Prevalence and 3-month follow-up of cerebrovascular MRI markers in hospitalized COVID-19 patients: the CORONIS study.

PURPOSE: To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months. METHODS: CORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders. RESULTS: 125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07-8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%). CONCLUSION: Overall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization.

Varicella Zoster Virus Vasculopathy: An Under-Recognized Entity.

Varicella zoster virus (VZV) vasculopathy is a rare yet potentially severe neurological manifestation resulting from VZV reactivation, primarily affecting immunocompromised individuals. We present a case report of a 61-year-old male with VZV vasculopathy who initially presented with herpes zoster ophthalmicus, subsequently complicated by meningoencephalitis and an acute infarct in the territory of the left middle cerebral artery (MCA). Imaging revealed acute and chronic infarcts in the capsuloganglionic regions, accompanied by thickening and enhancement of the left MCA wall. Treatment involved a 14-day course of intravenous acyclovir, supplemented with oral prednisolone, resulting in modest clinical improvement. VZV vasculopathy represents an infrequently acknowledged neurological syndrome, particularly prevalent among immunocompromised individuals. Early recognition and appropriate intervention offer promise in ameliorating outcomes for affected patients. This case emphasizes the importance of including VZV vasculopathy in the differential diagnosis of neurological deficits, especially within high-risk populations.

The relation of a cerebrospinal fluid profile associated with Alzheimer's disease with cognitive function and neuropsychiatric symptoms in sporadic cerebral amyloid angiopathy.

BACKGROUND: Patients with sporadic cerebral amyloid angiopathy (sCAA) frequently report cognitive or neuropsychiatric symptoms. The aim of this study is to investigate whether in patients with sCAA, cognitive impairment and neuropsychiatric symptoms are associated with a cerebrospinal fluid (CSF) biomarker profile associated with Alzheimer's disease (AD). METHODS: In this cross-sectional study, we included participants with sCAA and dementia- and stroke-free, age- and sex-matched controls, who underwent a lumbar puncture, brain MRI, cognitive assessments, and self-administered and informant-based-questionnaires on neuropsychiatric symptoms. CSF phosphorylated tau, total tau and Aß42 levels were used to divide sCAA patients in two groups: CAA with (CAA-AD+) or without a CSF biomarker profile associated with AD (CAA-AD-). Performance on global cognition, specific cognitive domains (episodic memory, working memory, processing speed, verbal fluency, visuoconstruction, and executive functioning), presence and severity of neuropsychiatric symptoms, were compared between groups. RESULTS: sCAA-AD+ (n=31; mean age: 72 ± 6; 42%, 61% female) and sCAA-AD- (n=23; 70 ± 5; 42% female) participants did not differ with respect to global cognition or type of affected cognitive domain(s). The number or severity of neuropsychiatric symptoms also did not differ between sCAA-AD+ and sCAA-AD- participants. These results did not change after exclusion of patients without prior ICH. CONCLUSIONS: In participants with sCAA, a CSF biomarker profile associated with AD does not impact global cognition or specific cognitive domains, or the presence of neuropsychiatric symptoms.

Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Mechanistic insights into the early life stage microbiota of silver pompano (Trachinotus blochii).

