Parental influence on intracerebral hemorrhage onset in hereditary Dutch-type cerebral amyloid angiopathy.

Introduction Dutch-type cerebral amyloid angiopathy (D-CAA) is an autosomal dominant hereditary form of CAA causing intracerebral hemorrhage (ICH) and cognitive decline. The age of onset of ICH in D-CAA mutation carriers is strikingly variable and ranges from end thirties up to seventy years. We investigated the presence of genetic anticipation and assessed the influence of parental age at onset and sex on age of ICH onset in offspring. Methods We included (potential) D-CAA mutation-carriers from our prospective D-CAA family database. Participants were sent a questionnaire by mail and asked for the onset age of symptomatic ICH and the onset age of symptomatic ICH of their affected first-degree relative(s); their siblings and affected parent. We used a Cox regression model with the age of onset of the parent as covariate and the sex of the offspring as factor. Next we replaced the sex of the offspring with a factor with four levels: mother/daughter, mother/son, father/daughter and father/son. We used a random effect per household. Results A total of 66 respondents completed the questionnaire. Reported mean age of first symptomatic ICH was similar (both 52 years, p=0.87) for D-CAA parents (n=60) and their offspring (n=100). Offspring with a mother with D-CAA seemed to have an earlier ICH onset (50 years, SD±7) than offspring with a paternal inheritance (54 years, SD±6, p=0.03). There was no association between onset of first ICH of the parent and offspring after adding sex of the offspring to the Cox regression model: hazard ratio (HR) 0.99, 95%CI: 0.94 to 1.03, p=0.51. The interaction between parent's sex and child's sex was not significant (p=0.70). The results with and without random effect were essentially identical. Conclusion We found no indication for genetic anticipation in D-CAA in general, although maternal inheritance seemed to be associated with an earlier ICH onset.

Ethylene Oxide in Southeastern Louisiana's Petrochemical Corridor: High Spatial Resolution Mobile Monitoring during HAP-MAP.

Ethylene oxide ("EtO") is an industrially made volatile organic compound and a known human carcinogen. There are few reliable reports of ambient EtO concentrations around production and end-use facilities, however, despite major exposure concerns. We present in situ, fast (1 Hz), sensitive EtO measurements made during February 2023 across the southeastern Louisiana industrial corridor. We aggregated mobile data at 500 m spatial resolution and reported average mixing ratios for 75 km of the corridor. Mean and median aggregated values were 31.4 and 23.3 ppt, respectively, and a majority (75%) of 500 m grid cells were above 10.9 ppt, the lifetime exposure concentration corresponding to 100-in-one million excess cancer risk (1 × 10-4). A small subset (3.3%) were above 109 ppt (1000-in-one million cancer risk, 1 × 10-3); these tended to be near EtO-emitting facilities, though we observed plumes over 10 km from the nearest facilities. Many plumes were highly correlated with other measured gases, indicating potential emission sources, and a subset was measured simultaneously with a second commercial analyzer, showing good agreement. We estimated EtO for 13 census tracts, all of which were higher than EPA estimates (median difference of 21.3 ppt). Our findings provide important information about EtO concentrations and potential exposure risks in a key industrial region and advance the application of EtO analytical methods for ambient sampling and mobile monitoring for air toxics.

Plugin-based interoperability and ecosystem management for the MolSSI Driver Interface Project.

The MolSSI Driver Interface (MDI) Project is an effort to simplify and standardize the process of enabling tight interoperability between independently developed code bases and is supported by numerous software packages across the domain of chemical physics. It enables a wide variety of use cases, including quantum mechanics/molecular mechanics, advanced sampling, path integral molecular dynamics, machine learning, ab initio molecular dynamics, etc. We describe two major developments within the MDI Project that provide novel solutions to key interoperability challenges. The first of these is the development of the MDI Plugin System, which allows MDI-supporting libraries to be used as highly modular plugins, with MDI enforcing a standardized application programming interface across plugins. Codes can use these plugins without linking against them during their build process, and end-users can select which plugin(s) they wish to use at runtime. The MDI Plugin System features a sophisticated callback system that allows codes to interact with plugins on a highly granular level and represents a significant advancement toward increased modularity among scientific codes. The second major development is MDI Mechanic, an ecosystem management tool that utilizes Docker containerization to simplify the process of developing, validating, maintaining, and deploying MDI-supporting codes. Additionally, MDI Mechanic provides a framework for launching MDI simulations in which each interoperating code is executed within a separate computational environment. This eliminates the need to compile multiple production codes within a single computational environment, reducing opportunities for dependency conflicts and lowering the barrier to entry for users of MDI-enabled codes.

