Distribution of rupture sites and blebs on intracranial aneurysm walls suggests distinct rupture patterns in ACom and MCA aneurysms.

The mechanisms behind intracranial aneurysm formation and rupture are not fully understood, with factors such as location, patient demographics, and hemodynamics playing a role. Additionally, the significance of anatomical features like blebs in ruptures is debated. This highlights the necessity for comprehensive research that combines patient-specific risk factors with a detailed analysis of local hemodynamic characteristics at bleb and rupture sites. Our study analyzed 359 intracranial aneurysms from 268 patients, reconstructing patient-specific models for hemodynamic simulations based on 3D rotational angiographic images and intraoperative videos. We identified aneurysm subregions and delineated rupture sites, characterizing blebs and their regional overlap, employing statistical comparisons across demographics, and other risk factors. This work identifies patterns in aneurysm rupture sites, predominantly at the dome, with variations across patient demographics. Hypertensive and anterior communicating artery (ACom) aneurysms showed specific rupture patterns and bleb associations, indicating two pathways: high-flow in ACom with thin blebs at impingement sites and low-flow, oscillatory conditions in middle cerebral artery (MCA) aneurysms fostering thick blebs. Bleb characteristics varied with gender, age, and smoking, linking rupture risks to hemodynamic factors and patient profiles. These insights enhance understanding of the hemodynamic mechanisms leading to rupture events. This analysis elucidates the role of localized hemodynamics in intracranial aneurysm rupture, challenging the emphasis on location by revealing how flow variations influence stability and risk. We identify two pathways to wall failure-high-flow and low-flow conditions-highlighting the complexity of aneurysm behavior. Additionally, this research advances our knowledge of how inherent patient-specific characteristics impact these processes, which need further investigation.

Investigating visual preferences of clinical mechanical anesthetic vibration: a cross-sectional image survey.

While mechanical vibration lessens discomfort associated with injection site pain (ISP), many local anesthetic injectors (LAIs) do not use vibratory anesthetic devices (VADs). Injector preference of vibration device is influenced by functional concerns, but qualitatively there is an element of adoption that is driven by visual feedback. We sought to capture operator preferences of vibration device design elements to further understand why injectors do not use these devices. We conducted a survey of image preferences among nurses and medical assistants employed at 8 dermatological clinics to investigate barriers to VAD use. Images were electronically modified with features distinct from the original device (a VAD commonly used in clinical practice). Participants rated their likelihood and comfort of use of each VAD represented in the images. Two-sample t-tests were used to compare the rating of the unmodified VAD to each modified VAD within participants. A response rate of 100% was achieved with 35 participants (average age, 38.5 years; 6 (17.1%) male, 29 (82.9%) female). Despite 28 (80%) participants knowing that mechanical vibration reduces ISP, only 16 (45.7%) endorsed ever using mechanical vibration as topical anesthetic. Images modified by pattern, color, and sterility covering were rated significantly lower than the original, unmodified VAD image (plain white VAD), confirming that visual feedback does impact adoption. Through independent comment categorization, aesthetics were found to be important to LAIs. Aesthetic preferences opposing functional concerns may factor into the lack of VAD use. Defining these visual preference barriers to adoption may help promote VAD use during dermatologic procedures.

Effect of Charge on the Rotation of Prolate Nitroxide Spin Probes in Room-Temperature Ionic Liquids.

We have studied the rotational diffusion of two prolate nitroxide probes, the doubly negatively charged peroxylamine disulfonate (Frémy's salt - FS) and neutral di-tert-butyl nitroxide (DTBN), in a series of 1-alkyl-3-methylimidazolium tetrafluoroborate room-temperature ionic liquids (RTILs) having alkyl chain lengths from two to eight carbons using electron paramagnetic resonance (EPR) spectroscopy. Though the size and shape of the probes are reasonably similar, they behave differently due to the charge difference. The rotation of FS is anisotropic, and the rotational anisotropy increases with the alkyl chain length of the cation, while the rotation of DTBN is isotropic. The hyperfine coupling constant of DTBN decreases as a function of the alkyl chain length and is proportional to the relative permittivity of ionic liquids. On the other hand, the hyperfine coupling constant of FS increases with increasing chain length. These behaviors indicate the location of each probe in RTILs. FS is likely located in the polar region near the network of charged imidazolium ions. DTBN molecules are predominately distributed in the nonpolar domains.

