STAREE-Mind Imaging Study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals.

Introduction: Cerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective effects. The STAREE-Mind Imaging Study is a randomised, double-blind, placebo-controlled clinical trial that will investigate the impact of atorvastatin on markers of neurovascular health and brain atrophy in a healthy, older population using MRI. This is a nested substudy of the 'Statins for Reducing Events in the Elderly' (STAREE) primary prevention trial. Methods: Participants aged 70 years or older (n=340) will be randomised to atorvastatin or placebo. Comprehensive brain MRI assessment will be undertaken at baseline and up to 4 years follow-up, including structural, diffusion, perfusion and susceptibility imaging. The primary outcome measures will be change in brain free water fraction (a composite marker of vascular leakage, neuroinflammation and neurodegeneration) and white matter hyperintensity volume (small vessel disease). Secondary outcomes will include change in perivascular space volume (glymphatic drainage), cortical thickness, hippocampal volume, microbleeds and lacunae, prefrontal cerebral perfusion and white matter microstructure. Ethics and dissemination: Academic publications from this work will address the current uncertainty regarding the impact of statins on brain structure and vascular integrity. This study will inform the utility of repurposing these well-tolerated, inexpensive and widely available drugs for primary prevention of neurological outcomes in older individuals. Ethics approval was given by Monash University Human Research Ethics Committee, Protocol 12206. Trial registration number: ClinicalTrials.gov Identifier: NCT05586750.

Oronasal vs Nasal Masks: The Impact of Mask Type on CPAP Requirement, Pharyngeal Critical Closing Pressure (Pcrit), and Upper Airway Cross-Sectional Areas in Patients With OSA.

BACKGROUND: CPAP delivered via an oronasal mask is associated with lower adherence, higher residual apnea-hypopnea index (AHI), and increased CPAP therapeutic pressure compared with nasal masks. However, the mechanisms underlying the increased pressure requirements are not well understood. RESEARCH QUESTION: How do oronasal masks affect upper airway anatomy and collapsibility? STUDY DESIGN AND METHODS: Fourteen patients with OSA underwent a sleep study with both a nasal and oronasal mask, each for one-half of the night (order randomized). CPAP was manually titrated to determine therapeutic pressure. Upper airway collapsibility was assessed using the pharyngeal critical closing pressure (Pcrit) technique. Cine MRI was done to dynamically assess the cross-sectional area of the retroglossal and retropalatal airway throughout the respiratory cycle with each mask interface. Scans were repeated at 4 cm H2O and at the nasal and oronasal therapeutic pressures. RESULTS: The oronasal mask was associated with higher therapeutic pressure requirements (ΔM ± SEM; +2.6 ± 0.5; P < .001) and higher Pcrit (+2.4 ± 0.5 cm H2O; P = .001) compared with the nasal mask. The change in therapeutic pressure between masks was strongly correlated with the change in Pcrit (r2 = 0.73; P = .003). Increasing CPAP increased both the retroglossal and retropalatal airway dimensions across both masks. After controlling for pressure and breath phase, the retropalatal cross-sectional area was moderately larger when using a nasal vs an oronasal mask (+17.2 mm2; 95% CI, 6.2-28.2, P < .001) while nasal breathing. INTERPRETATION: Oronasal masks are associated with a more collapsible airway than nasal masks, which likely contributes to the need for a higher therapeutic pressure.

Monash DaCRA fPET-fMRI: A dataset for comparison of radiotracer administration for high temporal resolution functional FDG-PET.