Introduction: Deep investigations of host-associated microbiota can illuminate microbe-based solutions to improve production in an unprecedented manner. The poor larval survival represents the critical bottleneck in sustainable marine aquaculture practices. However, little is known about the microbiota profiles and their governing eco-evolutionary processes of the early life stages of marine teleost, impeding the development of suitable beneficial microbial management strategies. The study provides first-hand mechanistic insights into microbiota and its governing eco-evolutionary processes in early life stages of a tropical marine teleost model, Trachinotus blochii. Methods: The microbiota profiles and their dynamics from the first day of hatching till the end of metamorphosis and that of fingerling's gut during the routine hatchery production were studied using 16S rRNA amplicon-based high-throughput sequencing. Further, the relative contributions of various external factors (rearing water, live feed, microalgae, and formulated feed) to the microbiota profiles at different ontogenies was also analyzed. Results: A less diverse but abundant core microbial community (~58% and 54% in the whole microbiota and gut microbiota, respectively) was observed throughout the early life stages, supporting 'core microbiota' hypothesis. Surprisingly, there were two well-differentiated clusters in the whole microbiota profiles, ≤10 DPH (days post-hatching) and > 10 DPH samples. The levels of microbial taxonomic signatures of stress indicated increased stress in the early stages, a possible explanation for increased mortality during early life stages. Further, the results suggested an adaptive mechanism for establishing beneficial strains along the ontogenetic progression. Moreover, the highly transient microbiota in the early life stages became stable along the ontogenetic progression, hypothesizing that the earlier life stages will be the best window to influence the microbiota. The egg microbiota also crucially affected the microbial community. Noteworthily, both water and the feed microbiota significantly contributed to the early microbiota, with the feed microbiota having a more significant contribution to fish microbiota. The results illustrated that rotifer enrichment would be the optimal medium for the early larval microbiota manipulations. Conclusion: The present study highlighted the crucial foundations for the microbial ecology of T. blochii during early life stages with implications to develop suitable beneficial microbial management strategies for sustainable mariculture production.

Unraveling the spawning and reproductive patterns of tomato hind grouper, Cephalopholis sonnerati (Valenciennes, 1828) from south Kerala waters.

The objective of this study is to provide information on the reproductive biology of tomato hind grouper, Cephalopholis sonnerati (Valenciennes, 1828) for conservation and management purposes. Fish caught by artisanal fishermen from September 2019 to August 2021 were analysed. A total of 280 females, 31 males, and 4 transitional and 178 sex-undetermined fish were analysed. The female to male sex proportion was 9:1, and the fish reached a maximum total body length of 38.5 and 54.5 cm for females and males, respectively. The following microscopic stages were identified: immature, developing, ripe, running ripe/releasing, and spent in both males and females. Several asynchronous development patterns were observed in the studied gonads, including multiple oocyte stages and early and advanced stages of sexual transition. High gonadosomatic index (GSI) for both males and females was recorded in March, May, and November. Running ripe and releasing stages in females were identified in the months from March to June, which indicates the spawning season. The absolute and relative fecundity of the species ranged from 162,723 ± 207,267 and 239 ± 285, respectively. An exponential relationship was found between fecundity and total body length (TL), fecundity and total body weight (TW), and fecundity and gonad weight (GW).

Preparation, Characterization, and Hepatoprotective Activity Evaluation of Quercetin-loaded Pluronic® F127/Chitosan-Myristic Acid Mixed Micelles.

BACKGROUND: Quercetin (QTN) is a flavonol antioxidant found in foods, medicinal plants, fruits, vegetables, and beverages. QTN oral consumption produces several biological effects, including antioxidant, cardioprotective, anti-apoptotic, anti-cancer, neuroprotection, anti-hypertensive, and chemo preventive. OBJECTIVE: The study aimed to prepare Pluronic®F127/chitosan-myristic acid copolymer (PF127/C-MAc)-based mixed micelles (QTN MM) to improve the biopharmaceutical and hepatoprotective potential of QTN. METHODS: QTN MM was developed employing thin-film hydration and optimized using full factorial design (FFD). Optimized QTN MM was analyzed using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), powder x-ray diffractometry (PXRD), in vitro dissolution, ex vivo permeation, and in vivo antioxidant activity in carbon tetrachloride (CCL4)-induced albino rats. RESULTS: PF127/C-MAc ratio (1:1) with CMC value ~ 5 µg/mL showed the suitability for MM. Characterization supported the formation of MM. QTN MM revealed prominent encapsulation efficiency and drug loading of about ~ 95.10% and ~ 12.28% w/w, respectively. MM spherical shape of QTN with a smaller particle size of ~ 34.08 nm and a higher zeta potential of ~ 36.24 nm indicated excellent physical stability. Dissolution and ex vivo permeation results revealed higher dissolution and permeation of QTN MM compared to QTN and PM. In vivo antioxidant activity suggested that QTN MM at (~ 20 mg/kg, p.o.) restored the enhanced marker enzyme level compared to QTN. CONCLUSION: The findings demonstrate that developed QTN MM could be used as an alternative nanocarrier to increase the biopharmaceutical and hepatoprotective potential of QTN and other flavonoids.