Resilience, Survival and Functional Independence in Older Adults Facing Critical Illness.

BACKGROUND: Older adults surviving critical illness often experience new or worsening functional impairments. Modifiable positive psychological constructs, like resilience, may mitigate post-intensive care morbidity. RESEARCH QUESTION: Is pre-ICU resilience associated with: (1) post-ICU survival; (2) the drop in post-ICU functional independence; and (3) a lesser decline of independence before versus after the ICU? STUDY DESIGN AND METHODS: We performed a retrospective cohort study using Medicare-linked Health and Retirement Study surveys from 2006-2018. We included Older adults ≥65 years admitted to an ICU. We calculated resilience before ICU admission. The resilience measure was defined from the Simplified Resilience Score which was previously adapted and validated for the Health and Retirement Study. Resilience was scored using the leave-behind survey normalized to 0 (lowest resilience) to 12 (highest resilience) point scale. Outcomes were survival and probability of functional independence. We modeled survival using Gompertz models and independence using joint survival models adjusting for sociodemographic and clinical variables. We estimated average marginal effects to determine independence probabilities. RESULTS: Across 3,409 patients ≥65 years old admitted to ICUs, pre-existing frailty (30.5%) and cognitive impairment (24.3%) were common. Most patients were previously independent (82.7%). Mechanical ventilation occurred in 14.8% and sepsis in 43.2%. Highest versus lowest resilience had lower risk of post-ICU mortality (aHR 0.81 95% CI [0.70, 0.94]). Higher resilience was associated with greater likelihood in post-ICU independence (estimated probability of independence 5 years post-ICU in highest-to-lowest resilience: 0.53 CI 95% [0.33, 0.74], 0.47 [0.26, 0.68], 0.49 [0.28, 0.70], 0.36 [0.17, 0.55] p<0.01). Resilience was not associated with a difference in the drop of independence across resilience groups, nor a difference in declines of independence post-ICU. INTERPRETATION: ICU survivors with higher resilience had increased rates of survival and functional independence, though the slope of functional decline did not differ by resilience group pre- to post-ICU.

Global shortfalls in documented actions to conserve biodiversity.

Threatened species are by definition species that are in need of assistance. In the absence of suitable conservation interventions, they are likely to disappear soon1. There is limited understanding of how and where conservation interventions are applied globally, or how well they work2,3. Here, using information from the International Union for Conservation of Nature Red List and other global databases, we find that for species at risk from three of the biggest drivers of biodiversity loss-habitat loss, overexploitation for international trade and invasive species4-many appear to lack the appropriate types of conservation interventions. Indeed, although there has been substantial recent expansion of the protected area network, we still find that 91% of threatened species have insufficient representation of their habitats within protected areas. Conservation interventions are not implemented uniformly across different taxa and regions and, even when present, have infrequently led to substantial improvements in the status of species. For 58% of the world's threatened terrestrial species, we find conservation interventions to be notably insufficient or absent. We cannot determine whether such species are truly neglected, or whether efforts to recover them are not included in major conservation databases. If they are indeed neglected, the outlook for many of the world's threatened species is grim without more and better targeted action.

Nonparametric richness estimators Chao1 and ACE must not be used with amplicon sequence variant data.

Microbial ecologists use alpha diversity metrics for estimating species richness and evenness from data obtained by high-throughput sequencing of small subunit ribosomal RNA genes. This perspective argues that the nonparametric richness estimators Chao1 and ACE should never be used with ASV data because the default process of generating amplicon sequence variants (ASVs) removes singletons, which are specifically required for these estimate calculations. In addition, retaining singletons, if/when possible, will contribute a large proportion of artifacts to this abundance category, leading to extreme richness overestimation. We recommend the use of alternative sequence clustering strategies and/or diversity metrics to avoid generating meaningless richness estimates from ASV data.

Sex-Specific Differences in the Relationship Between Prematurity and Ocular Geometry.