BACKGROUND: "Functional" [18F]-fluorodeoxyglucose positron emission tomography (FDG-fPET) is a new approach for measuring glucose uptake in the human brain. The goal of FDG-fPET is to maintain a constant plasma supply of radioactive FDG in order to track, with high temporal resolution, the dynamic uptake of glucose during neuronal activity that occurs in response to a task or at rest. FDG-fPET has most often been applied in simultaneous BOLD-fMRI/FDG-fPET (blood oxygenation level-dependent functional MRI fluorodeoxyglucose functional positron emission tomography) imaging. BOLD-fMRI/FDG-fPET provides the capability to image the 2 primary sources of energetic dynamics in the brain, the cerebrovascular haemodynamic response and cerebral glucose uptake. FINDINGS: In this Data Note, we describe an open access dataset, Monash DaCRA fPET-fMRI, which contrasts 3 radiotracer administration protocols for FDG-fPET: bolus, constant infusion, and hybrid bolus/infusion. Participants (n = 5 in each group) were randomly assigned to each radiotracer administration protocol and underwent simultaneous BOLD-fMRI/FDG-fPET scanning while viewing a flickering checkerboard. The bolus group received the full FDG dose in a standard bolus administration, the infusion group received the full FDG dose as a slow infusion over the duration of the scan, and the bolus-infusion group received 50% of the FDG dose as bolus and 50% as constant infusion. We validate the dataset by contrasting plasma radioactivity, grey matter mean uptake, and task-related activity in the visual cortex. CONCLUSIONS: The Monash DaCRA fPET-fMRI dataset provides significant reuse value for researchers interested in the comparison of signal dynamics in fPET, and its relationship with fMRI task-evoked activity.

Task-evoked simultaneous FDG-PET and fMRI data for measurement of neural metabolism in the human visual cortex.

Understanding how the living human brain functions requires sophisticated in vivo neuroimaging technologies to characterise the complexity of neuroanatomy, neural function, and brain metabolism. Fluorodeoxyglucose positron emission tomography (FDG-PET) studies of human brain function have historically been limited in their capacity to measure dynamic neural activity. Simultaneous [18 F]-FDG-PET and functional magnetic resonance imaging (fMRI) with FDG infusion protocols enable examination of dynamic changes in cerebral glucose metabolism simultaneously with dynamic changes in blood oxygenation. The Monash vis-fPET-fMRI dataset is a simultaneously acquired FDG-fPET/BOLD-fMRI dataset acquired from n = 10 healthy adults (18-49 yrs) whilst they viewed a flickering checkerboard task. The dataset contains both raw (unprocessed) images and source data organized according to the BIDS specification. The source data includes PET listmode, normalization, sinogram and physiology data. Here, the technical feasibility of using opensource frameworks to reconstruct the PET listmode data is demonstrated. The dataset has significant re-use value for the development of new processing pipelines, signal optimisation methods, and to formulate new hypotheses concerning the relationship between neuronal glucose uptake and cerebral haemodynamics.

A clinical trial of non-invasive imaging with an anti-HIV antibody labelled with copper-64 in people living with HIV and uninfected controls.

BACKGROUND: A research priority in finding a cure for HIV is to establish methods to accurately locate and quantify where and how HIV persists in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). Infusing copper-64 (64Cu) radiolabelled broadly neutralising antibodies targeting HIV envelope (Env) with CT scan and positron emission tomography (PET) identified HIV Env in tissues in SIV infected non-human primates . We aimed to determine if a similar approach was effective in people living with HIV (PLWH). METHODS: Unmodified 3BNC117 was compared with 3BNC117 bound to the chelator MeCOSar and 64Cu (64Cu-3BNC117) in vitro to assess binding and neutralization. In a clinical trial 64Cu-3BNC117 was infused into HIV uninfected (Group 1), HIV infected and viremic (viral load, VL >1000 c/mL; Group 2) and HIV infected aviremic (VL <20 c/mL; Group 3) participants using two dosing strategies: high protein (3mg/kg unlabeled 3BNC117 combined with <5mg 64Cu-3BNC117) and trace (<5mg 64Cu-3BNC117 only). All participants were screened for 3BNC117 sensitivity from virus obtained from viral outgrowth. Magnetic resonance imaging (MRI)/PET and pharmacokinetic assessments (ELISA for serum 3BNC117 concentrations and gamma counting for 64Cu) were performed 1, 24- and 48-hours post dosing. The trial (clincialtrials.gov NCT03063788) primary endpoint was comparison of PET standard uptake values (SUVs) in regions of interest (e.g lymph node groups and gastrointestinal tract). FINDINGS: Comparison of unmodified and modified 3BNC117 in vitro demonstrated no difference in HIV binding or neutralisation. 17 individuals were enrolled of which 12 were dosed including Group 1 (n=4, 2 high protein, 2 trace dose), Group 2 (n=6, 2 high protein, 4 trace) and Group 3 (n=2, trace only). HIV+ participants had a mean CD4 of 574 cells/microL and mean age 43 years. There were no drug related adverse effects and no differences in tissue uptake in regions of interest (e.g lymph node gut, pharynx) between the 3 groups. In the high protein dosing group, serum concentrations of 3BNC117 and gamma counts were highly correlated demonstrating that 64Cu-3BNC117 remained intact in vivo. INTERPRETATION: In PLWH on or off ART, the intervention of infusing 64Cu-3BNC117 and MRI/PET imaging over 48 hours, was unable to detect HIV-1 env expression in vivo. Future studies should investigate alternative radiolabels such as zirconium which have a longer half-life in vivo. FUNDING: Funded by the Alfred Foundation, The Australian Centre for HIV and Hepatitis Virology Research with additional support from the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (USAI126611). JHM and SRL are supported by the Australian National Health and Medical Research Council.