Trigger factors in patients with a patent foramen ovale-associated stroke: A case-crossover study.

BACKGROUND: Patent foramen ovale (PFO) is a congenital anatomical variant which is associated with strokes in young adults. Contrary to vascular risk factors and atherosclerosis, a PFO is present from birth. However, it is completely unknown how an anatomical structure that is already present at birth in a large proportion of the population can convert into a PFO that causes stroke in a few. Recent studies reported a significant association between certain trigger factors and ischemic stroke in young adults. This study aims to investigate these triggers in PFO-associated stroke. METHODS: The ODYSSEY study, a multicenter prospective cohort study between 2013 and 2021, included patients aged 18-49 years experiencing their first-ever ischemic event. Participants completed a questionnaire about exposure to potential trigger factors. A case-crossover design was used to assess the relative risks (RR) with 95% confidence intervals (95% CI). The primary outcome was the RR of potential trigger factors for PFO-associated stroke. RESULTS: Overall, 1043 patients completed the questionnaire and had an ischemic stroke, of which 124 patients had a PFO-associated stroke (median age 42.1 years, 45.2% men). For patients with PFO-associated stroke, the RR was 26.0 (95% CI 8.0-128.2) for fever, 24.2 (95% CI 8.5-68.7) for flu-like disease, and 3.31 (95% CI 2.2-5.1) for vigorous exercise. CONCLUSION: In conclusion, flu-like disease, fever, and vigorous exercise may convert an asymptomatic PFO into a stroke-causing PFO in young adults. DATA ACCESS STATEMENT: The raw and anonymized data used in this study can be made available to other researchers on request. Written proposals can be addressed to the corresponding author and will be assessed by the ODYSSEY investigators for appropriateness of use, and a data sharing agreement in accordance with Dutch regulations will be put in place before data are shared.

Visit-to-visit blood pressure variability and progression of white matter hyperintensities over 14 years.

Purpose: There is evidence that blood pressure variability (BPV) is associated with cerebral small vessel disease (SVD) and may therefore increase the risk of stroke and dementia. It remains unclear if BPV is associated with SVD progression over years. We examined whether visit-to-visit BPV is associated with white matter hyperintensity (WMH) progression over 14 years and MRI markers after 14 years.Materials and methods: We included participants with SVD from the Radboud University Nijmegen Diffusion tensor Magnetic resonance-imaging Cohort (RUNDMC) who underwent baseline assessment in 2006 and follow-up in 2011, 2015 and 2020. BPV was calculated as coefficient of variation (CV) of BP at all visits. Association between WMH progression rates over 14 years and BPV was examined using linear-mixed effects (LME) model. Regression models were used to examine association between BPV and MRI markers at final visit in participants.Results: A total of 199 participants (60.5 SD 6.6 years) who underwent four MRI scans and BP measurements were included, with mean follow-up of 13.7 (SD 0.5) years. Systolic BPV was associated with higher progression of WMH (ß = 0.013, 95% CI 0.005 - 0.022) and higher risk of incident lacunes (OR: 1.10, 95% CI 1.01-1.21). There was no association between systolic BPV and grey and white matter volumes, Peak Skeleton of Mean Diffusivity (PSMD) or microbleed count after 13.7 years.Conclusions: Visit-to-visit systolic BPV is associated with increased progression of WMH volumes and higher risk of incident lacunes over 14 years in participants with SVD. Future studies are needed to examine causality of this association.

High blood pressure (BP) is very common, especially among older individuals. BP is not constant but tends to go up and down over time.Earlier studies have shown that when your BP fluctuates more, this can give a higher risk of dementia, stroke, cardiovascular events and even mortality. Large BP fluctuations are likely damaging for your brain, but it remains unknown if it leads to progression of brain damage over a longer period of time.This study examined if fluctuations in BP over 14 years are associated with progression of brain damage in older individuals with a mean age of 60.5 years.The results indicate that markers of brain damage progress more in participants with more variation in BP.This suggests that fluctuations in BP can cause damage in your brain to progress more.However, it is difficult to determine based on these results if BP fluctuations are a cause or a result of brain damage. More research is needed to determine what the temporal order of this association is.If variations in BP can indeed damage the brain, we need to focus not only on lowering BP, but also on keeping BP stable when considering treatments.

