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Diffuse gliomas are incurable brain tumors, yet there is significant heterogeneity in patient survival. Advanced computational techniques such as radiomics show potential for presurgical prediction of survival and other outcomes from neuroimaging. However, these techniques ignore non-lesioned brain features that could be essential for improving prediction accuracy. Gray matter covariance network (connectome) features were retrospectively identified from the T1-weighted MRIs of 305 adult patients diagnosed with diffuse glioma. These features were entered into a Cox proportional hazards model to predict overall survival with 10-folds cross-validation. The mean time-dependent area under the curve (AUC) of the connectome model was compared with the mean AUCs of clinical and radiomic models using a pairwise t-test with Bonferroni correction. One clinical model included only features that are known presurgery (clinical) and another included an advantaged set of features that are not typically known presurgery (clinical +). The median survival time for all patients was 134.2 months. The connectome model (AUC 0.88 ± 0.01) demonstrated superior performance (P < 0.001, corrected) compared to the clinical (AUC 0.61 ± 0.02), clinical + (AUC 0.79 ± 0.01) and radiomic models (AUC 0.75 ± 0.02). These findings indicate that the connectome is a feasible and reliable early biomarker for predicting survival in patients with diffuse glioma. Connectome and other whole-brain models could be valuable tools for precision medicine by informing patient risk stratification and treatment decision-making.

Blood‐based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS‐AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood‐based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p‐tau217, p‐tau181) have been consistently shown to track disease progression for DS‐AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work is needed. Findings from stability work of blood‐based biomarkers conducted among non‐DS also support the potential longitudinal utility of biomarkers such as neurofilament light chain and p‐tau181 in DS. Gaps in our knowledge are highlighted, and a potential role for sex differences in biomarker outcomes is noted, along with recommendations for determining the appropriate context of use when translating biomarkers into clinical applications. Highlights An overview of blood‐based biomarkers for Alzheimer's disease (AD) was provided for consideration of their utility among individuals with Down syndrome when looking toward potential clinical applications. Longitudinal stability of many blood biomarkers and improvement in detection sensitivity make blood such as plasma a viable source for exploring AD pathology. Variability in reviewed findings regarding the application of blood biomarkers highlights the importance of understanding and defining the appropriate context of use, particularly when translating them into clinical practice.

PurposeCancer-related cognitive impairment (CRCI) is a common neurotoxicity among patients with breast and other cancers. Neuroimaging studies have demonstrated measurable biomarkers of CRCI but have largely neglected the potential heterogeneity of the syndrome.MethodsWe used retrospective functional MRI data from 80 chemotherapy-treated breast cancer survivors to examine neurophysiologic subtypes or “biotypes” of CRCI. The breast cancer group consisted of training (N = 57) and validation (N = 23) samples.ResultsAn unsupervised clustering approach using connectomes from the training sample identified three distinct biotypes. Cognitive performance (p < 0.05, corrected) and regional connectome organization (p < 0.001, corrected) differed significantly between the biotypes and also from 103 healthy female controls. We then built a random forest classifier using connectome features to distinguish between the biotypes (accuracy = 91%) and applied this to the validation sample to predict biotype assignment. Cognitive performance (p < 0.05, corrected) and regional connectome organization (p < 0.005, corrected) differed significantly between the predicted biotypes and healthy controls. Biotypes were also characterized by divergent clinical and demographic factors as well as patient reported outcomes.ConclusionsNeurophysiologic biotypes may help characterize the heterogeneity associated with CRCI in a data-driven manner based on neuroimaging biomarkers.Implications for Cancer SurvivorsOur novel findings provide a foundation for detecting potential risk and resilience factors that warrant further study. With further investigation, biotypes might be used to personalize assessments of and interventions for CRCI.