Microstructural white matter damage on MRI is associated with disease severity in Dutch-type cerebral amyloid angiopathy.

Peak width of skeletonized mean diffusivity (PSMD) is an emerging diffusion-MRI based marker to study subtle early alterations to white matter microstructure. We assessed PSMD over the clinical continuum in Dutch-type hereditary CAA (D-CAA) and its association with other CAA-related MRI-markers and cognitive symptoms. We included (pre)symptomatic D-CAA mutation-carriers and calculated PSMD from diffusion-MRI data. Associations between PSMD-levels, cognitive performance and CAA-related MRI-markers were assessed with linear regression models. We included 59 participants (25/34 presymptomatic/symptomatic; mean age 39/58 y). PSMD-levels increased with disease severity and were higher in symptomatic D-CAA mutation-carriers (median [range] 4.90 [2.77-9.50]mm2/s × 10-4) compared with presymptomatic mutation-carriers (2.62 [1.96-3.43]mm2/s × 10-4) p = <0.001. PSMD was positively correlated with age, CAA-SVD burden on MRI (adj.B [confidence interval] = 0.42 [0.16-0.67], p = 0.002), with number of cerebral microbleeds (adj.B = 0.30 [0.08-0.53], p = 0.009), and with both deep (adj.B = 0.46 [0.22-0.69], p = <0.001) and periventricular (adj.B = 0.38 [0.13-0.62], p = 0.004) white matter hyperintensities. Increasing PSMD was associated with decreasing Trail Making Test (TMT)-A performance (B = -0.42 [-0.69-0.14], p = 0.04. In D-CAA mutation-carriers microstructural white matter damage is associated with disease phase, CAA burden on MRI and cognitive impairment as reflected by a decrease in information processing speed. PSMD, as a global measure of alterations to the white matter microstructure, may be a useful tool to monitor disease progression in CAA.

Haemorrhagic stroke and brain vascular malformations in women: risk factors and clinical features.

Haemorrhagic stroke is a severe condition with poor prognosis. Biological sex influences the risk factors, presentations, treatment, and patient outcomes of intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and vascular malformations. Women are usually older at onset of intracerebral haemorrhage compared with men but have an increased risk of aneurysmal subarachnoid haemorrhage as they age. Female-specific factors such as pregnancy, eclampsia or pre-eclampsia, postmenopausal status, and hormone therapy influence a woman's long-term risk of haemorrhagic stroke. The presence of intracranial aneurysms, arteriovenous malformations, or cavernous malformations poses unique clinical dilemmas during pregnancy and delivery. In the absence of evidence-based guidelines for managing the low yet uncertain risk of haemorrhagic stroke during pregnancy and delivery in women with vascular malformations, multidisciplinary teams should carefully assess the risks and benefits of delivery methods for these patients. Health-care providers should recognise and address the challenges that women might have to confront when recovering from haemorrhagic stroke.

Investigation and response to an outbreak of Neisseria meningitidis serogroup Y ST-1466 urogenital infections, Australia.

Abstract: In 2023, an increased number of urogenital and anorectal infections with Neisseria meningitis serogroup Y (MenY) were reported in New South Wales (NSW). Whole genome sequencing (WGS) found a common sequence type (ST-1466), with limited sequence diversity. Confirmed outbreak cases were NSW residents with a N. meningitidis isolate matching the cluster sequence type; probable cases were NSW residents with MenY isolated from a urogenital or anorectal site from 1 July 2023 without WGS testing. Of the 41 cases, most were men (n = 27), of whom six reported recent contact with a female sex worker. Five cases were men who have sex with men and two were female sex workers. Laboratory alerts regarding the outbreak were sent to all Australian jurisdictions through the laboratories in the National Neisseria Network. Two additional states identified urogenital MenY ST-1466 infections detected in late 2023. Genomic analysis showed all MenY ST-1466 sequences were interspersed, suggestive of an Australia-wide outbreak. The incidence of these infections remains unknown, due to varied testing and reporting practices both within and across jurisdictions. Isolates causing invasive meningococcal disease (IMD) in Australia are typed, and there has been no MenY ST-1466 IMD recorded in Australia to end of March 2024. Concerns remain regarding the risk of IMD, given the similarity of these sequences with a MenY ST-1466 IMD strain causing a concurrent outbreak in the United States of America.