Radiotracer Administration for High Temporal Resolution Positron Emission Tomography of the Human Brain: Application to FDG-fPET.

Functional positron emission tomography (fPET) provides a method to track molecular targets in the human brain. With a radioactively-labelled glucose analogue, 18F-fluordeoxyglucose (FDG-fPET), it is now possible to measure the dynamics of glucose metabolism with temporal resolutions approaching those of functional magnetic resonance imaging (fMRI). This direct measure of glucose uptake has enormous potential for understanding normal and abnormal brain function and probing the effects of metabolic and neurodegenerative diseases. Further, new advances in hybrid MR-PET hardware make it possible to capture fluctuations in glucose and blood oxygenation simultaneously using fMRI and FDG-fPET. The temporal resolution and signal-to-noise of the FDG-fPET images is critically dependent upon the administration of the radiotracer. This work presents two alternative continuous infusion protocols and compares them to a traditional bolus approach. It presents a method for acquiring blood samples, time-locking PET, MRI, experimental stimulus, and administering the non-traditional tracer delivery. Using a visual stimulus, the protocol results show cortical maps of the glucose-response to external stimuli on an individual level with a temporal resolution of 16 s.

Do gray wolves (Canis lupus) support pack mates during aggressive inter-pack interactions?

For group-living mammals, social coordination increases success in everything from hunting and foraging (Crofoot and Wrangham in Mind the Gap, Springer, Berlin, 2010; Bailey et al. in Behav Ecol Sociobiol 67:1-17, 2013) to agonism (Mosser and Packer in Anim Behav 78:359-370, 2009; Wilson et al. in Anim Behav 83:277-291, 2012; Cassidy et al. in Behav Ecol 26:1352-1360, 2015). Cooperation is found in many species and, due to its low costs, likely is a determining factor in the evolution of living in social groups (Smith in Anim Behav 92:291-304, 2014). Beyond cooperation, many mammals perform costly behaviors for the benefit of group mates (e.g., parental care, food sharing, grooming). Altruism is considered the most extreme case of cooperation where the altruist increases the fitness of the recipient while decreasing its own fitness (Bell in Selection: the mechanism of evolution. Oxford University Press, Oxford 2008). Gray wolf life history requires intra-pack familiarity, communication, and cooperation in order to succeed in hunting (MacNulty et al. in Behav Ecol doi: 10.1093/beheco/arr159 2011) and protecting group resources (Stahler et al. in J Anim Ecol 82: 222-234, 2013; Cassidy et al. in Behav Ecol 26:1352-1360, 2015). Here, we report 121 territorial aggressive inter-pack interactions in Yellowstone National Park between 1 April 1995 and 1 April 2011 (>5300 days of observation) and examine each interaction where one wolf interferes when its pack mate is being attacked by a rival group. This behavior was recorded six times (17.6 % of interactions involving an attack) and often occurred between dyads of closely related individuals. We discuss this behavior as it relates to the evolution of cooperation, sociality, and altruism.