Purpose: To explore differences in the relationship between gestational age (GA) and birth weight (BW) percentile and ocular geometry between males and females. Methods: The Gutenberg Prematurity Eye Study involved a prospective ophthalmic examination of adults, aged 18 to 52 years, who were born preterm or at term, in Germany. The associations between GA and BW percentile on the main outcome measures were evaluated by uni- and multivariable linear regression analyses. The main outcome measures were central corneal thickness, corneal radius, anterior chamber depth, lens thickness, posterior segment length, and central foveal thickness. Potential sex-specific differences and an effect modification by sex were analyzed. Results: This study involved 438 participants (245 females, 193 males) with an average age of 28.6 ± 8.7 years. In female participants, central foveal thickness was negatively associated with a higher GA (B = -2.99; P < 0.001). Similarly, male participants also demonstrated a negative association between central foveal thickness and GA (B = -4.27; P < 0.001). The multivariable model with effect modification revealed that the central foveal thickness was thicker with lower GA. There was an association between the effect modification of GA with sex and central foveal thickness, demonstrating a more pronounced effect of GA on central foveal thickness in male participants (B = 1.29; P = 0.04). Conclusions: This study identified a sex-specific correlation between lower GA and thicker central foveal thickness, suggesting differences in the developmental trajectory of this biometric parameter concerning GA. A thicker central foveal thickness might affect the visual acuity of individuals born preterm in adulthood, with a more pronounced impact in males and a potential predisposition to age-related diseases later in life. Sex did not influence the association of GA or BW percentile to other ocular geometric parameters.

Psychosocial distress among spouses of persons with dementia before and after their partner's death.

BACKGROUND: Spouses of persons living with dementia may face heightened psychosocial distress in the years immediately before and after their partner's death. We compared the psychosocial needs of spouses of partners with dementia with spouses of partners with non-impaired cognition nearing and after the end of life, focusing on loneliness, depression, life satisfaction, and social isolation. METHODS: We used nationally representative Health and Retirement Study married couples data (2006-2018), restricting to spouses 50+ years old. We included 2098 spouses with data on loneliness and depressive symptoms 2 years before and after the partner's death. We additionally examined a subset of spouses (N = 1113) with available data on life satisfaction and social isolation 2 years before their partner's death. Cognitive status of partners was classified as non-impaired cognition, cognitive impairment not dementia (cognitive impairment), and dementia. We used multivariable logistic regression to determine: 1) the change in loneliness and depression for spouses pre- and post-partner's death, and 2) life satisfaction and social isolation 2 years before the partner's death. RESULTS: Spouses were on average 73 years old (SD: 10), 66% women, 7% Black, 7% Hispanic non-White, 24% married to persons with cognitive impairment, and 19% married to partners with dementia. Before their partner's death, spouses married to partners with dementia experienced more loneliness (non-impaired cognition: 8%, cognitive impairment: 16%, dementia: 21%, p-value = 0.002) and depressive symptoms (non-impaired cognition: 20%, cognitive impairment: 27%, dementia: 31%, p-value < 0.001), and after death a similar prevalence of loneliness and depression across cognitive status. Before their partner's death, spouses of partners with dementia reported less life satisfaction (non-impaired cognition: 74%, cognitive impairment: 68%; dementia: 64%, p-value = 0.02) but were not more socially isolated. CONCLUSION: Results emphasize a need for clinical and policy approaches to expand support for the psychosocial needs of spouses of partners with dementia in the years before their partner's death rather than only bereavement.

Characteristics and Treatment Outcomes of Hypotony Maculopathy Post-Glaucoma Filtering Surgery: An Optical Coherence Tomography-Based Study.

