RETROSPECTIVE HEMATOLOGY AND SERUM BIOCHEMISTRY OF RING-TAILED LEMURS (LEMUR CATTA) ON ST. CATHERINES ISLAND, GEORGIA, USA.

Annual health records were retrospectively analyzed for a colony of ring-tailed lemurs (Lemur catta) inhabiting St. Catherines Island, Georgia, USA to establish baseline hematological and serum biochemical parameters and determine sex- and age-related differences. Summarized complete blood count and serum biochemistry panel results are presented for 85 blood samples collected from 54 lemurs at annual health exams during 1998-2003. Within each of four age classes (infant, <1 yr; juvenile, 1-5 yr; adult, ≥ 6 yr), data were stratified and summarized based on sex. Lemur age was a significant positive predictor of mean corpuscular hemoglobin; absolute concentrations of neutrophils, monocytes, and band cells; serum concentrations of blood urea nitrogen (BUN), creatinine, globulins, lipase, and total protein; and gamma-glutamyl transferase (GGT) activity. Lemur age was a significant negative predictor of albumin:globulins ratio; alkaline phosphatase (ALP) activity; and serum concentrations of calcium, cholesterol, glucose, magnesium, phosphorus, potassium, and triglycerides. Neutrophil proportions increased with aging and lymphocyte proportions decreased with aging, particularly in females. Recent steep population declines of wild ring-tailed lemurs make their successful husbandry and medical care an increasingly pressing concern. These biomedical data will aid in clinical diagnosis and treatment of lemurs in human care, and support conservation efforts for this species.

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals.

BACKGROUND: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals. METHODS: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aß)42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p-tau217. The outcome was a change in a memory composite measure. RESULTS: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p-tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person-level prediction intervals were wide. DISCUSSION: Plasma p-tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level.

Pharmacokinetics, Safety, and Tolerability of a Single 5-Day Treatment of Tirbanibulin Ointment 1% in 100 cm2 : A Phase 1 Maximal-Use Trial in Patients with Actinic Keratosis.

Tirbanibulin ointment 1% is approved in the United States and Europe for the treatment of actinic keratosis with demonstrated efficacy, safety, and tolerability when applied over a field up to 25 cm2 . This Phase 1 maximal-use trial determines the plasma pharmacokinetics, safety, and tolerability of tirbanibulin ointment 1% applied to 100 cm2 of the face or balding scalp in adults with actinic keratosis. Twenty-eight patients self-applied tirbanibulin once daily for a single 5-day treatment course. On Day 5, the mean maximum plasma concentration was 1.06 ng/mL and area under the plasma concentration-time curve during a dosing interval was 16.2 ng â€¢ h/mL. Systemic exposure was approximately 4-fold higher than in a previous pharmacokinetic study with a 25 cm2 field, consistent with the increase in the treated area. Tirbanibulin applied to a 100-cm2 treatment field showed favorable safety and tolerability. The most common treatment-emergent adverse events were application site reactions (in 35.7% of patients). All treatment-emergent adverse events and most of the tolerability signs were mild/moderate and resolved or returned to baseline by Day 29. In summary, under maximal-use conditions, tirbanibulin ointment 1% was safe and well tolerated supporting its potential use over a field up to 100 cm2 .

Modeling the temporal evolution of plasma p-tau in relation to amyloid beta and tau PET.

INTRODUCTION: The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co-evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. METHODS: We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aß) PET, tau PET, plasma p-tau217, p-tau181, and glial fibrillary acidic protein (GFAP) as endpoints. RESULTS: Individual timing of plasma p-tau progression was strongly associated with Aß PET and GFAP progression. In the population, GFAP became abnormal first, then Aß PET, plasma p-tau, and tau PET temporal meta-regions of interest when applying cut points based on young, cognitively unimpaired participants. DISCUSSION: Plasma p-tau is a stronger indicator of a temporally linked response to elevated brain Aß than of tau pathology. While Aß deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p-tau and Aß PET was the strongest. HIGHLIGHTS: Plasma p-tau progression was more strongly associated with Aß than tau PET. Progression on plasma p-tau was associated with Aß PET and GFAP progression. P-tau181 and p-tau217 become abnormal after Aß PET and before tau PET. GFAP became abnormal first, before plasma p-tau and Aß PET.

Interim results from a phase I randomized, placebo-controlled trial of novel SARS-CoV-2 beta variant receptor-binding domain recombinant protein and mRNA vaccines as a 4th dose booster.

