renal pathology, renal morphometry, renal cortex, glomeruli, glomerulosclerosis, kidney biopsy

Objective: To describe first episodes of bacterial cholangitis complicating autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) and to identify risk factors for cholangitis episodes among patients with ADPKD-associated polycystic liver disease (PLD). Patients and Methods: We searched the electronic medical records at our tertiary referral center for episodes of cholangitis in patients with ADPKD or ADPLD from January 1, 1996, through June 30, 2017. Cases were categorized as suspected or definite cholangitis by expert review. Clinical, laboratory, and radiologic data were manually abstracted. A nested case-control study was conducted to investigate risk factors for cholangitis in patients with ADPKD. Results: We identified 29 cases of definite or suspected cholangitis complicating PLD (24 with ADPKD-associated PLD and 5 with ADPLD). Among patients with definite cholangitis in ADPKD-associated PLD (n=19) vs ADPLD (n=4), the mean ± SD age was 62.4±12.2 vs 55.1±8.6 years, and 9 (47.4%) vs 0 (0%), respectively, were male. The odds of gallstones (odds ratio [OR], 21.6; 95% CI, 3.17-927; P

Abstract Background The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. Methods Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. Results All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8+ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4+ T cells are eliminated by self-tolerance, while CD8+ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. Conclusions Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8+, but not autoimmune CD4+, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. Trial registration This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737

There is an increasingly urgent call to shift industrial processes from fossil fuel feedstock to sustainable bio-based resources. This change becomes of high importance considering new budget requirements for a carbon-neutral economy. Such a transformation can be driven by traditionally used plants that are able to produce large amounts of valuable biologically relevant secondary metabolites. Tobacco plants can play a leading role in providing value-added products in remote areas of the world. In this study, we propose a non-exhaustive list of compounds with potential economic interest that can be sourced from the tobacco plant. In order to optimize extraction methodologies, we first analyzed their physico-chemical properties using rapid solubility tests and high-resolution microfractionation techniques. Next, to identify an optimal extraction for a selected list of compounds, we compared 13 different extraction method–solvent combinations. We proceeded with profiling some of these compounds in a total of six varieties from Nicotiana tabacum and Nicotiana rustica species, identifying the optimal variety for each. The estimated expected yields for each of these compounds demonstrate that tobacco plants can be a superior source of valuable compounds with diverse applications beyond nicotine. Among the most interesting results, we found high variability of anatabine content between species and varieties, ranging from 287 to 1699 µg/g. In addition, we found that CGA (1305 µg/g) and rutin (7910 µg/g) content are orders of magnitude lower in the Burley variety as compared to all others.

Recent advances in automated face recognition algorithms have increased the risk that de-identified research MRI scans may be re-identifiable by matching them to identified photographs using face recognition. A variety of software exist to de-face (remove faces from) MRI, but their ability to prevent face recognition has never been measured and their image modifications can alter automated brain measurements. In this study, we compared three popular de-facing techniques and introduce our mri_reface technique designed to minimize effects on brain measurements by replacing the face with a population average, rather than removing it. For each technique, we measured 1) how well it prevented automated face recognition (i.e. effects on exceptionally-motivated individuals) and 2) how it altered brain measurements from SPM12, FreeSurfer, and FSL (i.e. effects on the average user of de-identified data). Before de-facing, 97% of scans from a sample of 157 volunteers were correctly matched to photographs using automated face recognition. After de-facing with popular software, 28-38% of scans still retained enough data for successful automated face matching. Our proposed mri_reface had similar performance with the best existing method (fsl_deface) at preventing face recognition (28-30%) and it had the smallest effects on brain measurements in more pipelines than any other, but these differences were modest.

Abstract Understanding the complex and unpredictable ways ecosystems are changing and predicting the state of ecosystems and the services they will provide in the future requires coordinated, long‐term research. This paper is a product of a U.S. National Science Foundation funded Long Term Ecological Research (LTER) network synthesis effort that addressed anticipated changes in future populations and communities. Each LTER site described what their site would look like in 50 or 100 yr based on long‐term patterns and responses to global change drivers in each ecosystem. Common themes emerged and predictions were grouped into state change, connectivity, resilience, time lags, and cascading effects. Here, we report on the “state change” theme, which includes examples from the Georgia Coastal (coastal marsh), Konza Prairie (mesic grassland), Luquillo (tropical forest), Sevilleta (arid grassland), and Virginia Coastal (coastal grassland) sites. Ecological thresholds (the point at which small changes in an environmental driver can produce an abrupt and persistent state change in an ecosystem quality, property, or phenomenon) were most commonly predicted. For example, in coastal ecosystems, sea‐level rise and climate change could convert salt marsh to mangroves and coastal barrier dunes to shrub thicket. Reduced fire frequency has converted grassland to shrubland in mesic prairie, whereas overgrazing combined with drought drive shrub encroachment in arid grasslands. Lastly, tropical cloud forests are susceptible to climate‐induced changes in cloud base altitude leading to shifts in species distributions. Overall, these examples reveal that state change is a likely outcome of global environmental change across a diverse range of ecosystems and highlight the need for long‐term studies to sort out the causes and consequences of state change. The diversity of sites within the LTER network facilitates the emergence of overarching concepts about state changes as an important driver of ecosystem structure, function, services, and futures.