PURPOSE: This study assesses morphological characteristics using SD-OCT in patients with hypotony maculopathy (HM) following glaucoma filtering surgery and evaluates the results of its treatment. MATERIAL AND METHODS: Retrospective analysis of all HM patients between January 2019 and March 2023. Inclusion criteria consisted of both pre-operative and post-revision SD-OCT images of the macula and the presence of HM as observed on OCT images preoperatively. HM was graded according to its appearance in OCT both pre- and post-revision surgery. Change in visual acuity and IOP were assessed. RESULTS: 45 eyes of 45 patients were included. 21 eyes had HM limited to retinal pigment epithelium (RPE), 18 eyes had involvement of RPE and photoreceptor layers and 6 eyes had additional intra- or subretinal edema. After revision surgery with IOP elevation, 64% of eyes had complete HM regression with no HM signs in OCT imaging. 80% of patients achieved at least one grade improvement in HM. Preoperative visual acuity increased from 0.7±0.4 (logMAR) to 0.4±0.4 at 2 weeks postoperatively, over the course of an increase of IOP from 3.5±1.8 mmHg to 17.1±10.6 mmHg at day one. Eyes with complete HM regression had higher IOP at day 1 compared to those without improvement (P=0.04). The median time between HM onset and revision was 10.0 days for those with complete regression and 27 days for those without improvement (P=0.04). CONCLUSIONS: Bleb revision procedures for HM following glaucoma filtering surgery show promising outcomes, including notable improvements in visual acuity and IOP. The timing of revision surgery appears to influence outcome. In our study earlier intervention was associated with better results. Even delayed surgeries can lead to an improvement, although complete morphological restoration may not be achieved in advanced grades of HM.

Optimized finite-time work protocols for the Higgs RNA model with external force.

The Higgs RNA model with an added term for a coupling to an external force is studied in regard to finite-time force-driving protocols with a minimal-work requirement. In this paper, RNA sequences which at low temperature exhibit hairpins are considered, which are often cited as typical template systems in stochastic thermodynamics. The optimized work protocols for this glassy many-particle system are determined numerically using the parallel tempering method. The protocols show distinct jumps at the beginning and end, which have been observed for single-particle systems and are proven to be optimal in the fast protocol limit generally. Optimality seems to be achieved by staying close to the equilibrium unfolding transition point, in agreement with experimental and theoretical observations. The change of work distributions, compared to those resulting from a naive linear driving protocol, are discussed generally and in terms of free energy estimation as well as the effect of optimized protocols on rare work process starting conditions.

Retinal Nerve Fiber Layer Optical Texture Analysis and 10-2 Visual Field Assessment in Glaucoma.

PURPOSE: To apply retinal nerve fiber layer (RNFL) optical texture analysis (ROTA) to 1) investigate the association between papillomacular and papillofoveal bundle defects with 10-2 visual field (VF) sensitivity abnormalities, and 2) integrate the information from RNFL bundle defect and 24-2 VF central test locations to determine the likelihood of 10-2 VF sensitivity abnormalities. DESIGN: Cross-sectional METHODS: A total of 841 eyes (144 healthy, 317 glaucoma suspect, and 380 glaucoma) of 442 participants were included. Eyes underwent 24-2, and 10-2 VF testing and OCT for ROTA. The borders of RNFL defects were delineated from ROTA, and the involvement of the arcuate, papillomacular, and papillofoveal bundles was determined for each eye. Multilevel logistic regression analysis was applied to evaluate the structure-function association. RESULTS: Papillomacular (92.1%) and papillofoveal (37.9%) RNFL bundle defects were prevalent in eyes with glaucoma. A 10-2 VF location that was projected onto a papillomacular or a papillofoveal RNFL bundle defect had a significantly increased likelihood of reduced sensitivity (ORs of 18.61 at PDP < 5%, and 20.17 at TDP < 5%, respectively, P < 0.001 for both). When predicting the likelihood of VF abnormality in a 10-2 test location, noticeably higher odds ratios were observed when overlapping with an RNFL bundle defect, compared to when an abnormal corresponding 24-2 central point was present. CONCLUSIONS: Papillomacular and papillofoveal RNFL bundle defects are present in a considerable proportion of eyes with glaucoma. When detected, they significantly increase the likelihood of abnormality in the corresponding central VF test locations assessed by the 10-2 test.

National Incidence, Outcomes, and Management Strategies for Pre- and Post-Transplant Atrial Fibrillation in Heart Transplant Recipients.