Uncommon Causes of Nontraumatic Intracerebral Hemorrhage.

Nontraumatic intracerebral hemorrhage is an important health issue. Although common causes such as hypertension and cerebral amyloid angiopathy predominantly affect the elderly, there exists a spectrum of uncommon etiologies that contribute to the overall incidence of intracerebral hemorrhage. The identification of these rare causes is essential for targeted clinical management, informed prognostication, and strategic secondary prevention where relevant. This topical review explores the uncommon intracerebral hemorrhage causes and provides practical clues for their clinical and imaging identification. By expanding the clinician's differential diagnosis, this review aims to bridge the gap between standard intracerebral hemorrhage classification systems and the nuanced reality of clinical practice.

Neuropsychiatric symptoms with focus on apathy and irritability in sporadic and hereditary cerebral amyloid angiopathy.

BACKGROUND: Neuropsychiatric symptoms (NPS) may affect cognition, but their burden in cerebral amyloid angiopathy (CAA), one of the main causes of intracerebral hemorrhage (ICH) and dementia in the elderly, remains unclear. We investigated NPS, with emphasis on apathy and irritability in sporadic (sCAA) and Dutch-type hereditary (D-)CAA. METHODS: We included patients with sCAA and (pre)symptomatic D-CAA, and controls from four prospective cohort studies. We assessed NPS per group, stratified for history of ICH, using the informant-based Neuropsychiatric Inventory (NPI-Q), Starkstein Apathy scale (SAS), and Irritability Scale. We modeled the association of NPS with disease status, executive function, processing speed, and CAA-burden score on MRI and investigated sex-differences. RESULTS: We included 181 participants: 82 with sCAA (mean[SD] age 72[6] years, 44% women, 28% previous ICH), 56 with D-CAA (52[11] years, 54% women, n = 31[55%] presymptomatic), and 43 controls (69[9] years, 44% women). The NPI-Q NPS-count differed between patients and controls (sCAA-ICH+:adj.ß = 1.4[95%CI:0.6-2.3]; sCAA-ICH-:1.3[0.6-2.0]; symptomatic D-CAA:2.0[1.1-2.9]; presymptomatic D-CAA:1.2[0.1-2.2], control median:0[IQR:0-3]), but not between the different CAA-subgroups. Apathy and irritability were reported most frequently: n = 12[31%] sCAA, 19[37%] D-CAA had a high SAS-score; n = 12[29%] sCAA, 14[27%] D-CAA had a high Irritability Scale score. NPS-count was associated with decreased processing speed (adj.ß=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.ß=-0.4[95%CI:-0.6;-0.1]), but not with radiological CAA-burden. Men had NPS more often than women. DISCUSSION: According to informants, one third to half of patients with CAA have NPS, mostly apathy, even in presymptomatic D-CAA and possibly with increased susceptibility in men. Neurologists should inform patients and caregivers of these disease consequences and treat or refer patients with NPS appropriately.

Serum and cerebrospinal fluid neurofilament light chain and glial fibrillary acid protein levels in early and advanced stages of cerebral amyloid Angiopathy.

BACKGROUND: Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking. We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA. METHODS: For this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aß40 and Aß42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups. RESULTS: We included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years). In presymptomatic D-CAA, only GFAP in CSF (7.7*103pg/mL vs. 4.4*103pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*102pg/mL vs. 7.8*102pg/mL; P=0.01 and GFAP:11.4*103pg/mL vs. 7.5*103pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*102pg/mL vs 7.8*102pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aß42 levels (P=0.01/0.02). CONCLUSIONS: GFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA.

Surgical intervention for cerebral amyloid angiopathy-related lobar intracerebral hemorrhage: a systematic review.