Short-Term and Long-Term Risk of Recurrent Vascular Event by Cause After Ischemic Stroke in Young Adults.

Importance: Cause of ischemic stroke in young people is highly variable; however, the risk of recurrence is often presented with all subtypes of stroke grouped together in classification systems such as the Trial of ORG (danaparoid sodium [Orgaran]) 10172 in Acute Stroke Treatment (TOAST) criteria, which limits the ability to individually inform young patients with stroke about their risk of recurrence. Objective: To determine the short-term and long-term risk of recurrent vascular events after ischemic stroke at a young age by stroke cause and to identify factors associated with recurrence. Design, Setting, and Participants: This cohort study used data from the Observational Dutch Young Symptomatic Stroke Study, a prospective, multicenter, hospital-based cohort study, conducted at 17 hospitals in the Netherlands between 2013 and 2021. Eligible participants included 30-day survivors of an initial, neuroimaging-proven ischemic stroke (aged 18-49 years). Data analysis was conducted from June to July 2023. Exposure: Diagnosis of a first-ever, ischemic stroke via neuroimaging. Main Outcome and Measures: The primary outcome was short-term (within 6 months) and long-term (within 5 years) recurrence risk of any vascular event, defined as fatal or nonfatal recurrent ischemic stroke, transient ischemic attack, myocardial infarction, and revascularization procedure. Predefined characteristics were chosen to identify factors associated with risk of recurrence (cause of stroke, age, sex, stroke severity, and cardiovascular health factors). Results: A total of 1216 patients (median [IQR] age, 44.2 [38.4-47.7] years; 632 male [52.0%]; 584 female [48.0%]) were included, with a median (IQR) follow-up of 4.3 (2.6-6.0) years. The 6-month risk of any recurrent ischemic event was 6.7% (95% CI, 5.3%-8.1%), and the 5-year risk was 12.2% (95% CI, 10.2%-14.2%)The short-term risk was highest for patients with cervical artery dissections (13.2%; 95% CI, 7.6%-18.7%). Other factors associated with a recurrent short-term event were atherothrombotic stroke, rare causes of stroke, and hypertension. The long-term cumulative risk was highest for patients with atherothrombotic stroke (22.7%; 95% CI, 10.6%-34.7%) and lowest for patients with cryptogenic stroke (5.8%; 95% CI, 3.0%-8.5%). Cardioembolic stroke was associated with a recurrent long-term event, as were diabetes and alcohol abuse. Conclusions and Relevance: The findings of this cohort study of 1216 patients with an ischemic stroke at a young age suggest that the risk of recurrent vascular events was high and varied by cause of stroke both for short-term and long-term follow-up, including causes that remained concealed when combined into 1 category in the routinely used TOAST criteria. This knowledge will allow for more personalized counseling of young patients with stroke.

Structural Network Efficiency Predicts Conversion to Incident Parkinsonism in Patients With Cerebral Small Vessel Disease.

BACKGROUND: To investigate whether structural network disconnectivity is associated with parkinsonian signs and their progression, as well as with an increased risk of incident parkinsonism. METHODS: In a prospective cohort (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study) consisting of 293 participants with small vessel disease (SVD), we assessed parkinsonian signs and incident parkinsonism over an 8-year follow-up. In addition, we reconstructed the white matter network followed by graph-theoretical analyses to compute the network metrics. Conventional magnetic resonance imaging markers for SVD were assessed. RESULTS: We included 293 patients free of parkinsonism at baseline (2011), with a mean age 68.8 (standard deviation [SD] 8.4) years, and 130 (44.4%) were men. Nineteen participants (6.5%) developed parkinsonism during a median (SD) follow-up time of 8.3 years. Compared with participants without parkinsonism, those with all-cause parkinsonism had higher Unified Parkinson's Disease Rating scale (UPDRS) scores and lower global efficiency at baseline. Baseline global efficiency was associated with UPDRS motor scores in 2011 (ß = -0.047, p < .001) and 2015 (ß = -0.84, p < .001), as well as with the changes in UPDRS scores during the 4-year follow-up (ß = -0.63, p = .004). In addition, at the regional level, we identified an inter-hemispheric disconnected network associated with an increased UPDRS motor score. Besides, lower global efficiency was associated with an increased risk of all-cause and vascular parkinsonism independent of SVD markers. CONCLUSIONS: Our findings suggest that global network efficiency is associated with a gradual decline in motor performance, ultimately leading to incident parkinsonism in the elderly with SVD. Global network efficiency may have the added value to serve as a useful marker to capture changes in motor signs.