Background: Among heart transplant candidates, atrial fibrillation (AF) is a common comorbidity; however, little is known about the impact of pre-transplant AF on incidence of post-transplant AF or other transplant outcomes. Methods: Adult heart transplant recipients transplanted from 07/01/2012 to 07/01/2021 with data available in both the Scientific Registry of Transplant Recipients and Symphony Health pharmacy databases were included. Recipients were categorized by presence of pre-transplant AF using prescription fill data. Perioperative outcomes and survival out to 5 years post-transplant were compared between those with and without pre-transplant AF. Results: Of the 11,789 heart transplant recipients, 2,477 (21.0%) had pre-transplant AF. Pre-transplant AF was associated with an increased likelihood of pre-discharge stroke (aOR 2.13 [95%CI: 1.07-4.26], p=0.03) and dialysis (aOR 1.45 [1.05-2.00], p=0.02), as well as of post-transplant AF at 6 months (aOR 2.42 [1.44-1.48], p=0.001) and 1 year (aOR 2.81 [1.72-4.56], p<0.001). Pre-transplant AF was associated with increased post-transplant mortality at 30 days (aHR 2.39 [1.29-4.44], p=0.006) and 1 year (aHR 1.46 [95% CI: 1.01-2.13], p=0.04), but similar mortality at 5 years (aHR 1.23 [0.96-1.58], p=0.11). Conclusion: Heart transplant recipients with pre-transplant AF had worse short-term outcomes and increased risk of developing post-transplant AF but comparable survival at 5 years post-transplant. Our findings emphasize the importance of increased monitoring for perioperative complications and highlight the long-term safety of heart transplantation in this population. What Is New?: Patients with atrial fibrillation who undergo heart transplantation have worse short term survival (30-days and 1-year) but similar long term survival (5-years) compared to recipients without pre-transplant atrial fibrillation.Pre-transplant atrial fibrillation increases the risk of clinically significant post-transplant atrial fibrillation and peri-operative stroke.Rate vs rhythm control pharmacotherapy for atrial fibrillation is not associated with differences in survival in heart transplant recipients with pre-transplant atrial fibrillation. What are the Clinical Implications?: Atrial fibrillation should not deter heart transplantation in appropriate candidates, though cardiovascular and stroke risk adjustment may be warranted.Use of amiodarone at doses ≤ 200 mg/day is not associated with reduced survival in heart transplant recipients with pre-transplant atrial fibrillation.

Epidemiology and Treatment of Patients With Primary Open Angle Glaucoma in Germany: A Health Claims Data Analysis.

PRCIS: Based on a large administrative database of German claims data, our study provides current estimates of the prevalence and incidence of primary open-angle glaucoma (POAG) in Germany and describes selected outcomes for prevalent POAG patients. PURPOSE: To estimate the prevalence and incidence of POAG in Germany, to describe the patient population in terms of comorbidity burden, routine care, and overall healthcare resource utilization (HCRU) and associated costs, and to describe treatment patterns over time in patients undergoing relevant laser procedures. MATERIALS AND METHODS: Based on anonymized German claims data, we carried out a retrospective, non-interventional study covering calendar years 2016 to 2021. RESULTS: For the adult German population (≥18 y), we estimated a POAG one-year prevalence of 1.70% and a one-year incidence of 0.17% in 2018; both increased with age, peaking in 80-89 year-olds. Prevalence and incidence were lower in 2020 (1.65% and 0.16%, respectively), the first year of the SARS-CoV-2 pandemic. Most patients solely received topical treatment. Most surgically-treated patients underwent laser trabeculoplasty, followed by laser iridotomy, trabeculectomy, and filtration operations with implant. In patients undergoing laser trabeculoplasty, the treatment regimen was nearly unchanged in the second year after, compared to two years before the procedure. Multimorbidity was commonly observed; 75.5% of patients had arterial hypertension and 50.0% had disorders of lipoprotein metabolism and other lipidemias, compared to 60.1% and 39.2%, respectively, in an age- and sex-matched control sample. CONCLUSIONS: Our study provides insights into epidemiology and routine care of POAG in Germany and HCRU in prevalent patients. There was little change in treatment regimens in patients who underwent laser trabeculoplasty, two years after the procedure. Most patients were multimorbid highlighting the need for comprehensive care.

Endogenous Cellular Metabolite Methylglyoxal Induces DNA-Protein Cross-Links in Living Cells.