Early detection of ventilation-induced brain injury using magnetic resonance spectroscopy and diffusion tensor imaging: an in vivo study in preterm lambs.

BACKGROUND AND AIM: High tidal volume (VT) ventilation during resuscitation of preterm lambs results in brain injury evident histologically within hours after birth. We aimed to investigate whether magnetic resonance spectroscopy (MRS) and/or diffusion tensor imaging (DTI) can be used for early in vivo detection of ventilation-induced brain injury in preterm lambs. METHODS: Newborn lambs (0.85 gestation) were stabilized with a "protective ventilation" strategy (PROT, n = 7: prophylactic Curosurf, sustained inflation, VT 7 mL/kg, positive end expiratory pressure (PEEP) 5 cmH2O) or an initial 15 minutes of "injurious ventilation" (INJ, n = 10: VT 12 mL/kg, no PEEP, late Curosurf) followed by PROT ventilation for the remainder of the experiment. At 1 hour, lambs underwent structural magnetic resonance imaging (Siemens, 3 Tesla). For measures of mean/axial/radial diffusivity (MD, AD, RD) and fractional anisotropy (FA), 30 direction DTI was performed. Regions of interests encompassed the thalamus, internal capsule, periventricular white matter and the cerebellar vermis. MRS was performed using a localized single-voxel (15×15×20 mm3, echo time 270 ms) encompassing suptratentorial deep nuclear grey matter and central white matter. Peak-area ratios for lactate (Lac) relative to N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were calculated. Groups were compared using 2-way RM-ANOVA, Mann-Whitney U-test and Spearman's correlations. RESULTS: No cerebral injury was seen on structural MR images. Lambs in the INJ group had higher mean FA and lower mean RD in the thalamus compared to PROT lambs, but not in the other regions of interest. Peak-area lactate ratios >1.0 was only seen in INJ lambs. A trend of higher mean peak-area ratios for Lac/Cr and Lac/Cho was seen, which correlated with lower pH in both groups. CONCLUSION: Acute changes in brain diffusion measures and metabolite peak-area ratios were observed after injurious ventilation. Early MRS/DTI is able to detect the initiation of ventilation-induced brain injury.

Prospective audit of parastomal hernia: prevalence and associated comorbidities.

PURPOSE: There is little evidence regarding the prevalence or incidence of parastomal hernia, but it is thought to be common. Repair of parastomal hernia can be troublesome, and methods of repair need to be validated based on reduced incidence following surgery. The true rate of parastomal herniation needs to be determined prospectively, and risk factors for developing such hernias need to be more clearly defined. METHODS: To determine prevalence and associated risk factors, prospective data were collected regarding initial stoma surgery, presence of parastomal hernia, and comorbidities. RESULTS: Ninety patients were prospectively audited. For stomas formed at emergency or elective surgery, regardless of surgical indication, the overall rate of parastomal hernia was 33%. Aperture size and patient age were independently predictive of parastomal hernia in multivariate analysis. For every millimeter increase in aperture size, the risk of developing a hernia increased by 10% (odds ratio, 1.10 (CI, 1.03-1.18); P = .005). For every additional year of patient age, the risk of developing a hernia increased by 4% (odds ratio, 1.04 (CI, 1.00-1.08); P = .04). There was a significantly higher prevalence of hernia following sigmoid colostomy than following ileostomy (45.9% vs. 22%; P < .05). The hernia rate was higher but did not reach statistical significance in patients with disseminated malignancy, body mass index >35 kg/m2, diabetes, prostate hypertrophy, ascites, or chronic constipation. CONCLUSION: This study of carefully and prospectively collected data shows the prevalence of parastomal herniation to be 33%. This rate was higher with larger aperture size and increased age in multivariate analysis.