Cognitive trajectory in the first year after first-ever ischaemic stroke in young adults: the ODYSSEY study.

BACKGROUND: Limited data exists on cognitive recovery in young stroke patients. We aimed to investigate the longitudinal course of cognitive performance during the first year after stroke at young age and identify predictors for cognitive recovery. METHODS: We conducted a multicentre prospective cohort study between 2013 and 2021, enrolling patients aged 18-49 years with first-ever ischaemic stroke. Cognitive assessments were performed within 6 months and after 1 year following the index event, covering seven cognitive domains. Composite Z-scores using normative data determined cognitive impairment (Z-score<-1.5). A Reliable Change Index (RCI) assessed cognitive recovery (RCI>1.96) or decline (RCI<-1.96). RESULTS: 393 patients (median age 44.3 years, IQR 38.4-47.2) completed cognitive assessments with a median time interval of 403 days (IQR 364-474) between assessments. Based on RCI, a similar proportion of patients showed improvement and decline in each cognitive domain, while the majority exhibited no cognitive change. Among cognitively impaired patients at baseline, improvements were observed in processing speed (23.1%), visuoconstruction (40.1%) and executive functioning (20.0%). Younger age was associated with better cognitive recovery in visuoconstruction, and larger lesion volume was related to cognitive recovery in processing speed. No other predictors for cognitive recovery were identified. CONCLUSIONS: Cognitive impairment remains prevalent in young stroke even 1 year after the event. Most patients showed no cognitive change, however, recovery may have occurred in the early weeks after stroke, which was not assessed in our study. Among initially cognitively impaired patients, cognitive recovery is observed in processing speed, visuoconstruction and executive functioning. It is still not possible to predict cognitive recovery in individual patients.

Functional brain connectivity in young adults with post-stroke epilepsy.

Approximately 1 in 10 young stroke patients (18-50 years) will develop post-stroke epilepsy, which is associated with cognitive impairment. While previous studies have shown altered brain connectivity in patients with epilepsy, little is however known about the changes in functional brain connectivity in young stroke patients with post-stroke epilepsy and their relationship with cognitive impairment. Therefore, we aimed to investigate whether young ischaemic stroke patients have altered functional networks and whether this alteration is related to cognitive impairment. We included 164 participants with a first-ever cerebral infarction at young age (18-50 years), along with 77 age- and sex-matched controls, from the Follow-Up of Transient Ischemic Attack and Stroke patients and Unelucidated Risk Factor Evaluation study. All participants underwent neuropsychological testing and resting-state functional MRI to generate functional connectivity networks. At follow-up (10.5 years after the index event), 23 participants developed post-stroke epilepsy. Graph theoretical analysis revealed functional network reorganization in participants with post-stroke epilepsy, in whom a weaker (i.e. network strength), less-integrated (i.e. global efficiency) and less-segregated (i.e. clustering coefficient and local efficiency) functional network was observed compared with the participants without post-stroke epilepsy group and the controls (P < 0.05). Regional analysis showed a trend towards decreased clustering coefficient, local efficiency and nodal efficiency in contralesional brain regions, including the caudal anterior cingulate cortex, posterior cingulate cortex, precuneus, superior frontal gyrus and insula in participants with post-stroke epilepsy compared with those without post-stroke epilepsy. Furthermore, participants with post-stroke epilepsy more often had impairment in the processing speed domain than the group without post-stroke epilepsy, in whom the network properties of the precuneus were positively associated with processing speed performance. Our findings suggest that post-stroke epilepsy is associated with functional reorganization of the brain network after stroke that is characterized by a weaker, less-integrated and less-segregated brain network in young ischaemic stroke patients compared with patients without post-stroke epilepsy. The contralesional brain regions, which are mostly considered as hub regions, might be particularly involved in the altered functional network and may contribute to cognitive impairment in post-stroke epilepsy patients. Overall, our findings provide additional evidence for a potential role of disrupted functional network as underlying pathophysiological mechanism for cognitive impairment in patients with post-stroke epilepsy.