OBJECTIVE: The risks and benefits of surgery for cerebral amyloid angiopathy (CAA)-related lobar intracerebral hemorrhage (ICH) are unclear. The aim of this study was to systematically review the literature on this topic. METHODS: The authors conducted a systematic review according to the 2020 PRISMA statement. PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier were searched (on December 27, 2022) for relevant articles. Study inclusion criteria were: 1) randomized controlled trial (RCT), cohort study, cross-sectional design, or case series with more than 5 patients; 2) possible, probable, or definite CAA according to the Boston criteria (version 1.0 or 1.5) or autopsy; 3) surgical intervention for acute ICH; and 4) data on peri- and/or postoperative outcomes. Primary outcomes were the presence of intraoperative hemorrhage (IOH), postoperative hemorrhage (POH), and early ICH recurrence. Secondary outcomes were 3-month mortality, late ICH recurrence, functional outcome at discharge, and factors associated with poor outcome. Pooled estimates were calculated, and the Joanna Briggs Institute Critical Appraisal Tool was used to assess risk of bias. RESULTS: Four cohort studies and 15 case series (n = 738 patients, mean age 70 years, 56% women) were included. IOH occurred in 2 (0.6%) of 352 patients. Pooled estimates for POH were 13.0% (30/225) for less than 48 hours and 6.2% (3/437) for 48 hours to 14 days. Overall recurrent ICH (mean follow-up 19 months, n = 5 studies) occurred in 11% of patients. Outcome was predominantly poor with a pooled 3-month mortality rate of 19% and good outcome of 23%. Factors associated with poor outcome were advanced age, poor condition on admission, preexisting dementia, and concomitant intraventricular, subarachnoid, or subdural hemorrhage. All studies contained possible sources of bias and reporting was heterogeneous. CONCLUSIONS: Surgery in CAA-related ICH is safe with no substantial IOH, POH, and early recurrent hemorrhage risk. Outcome appears to be poor, however, especially in older patients, although good quality of evidence is lacking. Patients with CAA should not be excluded from ongoing surgery RCTs in ICH to enable future subgroup analysis of this specific patient population.

Temporal Ordering of Biomarkers in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date. METHODS: We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-ß40 and amyloid-ß42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots. RESULTS: We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-ß40 and amyloid-ß42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-ß40 and amyloid-ß42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis). CONCLUSIONS: Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

Assessing the Oxidative Potential of Outdoor PM2.5 in Wintertime Fairbanks, Alaska.

The oxidative potential (OP) of outdoor PM2.5 in wintertime Fairbanks, Alaska, is investigated and compared to those in wintertime Atlanta and Los Angeles. Approximately 40 filter samples collected in January-February 2022 at a Fairbanks residential site were analyzed for OP utilizing dithiothreitol-depletion (OPDTT) and hydroxyl-generation (OPOH) assays. The study-average PM2.5 mass concentration was 12.8 µg/m3, with a 1 h average maximum of 89.0 µg/m3. Regression analysis, correlations with source tracers, and contrast between cold and warmer events indicated that OPDTT was mainly sensitive to copper, elemental carbon, and organic aerosol from residential wood burning, and OPOH to iron and organic aerosol from vehicles. Despite low photochemically-driven oxidation rates, the water-soluble fraction of OPDTT was unusually high at 77%, mainly from wood burning emissions. In contrast to other locations, the Fairbanks average PM2.5 mass concentration was higher than Atlanta and Los Angeles, whereas OPDTT in Fairbanks and Atlanta were similar, and Los Angeles had the highest OPDTT and OPOH. Site differences were observed in OP when normalized by both the volume of air sampled and the particle mass concentration, corresponding to exposure and the intrinsic health-related properties of PM2.5, respectively. The sensitivity of OP assays to specific aerosol components and sources can provide insights beyond the PM2.5 mass concentration when assessing air quality.

Indoor-Outdoor Oxidative Potential of PM2.5 in Wintertime Fairbanks, Alaska: Impact of Air Infiltration and Indoor Activities.