BACKGROUND: SARS-CoV-2 booster vaccination should ideally enhance protection against variants and minimise immune imprinting. This Phase I trial evaluated two vaccines targeting SARS-CoV-2 beta-variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. METHODS: 76 healthy adults aged 18-64 y, previously triple vaccinated with licensed SARS-CoV-2 vaccines, were randomised to receive a 4th dose of either an adjuvanted (MF59®, CSL Seqirus) protein vaccine (5, 15 or 45 µg, N = 32), mRNA vaccine (10, 20, or 50 µg, N = 32), or placebo (saline, N = 12) at least 90 days after a 3rd boost vaccination or SARS-CoV-2 infection. Bleeds occurred on days 1 (prior to vaccination), 8, and 29. CLINICALTRIALS: govNCT05272605. FINDINGS: No vaccine-related serious or medically-attended adverse events occurred. The protein vaccine reactogenicity was mild, whereas the mRNA vaccine was moderately reactogenic at higher dose levels. Best anti-RBD antibody responses resulted from the higher doses of each vaccine. A similar pattern was seen with live virus neutralisation and surrogate, and pseudovirus neutralisation assays. Breadth of immune response was demonstrated against BA.5 and more recent omicron subvariants (XBB, XBB.1.5 and BQ.1.1). Binding antibody titres for both vaccines were comparable to those of a licensed bivalent mRNA vaccine. Both vaccines enhanced CD4+ and CD8+ T cell activation. INTERPRETATION: There were no safety concerns and the reactogenicity profile was mild and similar to licensed SARS-CoV-2 vaccines. Both vaccines showed strong immune boosting against beta, ancestral and omicron strains. FUNDING: Australian Government Medical Research Future Fund, and philanthropies Jack Ma Foundation and IFM investors.

Excess mortality among people with communicable diseases over a 30-year period, Victoria, Australia: a whole of population cohort study.

Background: Understanding mortality burden associated with communicable diseases is key to informing resource allocation, disease prevention and control efforts, and evaluating public health interventions. We quantified excess mortality among people notified with communicable diseases in Victoria, Australia. Methods: Cases of communicable disease notified in Victoria between 1 January 1991 and 31 December 2021 were linked to the death registry. Informational gain obtained through linkage and 30-day case fatality rates were calculated for each disease. Standardised mortality ratios (SMR) and 95% confidence intervals were calculated up to a year following illness onset. Findings: There were 1,032,619 cases and 5985 (0.58%) died ≤30 days of illness onset. Following linkage, the 30-day case fatality rate increased more than 2-fold. Diseases with high 7-day SMR signifying excess mortality included invasive pneumococcal disease (167.7, 95% CI 153.4-182.7); listeriosis (166.2, 95% CI 121.2-218.3); invasive meningococcal disease (145.9, 95% CI 116.7-178.3); legionellosis (43.3, 95% CI 28.0-62.0); and COVID-19 (21.9, 95% CI 19.7-24.3). Most diseases exhibited a strong negative gradient, with high SMRs in the first 7-days of illness onset that reduced over time. Interpretation: We demonstrated that the rate of death in Victoria's notifiable disease surveillance dataset is underestimated. Further, compared to a general population, there is evidence of elevated all-cause mortality among people notified with communicable diseases often up to one year following illness onset. Not all elevated risk is likely directly attributable to the communicable diseases of interest, rather, it may reflect underlying comorbidities or behaviours in these individuals. Regardless of attribution, infection with communicable diseases may represent a marker of mortality. Key to preventing deaths may be through timely and appropriate transition to primary and preventive healthcare following diagnosis. Funding: No funding was provided for this study.

A real-time analysis of protein transport via the twin arginine translocation pathway in response to different components of the protonmotive force.

The twin arginine translocation (Tat) pathway transports folded protein across the cytoplasmic membrane in bacteria, archaea, and across the thylakoid membrane in plants as well as the inner membrane in some mitochondria. In plant chloroplasts, the Tat pathway utilizes the protonmotive force (PMF) to drive protein translocation. However, in bacteria, it has been shown that Tat transport depends only on the transmembrane electrical potential (Δψ) component of PMF in vitro. To investigate the comprehensive PMF requirement in Escherichia coli, we have developed the first real-time assay to monitor Tat transport utilizing the NanoLuc Binary Technology in E. coli spheroplasts. This luminescence assay allows for continuous monitoring of Tat transport with high-resolution, making it possible to observe subtle changes in transport in response to different treatments. By applying the NanoLuc assay, we report that, under acidic conditions (pH = 6.3), ΔpH, in addition to Δψ, contributes energetically to Tat transport in vivo in E. coli spheroplasts. These results provide novel insight into the mechanism of energy utilization by the Tat pathway.

Quantitative analysis of naphthalene, 1-naphthol and 2-naphthol at nanomol levels in geothermal fluids using SPE with HPLC.

Naphthalene (NAP), 1-naphthol (1-NAP) and 2-naphthol (2-NAP) are the thermal decomposition products of naphthalene sulfonates making them potentially new geothermal reservoir permeability tracers, however, to date, no sensitive and fast detection method for these compounds has been developed. In order to facilitate sensitive and rapid analysis of these compounds in geothermal brines and associated steam condensates, a high-performance liquid chromatography (HPLC) method combined with solid-phase extraction (SPE) has been developed.•A method for determination of naphthalene, 1- and 2-naphthol from brines has been developed.•These compounds have been detected in steam samples from three New Zealand geothermal fields.•As breakdown products of NDS/NSA, these compounds have potential use as geothermal tracers.