Abstract We analyze here the nature of research in freshwater macrosystem biology (especially lotic studies) from both conceptual and current research perspectives. The boundaries of permanent and transitional lotic macrosystems from the smallest to largest spatial extents are described. We contrast ecosystem vs. macrosystem research and macroecology vs. macrosystems ecology and provide some examples of representative aquatic macrosystems ecology projects in the USA. We recommend approaches for incorporating certain large‐scale lotic concepts developed over the last 40 yr as the bases for lotic macrosystem studies. Of these, the three most appropriate in chronological order are the River Continuum Concept, the Riverine Ecosystem Synthesis, and the Stream Biome Gradient Concept. Four other concepts would be suitable for testing macrosystem hypotheses after incorporating small to large conceptual or geographic expansions of the models. We suggest future research directions in lotic macrosystem research in areas of climate change and teleconnections among distant organisms and systems and include general recommendations for conducting macrosystem‐level research.

Abstract Introduction The aim of this study was to examine white matter hyperintensities (WMH) and fractional anisotropy (FA) in empirically derived incident mild cognitive impairment (MCI) subtypes. Methods We evaluated 188 participants with incident MCI in the Mayo Clinic Study of Aging (MCSA) identified as having one of four cluster‐derived subtypes: subtle cognitive impairment, amnestic, dysnomic, and dysexecutive. We used linear regression models to evaluate whole brain and regional WMH volumes. We examined fractional anisotropy (FA) on a subset of 63 participants with diffusion tensor imaging. Results Amnestic and dysexecutive subtypes had higher WMH volumes in differing patterns than cognitively unimpaired; the dysexecutive subtype had higher WMH than subtle cognitive impairment. There was widespread WM degeneration in long association and commissural fibers in the amnestic, dysnomic, and dysexecutive subtypes, and corpus callosum FA accounted for significant variability in global cognition. Discussion White matter changes likely contribute to cognitive symptoms in incident MCI.

The adverse effects of cigarette smoking are well documented, and the two main strategies for reducing smoking prevalence are prevention of smoking initiation and promotion of smoking cessation. More recently, a third and complementary avenue, tobacco harm reduction has emerged, which is aimed to reduce the burden of smoking-related diseases. This has been enabled by the development of novel products such as electronic cigarettes (e-cigarettes) and heated tobacco products, designed to deliver nicotine with significantly reduced levels of the toxicants that are emitted by cigarettes. Several potential modified risk tobacco products (pMRTP) have been reported to emit significantly less toxicants than cigarettes and significantly reduce toxicant exposure in smokers who switch completely to such products. These are two prerequisites for pMRTPs to reduce harm and the risk of smoking-related disease. However, concerns remain regarding the addictive nature of these products. Smoking addiction is a complex phenomenon involving multiple pharmacological and non-pharmacological factors. Although the main pharmacological substance associated with smoking addiction is nicotine, accumulating evidence suggests that nicotine mostly acts as a primary reinforcer and that other factors are involved in establishing smoking addiction. Inhibition of monoamine oxidases (MAO)—mammalian flavoenzymes with a central role in neurotransmitter metabolism—has also been suggested to be involved in this process. Therefore, we aimed to comparatively investigate the ability of several types of pMRTPs and cigarette smoke (3R4F) to inhibit MAO activity. The results showed that the heated tobacco product Tobacco Heating System (THS) 2.2 and the MESH 1.1 e-cigarette possessed no MAO inhibitory activity while 3R4F significantly inhibits the levels of MAO activity (3R4F MAO-A and B; > 2 μM nicotine). Snus products have similar inhibition profiles as 3R4F but for larger nicotine concentrations (snus MAO-A; ∼68-fold, snus MAO-B; ∼23-fold higher compared to 3R4F). These observations were confirmed by analytical datasets of potential MAO inhibitors emitted by these products. In conclusion, we have demonstrated that specific pMRTPs, namely THS 2.2 and MESH 1.1, have a significantly lower MAO-inhibitory activity than 3R4F. These findings provide a basis for further investigation of the role of MAO inhibitors in cigarette addiction as well as the implications of the findings for abuse liability of pMRTPs in comparison with cigarettes. Keywords: Monoamine oxidase, Harm reduction, Tobacco heating system, E-cigarettes, Snus

Stimulant drugs are most commonly used to treat ADHD. Here, the authors demonstrate that in adolescents with ADHD who also have genetic variation in genes impacting metabotropic glutamate signaling, the non-stimulant mGluR activator fasoracetam is well tolerated and may be beneficial in alleviating symptoms of this disease.