Background The invasive tick species, Haemaphysalis longicornis , is becoming established in the USA, presenting a growing threat to dogs and cats. Two 90-day studies were initiated, the same protocol in each, to confirm the efficacy of a single application of two fluralaner formulations against H. longicornis infestations of cats. Methods Cats were randomized among three groups in a 1:1:1 ratio (10 cats/group). Group 1 cats were untreated controls; Group 2 cats were treated with a topical fluralaner formulation (Bravecto®); Group 3 cats received a topical formulation containing fluralaner and moxidectin (Bravecto® Plus). Treatments were administered once (Day 0) at the label dose rates. Each cat was infested with 50 H. longicornis ticks on Day −7 for study qualification and also infested with 50 ticks on Days −2, 28, 58 and 88. Tick counts were completed on Days −5, 2, 30, 60 and 90. The primary objective was based on percentage reductions in arithmetic mean tick counts. Results Pre-study infestations showed all study cats were susceptible to tick challenge. Except for Day 2 in one study, at least six control cats retained ≥ 25% of each challenge, demonstrating an adequate infestation for efficacy assessments. Across studies on Days 2, 30, 60 and 90, the mean live tick infestation rate (number of ticks recovered from each cat/infesting challenge to each cat) of Group 1 cats ranged from 25.0 to 69.6%. Efficacy of each formulation, based on live tick counts, was 100% on Day 2 and > 95 to 100% at each subsequent assessment. Between-group differences were statistically significant ( P  < 0.0001) for each treatment versus control comparison. Conclusion At the label dose rate, both topical fluralaner formulations were 100% effective in eliminating H. longicornis ticks from cats infested at the time of treatment. Efficacy of > 95 to 100% was then maintained through 90 days following a single application. Fluralaner is therefore a treatment of choice for protecting cats against this invasive tick species. Graphical Abstract

Introduction Mexican Americans remain severely underrepresented in Alzheimer's disease (AD) research. The Health & Aging Brain among Latino Elders (HABLE) study was created to fill important gaps in the existing literature. Methods Community‐dwelling Mexican Americans and non‐Hispanic White adults and elders (age 50 and above) were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T magnetic resonance imaging (MRI) of the brain. Amyloid and tau positron emission tomography (PET) scans were added at visit 2. Blood samples were stored in the Biorepository. Results Data was examined from n = 1705 participants. Significant group differences were found in medical, demographic, and sociocultural factors. Cerebral amyloid and neurodegeneration imaging markers were significantly different between Mexican Americans and non‐Hispanic Whites. Discussion The current data provide strong support for continued investigations that examine the risk factors for and biomarkers of AD among diverse populations.

A mean field microkinetic evaluation of previously reported DFT-derived Gibbs free energy profiles for CO and CO 2 hydrogenation to methanol on Cu(111), Cu(211) and Zn-modified Cu(211) is presented. It is demonstrated that explicit consideration of the effect of surface coverages of reaction intermediates on rates is needed in order to arrive at a realistic evaluation of the activity and selectivity. In particular, both the methanol formation rate and the CO/CO 2 selectivity for methanol production are demonstrated to be highly sensitive to the saturation coverage of formate at steady state. In general, the study emphasises the importance of including explicit kinetic analyses when mechanistic DFT-derived energy profiles are interpreted for catalytic processes. Graphical Abstract

Background The parthenogenic reproductive ability of Haemaphysalis longicornis , facilitating quick life cycle completion and rapid geographic spread and its pathogen vector potential make infestations a risk to human and canine health. Two 90-day studies were initiated to evaluate the efficacy of a single fluralaner administration for the treatment and prevention of H. longicornis infestations on dogs. Methods Dogs were randomly assigned (10 dogs/group) to either an untreated control group or a group treated once (Day 0) with 13.64% w/w fluralaner chewable tablets (Bravecto ® ) at the minimum label dose rate of 25 mg/kg. Each dog was infested with approximately 50 H. longicornis ticks on Days -9 or -6 and on Days -2, 28, 58 and 88. A different US tick isolate was used in each study. Tick counts were completed on Days -7 or -4, 2, 30, 60 and 90. The primary efficacy criterion was a 90% reduction in arithmetic mean tick counts between the treated and control groups. For between-group comparisons at any assessment, at least six control dogs were required to retain at least 25% of the infestation dose (13 live ticks). Results Pre-study infestations demonstrated susceptibility of all study dogs to challenge with H. longicornis . At each subsequent assessment in both studies, at least seven untreated control dogs retained ≥ 25% of the challenge, demonstrating adequate infestations for each efficacy calculation. On Days 2, 30, 60 and 90 the mean live tick infestation rate (number of ticks recovered from each dog/infesting challenge of each dog) of untreated control dogs ranged from 27.8 to 60.8%. No live ticks, free or attached, were found on any fluralaner-treated dog in either study. Between-group differences were statistically significant ( P  ≤ 0.0002) at each assessment. Conclusion At the minimum recommended label dose rate of 25 mg/kg, fluralaner chewable tablets were 100% effective in eliminating H. longicornis ticks from dogs infested at the time of treatment. Complete efficacy against both US isolates of this tick was maintained through 90 days following a single treatment. Therefore, fluralaner is a treatment of choice for protecting dogs against this invasive tick species. Graphical abstract