Methylglyoxal (MGO) is an electrophilic α-oxoaldehyde generated endogenously through metabolism of carbohydrates and exogenously due to autoxidation of sugars, degradation of lipids, and fermentation during food and drink processing. MGO can react with nucleophilic sites within proteins and DNA to form covalent adducts. MGO-induced advanced glycation end-products such as protein and DNA adducts are thought to be involved in oxidative stress, inflammation, diabetes, cancer, renal failure, and neurodegenerative diseases. Additionally, MGO has been hypothesized to form toxic DNA-protein cross-links (DPC), but the identities of proteins participating in such cross-linking in cells have not been determined. In the present work, we quantified DPC formation in human cells exposed to MGO and identified proteins trapped on DNA upon MGO exposure using mass spectrometry-based proteomics. A total of 265 proteins were found to participate in MGO-derived DPC formation including gene products engaged in telomere organization, nucleosome assembly, and gene expression. In vitro experiments confirmed DPC formation between DNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as well as histone proteins H3.1 and H4. Collectively, our study provides the first evidence for MGO-mediated DNA-protein cross-linking in living cells, prompting future studies regarding the relevance of these toxic lesions in cancer, diabetes, and other diseases linked to elevated MGO levels.

Paul Glaucoma Implant following Congenital Cataract Surgery in a Pediatric Cohort.

Background: The aim of this study was to evaluate the short-term efficacy and safety of the Paul Glaucoma Implant (PGI) in pediatric eyes diagnosed with glaucoma following congenital cataract surgery (GFCS). Methods: A retrospective, single-center, descriptive study was conducted on consecutive children diagnosed with GFCS who underwent PGI implantation between July 2022 and November 2023 at the University Medical Center Mainz. The primary outcome measure was the reduction in IOP at the last follow-up visit. Results: Ten eyes of nine children were included in the study. The mean follow-up time was 7.70 ± 4.22 months (4.68-10.72 months). At the end of the study follow-up, the mean (95% CI) reduction in IOP was -14.8 ± 8.73 mmHg (-8.56 to -21.04 mmHg, p < 0.001). At the last follow-up, 30.0% (3/10) of patients achieved an IOP (intraocular pressure) of ≥6 and ≤21 mmHg with a reduction in IOP of ≥25% without treatment, while 90.0% (9/10) achieved this target IOP regardless of glaucoma medication treatment. The mean number of antiglaucoma medications was significantly reduced from 3.50 (IQR = 1) to 2.0 (IQR = 2, p = 0.01), and the visual acuity logMAR improved from 1.26 ± 0.62 to 1.03 ± 0.48 (p = 0.04). Only one eye experienced numerical hypotony (4 mmHg) without choroidal detachment or anterior chamber shallowing within the first 24 h. No other adverse events were observed during the follow-up period. Conclusions: PGI implantation significantly lowered IOP and the number of antiglaucoma eye drops with a favorable safety profile in children diagnosed with GFCS, thereby achieving a high rate of qualified surgical success in the short term.

Directly visualizing individual polyorganophosphazenes and their single-chain complexes with proteins.

Polyorganophosphazenes are water-soluble macromolecules with immunoadjuvant activity that self-assemble with proteins to enable biological functionality. Direct imaging by cryogenic electron microscopy uncovers the coil structure of those highly charged macromolecules. The successful visualization of individual polymer chains within the vitrified state is achieved in the absence of additives for contrast enhancement and is attributed to the high mass contrast of the inorganic backbone. Upon assembly with proteins, multiple protein copies bind at the single polymer chain level resulting in structures reminiscent of compact spherical complexes or stiffened coils. The outcome depends on protein characteristics and cannot be deduced by commonly used characterization techniques, such as light scattering, thus revealing direct morphological insights crucial for understanding biological activity. Atomic force microscopy supports the morphology outcomes while advanced analytical techniques confirm protein-polymer binding. The chain visualization methodology provides tools for gaining insights into the processes of supramolecular assembly and mechanistic aspects of polymer enabled vaccine delivery.

Reduced cerebrospinal fluid motion in patients with Parkinson's disease revealed by magnetic resonance imaging with low b-value diffusion weighted imaging.