3D US-CT/MRI registration for percutaneous focal liver tumor ablations.

PURPOSE: US-guided percutaneous focal liver tumor ablations have been considered promising curative treatment techniques. To address cases with invisible or poorly visible tumors, registration of 3D US with CT or MRI is a critical step. By taking advantage of deep learning techniques to efficiently detect representative features in both modalities, we aim to develop a 3D US-CT/MRI registration approach for liver tumor ablations. METHODS: Facilitated by our nnUNet-based 3D US vessel segmentation approach, we propose a coarse-to-fine 3D US-CT/MRI image registration pipeline based on the liver vessel surface and centerlines. Then, phantom, healthy volunteer and patient studies are performed to demonstrate the effectiveness of our proposed registration approach. RESULTS: Our nnUNet-based vessel segmentation model achieved a Dice score of 0.69. In healthy volunteer study, 11 out of 12 3D US-MRI image pairs were successfully registered with an overall centerline distance of 4.03±2.68 mm. Two patient cases achieved target registration errors (TRE) of 4.16 mm and 5.22 mm. CONCLUSION: We proposed a coarse-to-fine 3D US-CT/MRI registration pipeline based on nnUNet vessel segmentation models. Experiments based on healthy volunteers and patient trials demonstrated the effectiveness of our registration workflow. Our code and example data are publicly available in this r epository.

Evidence against a temporal association between cerebrovascular disease and Alzheimer's disease imaging biomarkers.

Whether a relationship exists between cerebrovascular disease and Alzheimer's disease has been a source of controversy. Evaluation of the temporal progression of imaging biomarkers of these disease processes may inform mechanistic associations. We investigate the relationship of disease trajectories of cerebrovascular disease (white matter hyperintensity, WMH, and fractional anisotropy, FA) and Alzheimer's disease (amyloid and tau PET) biomarkers in 2406 Mayo Clinic Study of Aging and Mayo Alzheimer's Disease Research Center participants using accelerated failure time models. The model assumes a common pattern of progression for each biomarker that is shifted earlier or later in time for each individual and represented by a per participant age adjustment. An individual's amyloid and tau PET adjustments show very weak temporal association with WMH and FA adjustments (R = -0.07 to 0.07); early/late amyloid or tau timing explains <1% of the variation in WMH and FA adjustment. Earlier onset of amyloid is associated with earlier onset of tau (R = 0.57, R2 = 32%). These findings support a strong mechanistic relationship between amyloid and tau aggregation, but not between WMH or FA and amyloid or tau PET.

Head-to-head comparison of magnetic resonance elastography-based liver stiffness, fat fraction, and T1 relaxation time in identifying at-risk NASH.

BACKGROUND AND AIMS: The presence of at-risk NASH is associated with an increased risk of cirrhosis and complications. Therefore, noninvasive identification of at-risk NASH with an accurate biomarker is a critical need for pharmacologic therapy. We aim to explore the performance of several magnetic resonance (MR)-based imaging parameters in diagnosing at-risk NASH. APPROACH AND RESULTS: This prospective clinical trial (NCT02565446) includes 104 paired MR examinations and liver biopsies performed in patients with suspected or diagnosed NAFLD. Magnetic resonance elastography-assessed liver stiffness (LS), 6-point Dixon-derived proton density fat fraction (PDFF), and single-point saturation-recovery acquisition-calculated T1 relaxation time were explored. Among all predictors, LS showed the significantly highest accuracy in diagnosing at-risk NASH [AUC LS : 0.89 (0.82, 0.95), AUC PDFF : 0.70 (0.58, 0.81), AUC T1 : 0.72 (0.61, 0.82), z -score test z >1.96 for LS vs any of others]. The optimal cutoff value of LS to identify at-risk NASH patients was 3.3 kPa (sensitivity: 79%, specificity: 82%, negative predictive value: 91%), whereas the optimal cutoff value of T1 was 850 ms (sensitivity: 75%, specificity: 63%, and negative predictive value: 87%). PDFF had the highest performance in diagnosing NASH with any fibrosis stage [AUC PDFF : 0.82 (0.72, 0.91), AUC LS : 0.73 (0.63, 0.84), AUC T1 : 0.72 (0.61, 0.83), |z| <1.96 for all]. CONCLUSION: Magnetic resonance elastography-assessed LS alone outperformed PDFF, and T1 in identifying patients with at-risk NASH for therapeutic trials.

Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress.

The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-µM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but the physiological significance of this competition remains elusive. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, ß-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2-/- mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.