INTRODUCTION Despite having few vascular risk factors, people with Down syndrome (DS) have MRI evidence of cerebrovascular disease (CVD) and neuroinflammation that worsens with Alzheimer's disease (AD) severity. We investigated whether markers of CVD and inflammation are associated with AD‐related diagnostic progression in people with DS. METHODS We included 149 participants (mean age [SD] = 44.6 [9]) from the Alzheimer's Biomarkers Consortium–Down Syndrome who had two (n = 24) or three follow‐up visits (n = 125). We derived white matter hyperintensity (WMH) volume and plasma biomarker (glial fibrillary acidic protein [GFAP], amyloid beta [Aβ]42/Aβ40, hyperphosphorylated tau‐217 [p‐tau217], and neurofilament light [NfL]) concentrations at baseline and examined their association with progression in clinical diagnosis. RESULTS Higher baseline WMH volume and higher GFAP were associated with a greater likelihood of diagnostic progression. Combining WMH and GFAP with p‐tau217 improved clinical conversion classification accuracy over AD biomarkers alone. Among individuals with evidence of amyloidosis, both WMH and GFAP were associated with clinical progression. DISCUSSION In DS, markers of CVD and inflammation are independently and synergistically associated with clinical AD progression. Highlights Higher baseline white matter hyperintensity (WMH) volume and plasma glial fibrillary acidic protein (GFAP) concentration were associated with a higher likelihood of progressing from cognitively stable to either mild cognitive impairment or clinical Alzheimer's disease in Down syndrome. WMH volume and GFAP concentration discriminated between those who progressed and those who did not. Models including the independent and interactive effects of WMH and GFAP more accurately discriminated between participants who progressed diagnostically from those who did not. Individuals with evidence of amyloid pathology were more likely to progress if they also had elevated WMH or GFAP.

INTRODUCTION Alzheimer's disease (AD) biomarkers of Amyloid(A), Tau(T), and Neurodegeneration(N) have been increasingly studied to fill the gap in our understanding of racial and ethnic differences. This study aimed to examine the relationship between plasma AT(N) biomarkers and (1) AT(N) neuroimaging biomarkers, (2) demographics, (3) medical comorbidities, and (4) cognitive diagnosis. METHODS Data were analyzed from n = 764 non‐Hispanic Black (NHB), n = 1230 Hispanic, and n = 1232 non‐Hispanic White (NHW) participants. Plasma AT(N) biomarkers were derived using single molecule array (SIMOA) technology on an HD‐X imager and included amyloid beta (Aβ)42/40, total tau, ptau181, and neurofilament light chain (NfL). Clinical reads of positron emission tomography (PET) amyloid and tau positivity were used to examine the link between AT(N) plasma and neuroimaging biomarkers. Generalized linear models were conducted to examine the relationship between plasma AT(N) biomarkers and select demographic, diagnostic, and medical comorbidities (hypertension, diabetes, dyslipidemia, chronic kidney disease). RESULTS Differences in the AT(N) biomarkers were found across racial/ethnic groups. Plasma Aβ42/40 was found to be associated with PET amyloid positivity only among NHW participants, while plasma NfL was found to correlate with Meta‐ROI among NHB and Hispanic participants. Ptau181 was associated with PET amyloid positivity among NHB and NHW participants and well as PET tau positivity among the latter group and Hispanic participants. Diabetes was related to increased plasma AT(N) biomarkers among NHB and Hispanic participants. CKD was associated with increased AT(N) biomarkers for all race/ethnic groups with the exception of Aβ42/40. While Aβ42/40, total tau, ptau181, and NfL were found to be related to a dementia diagnosis among NHW participants, only ptau181 and NfL were found to be related to this same diagnostic category among NHB and Hispanic participants. DISCUSSION Our findings indicate differential relationships between comorbidities (demographic, medical, diagnostic) across NHB, Hispanic, and NHW participants. This work expands our knowledge regarding the associations of plasma biomarkers to AD pathology in diverse populations. Highlights Differences in AT(N) plasma biomarkers were found in a diverse community cohort. While plasma Aβ42/40 was associated with PET amyloid positivity among non‐Hispanic white participants, this did not apply to non‐Hispanic Black or Hispanic participants. Medical comorbidity of diabetes and chronic kidney disease was related to increased plasma AT(N) biomarkers among the ethnically diverse segment of the cohort. Plasma AT(N) biomarkers were more so related to a diagnosis of dementia for non‐Hispanic white as compared to Hispanic or non‐Hispanic Black participants. Across racial/ethnic groups, the plasma biomarkers of neurodegeneration (NfL) and ptau181 were related to a diagnosis of dementia.