BACKGROUND: Parkinson's disease is characterized by dopamine-responsive symptoms as well as aggregation of α-synuclein protofibrils. New diagnostic methods assess α-synuclein aggregation characteristics from cerebrospinal fluid (CSF) and recent pathophysiologic mechanisms suggest that CSF circulation disruptions may precipitate α-synuclein retention. Here, diffusion-weighted MRI with low-to-intermediate diffusion-weightings was applied to test the hypothesis that CSF motion is reduced in Parkinson's disease relative to healthy participants. METHODS: Multi-shell diffusion weighted MRI (spatial resolution = 1.8 × 1.8 × 4.0 mm) with low-to-intermediate diffusion weightings (b-values = 0, 50, 100, 200, 300, 700, and 1000 s/mm2) was applied over the approximate kinetic range of suprasellar cistern fluid motion at 3 Tesla in Parkinson's disease (n = 27; age = 66 ± 6.7 years) and non-Parkinson's control (n = 32; age = 68 ± 8.9 years) participants. Wilcoxon rank-sum tests were applied to test the primary hypothesis that the noise floor-corrected decay rate of CSF signal as a function of b-value, which reflects increasing fluid motion, is reduced within the suprasellar cistern of persons with versus without Parkinson's disease and inversely relates to choroid plexus activity assessed from perfusion-weighted MRI (significance-criteria: p < 0.05). RESULTS: Consistent with the primary hypothesis, CSF decay rates were higher in healthy (D = 0.00673 ± 0.00213 mm2/s) relative to Parkinson's disease (D = 0.00517 ± 0.00110 mm2/s) participants. This finding was preserved after controlling for age and sex and was observed in the posterior region of the suprasellar cistern (p < 0.001). An inverse correlation between choroid plexus perfusion and decay rate in the voxels within the suprasellar cistern (Spearman's-r=-0.312; p = 0.019) was observed. CONCLUSIONS: Multi-shell diffusion MRI was applied to identify reduced CSF motion at the level of the suprasellar cistern in adults with versus without Parkinson's disease; the strengths and limitations of this methodology are discussed in the context of the growing literature on CSF flow.

The clinical and genetic spectrum of paediatric speech and language disorders in 52,143 individuals.

Speech and language disorders are known to have a substantial genetic contribution. Although frequently examined as components of other conditions, research on the genetic basis of linguistic differences as separate phenotypic subgroups has been limited so far. Here, we performed an in-depth characterization of speech and language disorders in 52,143 individuals, reconstructing clinical histories using a large-scale data mining approach of the Electronic Medical Records (EMR) from an entire large paediatric healthcare network. The reported frequency of these disorders was the highest between 2 and 5 years old and spanned a spectrum of twenty-six broad speech and language diagnoses. We used Natural Language Processing to assess to which degree clinical diagnosis in full-text notes were reflected in ICD-10 diagnosis codes. We found that aphasia and speech apraxia could be easily retrieved through ICD-10 diagnosis codes, while stuttering as a speech phenotype was only coded in 12% of individuals through appropriate ICD-10 codes. We found significant comorbidity of speech and language disorders in neurodevelopmental conditions (30.31%) and to a lesser degree with epilepsies (6.07%) and movement disorders (2.05%). The most common genetic disorders retrievable in our EMR analysis were STXBP1 (n=21), PTEN (n=20), and CACNA1A (n=18). When assessing associations of genetic diagnoses with specific linguistic phenotypes, we observed associations of STXBP1 and aphasia (P=8.57 × 10-7, CI=18.62-130.39) and MYO7A with speech and language development delay due to hearing loss (P=1.24 × 10-5, CI=17.46-Inf). Finally, in a sub-cohort of 726 individuals with whole exome sequencing data, we identified an enrichment of rare variants in synaptic protein and neuronal receptor pathways and associations of UQCRC1 with expressive aphasia and WASHC4 with abnormality of speech or vocalization. In summary, our study outlines the landscape of paediatric speech and language disorders, confirming the phenotypic complexity of linguistic traits and novel genotype-phenotype associations. Subgroups of paediatric speech and language disorders differ significantly with respect to the composition of monogenic aetiologies.