Predicting incident dementia in cerebral small vessel disease: comparison of machine learning and traditional statistical models.

Background: Cerebral small vessel disease (SVD) contributes to 45% of dementia cases worldwide, yet we lack a reliable model for predicting dementia in SVD. Past attempts largely relied on traditional statistical approaches. Here, we investigated whether machine learning (ML) methods improved prediction of incident dementia in SVD from baseline SVD-related features over traditional statistical methods. Methods: We included three cohorts with varying SVD severity (RUN DMC, n = 503; SCANS, n = 121; HARMONISATION, n = 265). Baseline demographics, vascular risk factors, cognitive scores, and magnetic resonance imaging (MRI) features of SVD were used for prediction. We conducted both survival analysis and classification analysis predicting 3-year dementia risk. For each analysis, several ML methods were evaluated against standard Cox or logistic regression. Finally, we compared the feature importance ranked by different models. Results: We included 789 participants without missing data in the survival analysis, amongst whom 108 (13.7%) developed dementia during a median follow-up of 5.4 years. Excluding those censored before three years, we included 750 participants in the classification analysis, amongst whom 48 (6.4%) developed dementia by year 3. Comparing statistical and ML models, only regularised Cox/logistic regression outperformed their statistical counterparts overall, but not significantly so in survival analysis. Baseline cognition was highly predictive, and global cognition was the most important feature. Conclusions: When using baseline SVD-related features to predict dementia in SVD, the ML survival or classification models we evaluated brought little improvement over traditional statistical approaches. The benefits of ML should be evaluated with caution, especially given limited sample size and features.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

Development and Characterization of Pentaerythritol-EudragitRS100 Co-processed Excipients as Solid Dispersion Carriers for Enhanced Aqueous Solubility, In Vitro Dissolution, and Ex Vivo Permeation of Atorvastatin.

Atorvastatin (ATV), a lipid-lowering agent, has low oral bioavailability due to its poor water solubility, permeability, and low dissolution rate. Therefore, pentaerythritol-EudragitRS100 co-processed excipients (PECE) were synthesized, and their feasibility as solid dispersion carriers (ATV-PECE-SD) for improving the solubility, permeability, and dissolution rate of ATV was explored. Solid dispersions were assessed in terms of particle size and zeta potential, and solubility, in vitro dissolution, and ex vivo permeation studies were studied. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) were used as characterization tools. ATV-PECE-SD3 (1:4) formulations exhibited a small particle size with high stability. Physicochemical evaluation evidenced the formation of solid dispersion due to the involvement of weak electrostatic interaction between the polar functional groups of ATV and PECE carriers. ATV-PECE-SD3 (1:4) significantly enhanced the water solubility by ∼43-fold compared to pure ATV. In vitro dissolution studies showed that optimized formulation enhanced the dissolution rate of ATV compared to pure ATV. Ex vivo permeation results revealed that ATV-PECE-SD3 (1:4) enhanced the permeation rate of ATV compared to pure ATV. The optimized formulations significantly improved the dissolution rate of ATV in the fed state due to the food effect and micelle formation mechanism compared to the fasted state. The study concludes that co-processed excipients could be used as promising solid dispersion carriers to enhance the aqueous solubility, permeability, and dissolution rate of ATV.

Gallium-68 labelled RGD PET/CT imaging of endothelial activation in COVID-19 patients.