The indoor air quality of a residential home during winter in Fairbanks, Alaska, was investigated and contrasted with outdoor levels. Twenty-four-hour average indoor and outdoor filter samples were collected from January 17 to February 25, 2022, in a residential area with high outdoor PM2.5 concentrations. The oxidative potential of PM2.5 was determined using the dithiothreitol-depletion assay (OPDTT). For the unoccupied house, the background indoor-to-outdoor (I/O) ratio of mass-normalized OP (OPmDTT), a measure of the intrinsic health-relevant properties of the aerosol, was less than 1 (0.53 ± 0.37), implying a loss of aerosol toxicity as air was transported indoors. This may result from transport and volatility losses driven by the large gradients in temperature (average outdoor temperature of -19°C/average indoor temperature of 21 °C) or relative humidity (average outdoor RH of 78%/average indoor RH of 11%), or both. Various indoor activities, including pellet stove use, simple cooking experiments, incense burning, and mixtures of these activities, were conducted. The experiments produced PM2.5 with a highly variable OPmDTT. PM2.5 from cooking emissions had the lowest OP values, while pellet stove PM2.5 had the highest. Correlations between volume-normalized OPDTT (OPvDTT), relevant to exposure, and indoor PM2.5 mass concentration during experiments were much lower compared to those in outdoor environments. This suggests that mass concentration alone can be a poor indicator of possible adverse effects of various indoor emissions. These findings highlight the importance of considering both the quantity of particles and sources (chemical composition), as health metrics for indoor air quality.

Fluid biomarkers in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid ß, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.

Delta power during sleep is modulated by EEG-gated auricular vagal afferent nerve stimulation (EAVANS).

Vagus nerve stimulation (VNS) has many clinical applications under development. In particular, there is a large interest in transcutaneous auricular VNS (taVNS) because it is non-invasive and provides easy access to neuromodulation. The present study proposes a novel approach for electroencephalography (EEG)-gated taVNS, with the ultimate goal of enhancing therapeutic outcomes, including for the treatment of delirium. Delirium arises from an altered state of consciousness and is the most common neuropsychiatric disorder observed in hospitalized patients, especially the elderly. Delirium has been linked to specific disturbances in EEG rhythms. Here, we propose an EEG-gated auricular vagal afferent nerve stimulation (EAVANS) approach to deliver stimulation targeting a specific instantaneous phase of the EEG Delta rhythm to modulate arousal and downstream reduction of neuroinflammation, two of the contributing factors to delirium. We hypothesize that treatment with EAVANS will modulate Delta power, which has been linked with delirium. As dominant Delta power is also a typical feature of non-rapid eye movement (NREM) sleep, we applied a prototype of an EAVANS device on healthy volunteers during sleep to establish preliminary validation. We successfully employed our closed-loop approach to target vagal afference during the rising Delta phase in the range [-π/2 0] radians. We found a significant reduction in Delta wave power for stimulation during the rising Delta phase compared to 1) absence of stimulation, 2) active stimulation during the descending Delta phase, and 3) active stimulation targeting non-vagal territory (i.e. greater auricular nerve) during the rising Delta phase. Further validation of our EEG-gated taVNS approach in the peri-operative period will be needed. As there is presently a lack of effective treatments for delirium, our non-pharmacological and non-invasive approach, if validated, could be easily deployed in clinical settings.Clinical Relevance- Given the serious health consequences and costs associated with delirium, and the absence of effective non-pharmacological treatments, the proposed neuromodulatory approach may be a promising option for reducing delirium and other disorders of consciousness. Our EAVANS prototype system has been tested on healthy volunteers during a NREM sleep state and will require further validation in different patient populations to optimize the proposed technology and gather more evidence to support its clinical utility. This novel non-pharmacological and non-invasive closed-loop neuromodulatory device could be used peri-operatively and in inpatient hospital settings to treat patients at risk of developing delirium. For instance, in a pre-operative setting, this technology may provide an effective preventative "pre-habilitation" approach for patients at high risk of developing delirium. Post-operatively, our technology may help manage patients with delirium more effectively.

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy.

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-ß accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters - amplitude, time-to-peak (TTP), and time-to-baseline (TTB) - and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized ß = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (ß = 8.34 × 10-6, 95%CI [1.84 × 10-6, 1.48 × 10-5], p = 0.02, Adj. R2 = 0.25) and TTB (ß = 6.57 × 10-6, 95%CI [1.92 × 10-6, 1.12 × 10-5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.

Enhancing metabolite coverage in MALDI-MSI using laser post-ionisation (MALDI-2).

Matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) of metabolites can reveal how metabolism is altered throughout heterogeneous tissues. Here negative ion mode MALDI-MSI has been coupled with laser post-ionisation (MALDI-2) and applied to the MSI of low molecular weight (LMW) metabolites (

Characterizing metals in particulate pollution in communities at the fenceline of heavy industry: combining mobile monitoring and size-resolved filter measurements.