In coronavirus disease 2019 (COVID-19), endothelial cells play a central role and an inadequate response is associated with vascular complications. PET imaging with gallium-68 labelled RGD-peptide (68Ga-RGD) targets αvß3 integrin expression which allows quantification of endothelial activation. In this single-center, prospective observational study, we included ten hospitalized patients with COVID-19 between October 2020 and January 2021. Patients underwent 68Ga-RGD PET/CT followed by iodine mapping of lung parenchyma. CT-based segmentation of lung parenchyma, carotid arteries and myocardium was used to quantify tracer uptake by calculating standardized uptake values (SUV). Five non-COVID-19 patients were used as reference. The study population was 68.5 (IQR 52.0-74.5) years old, with median oxygen need of 3 l/min (IQR 0.9-4.0). 68Ga-RGD uptake quantified as SUV ± SD was increased in lungs (0.99 ± 0.32 vs. 0.45 ± 0.18, p < 0.01) and myocardium (3.44 ± 1.59 vs. 0.65 ± 0.22, p < 0.01) of COVID-19 patients compared to reference but not in the carotid arteries. Iodine maps showed local variations in parenchymal perfusion but no correlation with SUV. In conclusion, using 68Ga-RGD PET/CT in COVID-19 patients admitted with respiratory symptoms, we demonstrated increased endothelial activation in the lung parenchyma and myocardium. Our findings indicate the involvement of increased and localized endothelial cell activation in the cardiopulmonary system in COVID-19 patients.Trail registration: NCT04596943.

Integrating High-Impact Practices (HIPs) In Medical Curriculum At Northern Border University: Strengths, Challenges, and Examples.

BACKGROUND: High-Impact Practices (HIPs) are educational practices that have been shown to increase rates of student retention, engagement, and persistence to graduation which help them to become high achievers and lifelong learners. Universities strongly encourage faculty members to incorporate one or more of these HIPs in order to improve active learning among students. Students are met with a variety of experiences that are not entirely of their choice, including expectations for academic performance, interactions with faculty, staff, and peers, and extracurricular activities that may or may not match their expectations and skills. Higher retention and high-grade achievement rates are attributed to HIPs. The mechanism by which HIPs improve retention is poorly understood. AIMS AND OBJECTIVES: There are numerous analyses of the objectives particular to undergraduate medical education in recent years. There have been proposed three major target categories. Undergraduate medical education has been positioned within a liberal education framework, where the main objective is to equip students with the critical thinking abilities, broad general education, and subject-specific knowledge they will need to be able to effectively problem-solve, adapt to new roles, and apply public health thinking and practices to a variety of situations. We tried to incorporate HIPs in a medical curriculum at the Faculty of Medicine, Northern Border University, by giving them topics that can be used to create public awareness about the selected objectives which may help the community greatly. METHODOLOGY: Students were asked to make posters or videos on the topics and were asked to write reflections about their experience and give feedback to the coordinators for improvements and to make these HIPs better so that they can be included uniformly in the other courses as well. RESULTS AND CONCLUSIONS: Based on results from a random sample of undergraduate students, we draw the conclusion that HIPs are correlated with engagement, which is the alignment of the student's critical thinking and ability to work in effective teams, group projects, learning communities, and sequence courses. HIPs have an impact on involvement among students across the world. HIPs are effective to the extent that they engage pupils, encouraging a greater commitment, which is one way to understand their success.

Cortical Thickness and Brain Connectivity Mediate the Relation Between White Matter Hyperintensity and Information Processing Speed in Cerebral Small Vessel Disease.

White matter hyperintensities of presumed vascular origin (WMH) are the most common imaging feature of cerebral small vessel disease (cSVD) and are associated with cognitive impairment, especially information processing speed (IPS) deficits. However, it is unclear how WMH can directly impact IPS or whether the cortical thickness and brain connectivity mediate such association. In this study, it was evaluated the possible mediating roles of cortical thickness and brain (structural and functional) connectivity on the relationship between WMH (also considering its topography distribution) and IPS in 389 patients with cSVD from the RUN-DMC (Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort) database. Significant (p < 0.05 after multiple comparisons correction) associations of WMH volume and topography with cortical thickness, brain connectivity, and IPS performance in cSVD individuals were found. Additionally, cortical thickness and brain structural and functional connectivity were shown to mediate the association of WMH volume and location with IPS scores. More specifically, frontal cortical thickness, functional sensorimotor network, and posterior thalamic radiation tract were the essential mediators of WMH and IPS in this clinical group. This study provided insight into the mechanisms underlying the clinical relevance of white matter hyperintensities in information processing speed deficits in cSVD through cortical thinning and network disruptions.