Exposures to metals from industrial emissions can pose important health risks. The Chester-Trainer-Marcus Hook area of southeastern Pennsylvania is home to multiple petrochemical plants, a refinery, and a waste incinerator, most abutting socio-economically disadvantaged residential communities. Existing information on fenceline community exposures is based on monitoring data with low temporal and spatial resolution and EPA models that incorporate industry self-reporting. During a 3 week sampling campaign in September 2021, size-resolved particulate matter (PM) metals concentrations were obtained at a fixed site in Chester and on-line mobile aerosol measurements were conducted around Chester-Trainer-Marcus Hook. Fixed-site arsenic, lead, antimony, cobalt, and manganese concentrations in total PM were higher (p < 0.001) than EPA model estimates, and arsenic, lead, and cadmium were predominantly observed in fine PM (<2.5 µm), the PM fraction which can penetrate deeply into the lungs. Hazard index analysis suggests adverse effects are not expected from exposures at the observed levels; however, additional chemical exposures, PM size fraction, and non-chemical stressors should be considered in future studies for accurate assessment of risk. Fixed-site MOUDI and nearby mobile aerosol measurements were moderately correlated (r ≥ 0.5) for aluminum, potassium and selenium. Source apportionment analyses suggested the presence of four major emissions sources (sea salt, mineral dust, general combustion, and non-exhaust vehicle emissions) in the study area. Elevated levels of combustion-related elements of health concern (e.g., arsenic, cadmium, antimony, and vanadium) were observed near the waste incinerator and other industrial facilities by mobile monitoring, as well as in residential-zoned areas in Chester. These results suggest potential co-exposures to harmful atmospheric metal/metalloids in communities surrounding the Chester-Trainer-Marcus Hook industrial area at levels that may exceed previous estimates from EPA modeling.

Plasma amyloid beta 42 is a biomarker for patients with hereditary, but not sporadic, cerebral amyloid angiopathy.

BACKGROUND: The diagnosis of probable cerebral amyloid angiopathy (CAA) is currently mostly based on characteristics of brain MRI. Blood biomarkers would be a cost-effective, easily accessible diagnostic method that may complement diagnosis by MRI and aid in monitoring disease progression. We studied the diagnostic potential of plasma Aß38, Aß40, and Aß42 in patients with hereditary Dutch-type CAA (D-CAA) and sporadic CAA (sCAA). METHODS: All Aß peptides were quantified in the plasma by immunoassays in a discovery cohort (11 patients with presymptomatic D-CAA and 24 patients with symptomatic D-CAA, and 16 and 24 matched controls, respectively) and an independent validation cohort (54 patients with D-CAA, 26 presymptomatic and 28 symptomatic, and 39 and 46 matched controls, respectively). In addition, peptides were quantified in the plasma in a group of 61 patients with sCAA and 42 matched controls. We compared Aß peptide levels between patients and controls using linear regression adjusting for age and sex. RESULTS: In the discovery cohort, we found significantly decreased levels of all Aß peptides in patients with presymptomatic D-CAA (Aß38: p < 0.001; Aß40: p = 0.009; Aß42: p < 0.001) and patients with symptomatic D-CAA (Aß38: p < 0.001; Aß40: p = 0.01; Aß42: p < 0.001) compared with controls. In contrast, in the validation cohort, plasma Aß38, Aß40, and Aß42 were similar in patients with presymptomatic D-CAA and controls (Aß38: p = 0.18; Aß40: p = 0.28; Aß42: p = 0.63). In patients with symptomatic D-CAA and controls, plasma Aß38 and Aß40 were similar (Aß38: p = 0.14; Aß40: p = 0.38), whereas plasma Aß42 was significantly decreased in patients with symptomatic D-CAA (p = 0.033). Plasma Aß38, Aß40, and Aß42 levels were similar in patients with sCAA and controls (Aß38: p = 0.092; Aß40: p = 0.64. Aß42: p = 0.68). CONCLUSIONS: Plasma Aß42 levels, but not plasma Aß38 and Aß40, may be used as a biomarker for patients with symptomatic D-CAA. In contrast, plasma Aß38, Aß40, and Aß42 levels do not appear to be applicable as a biomarker in patients with sCAA.