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INTRODUCTION: Large vessel occlusion-acute ischemic stroke (LVO-AIS) is infrequent in young adults and exhibits distinct stroke mechanisms compared to older adults. This study sought to evaluate the impact of varying stroke etiologies on treatment-related outcomes in young adults with LVO-AIS, an aspect that remains unclear. METHODS: This retrospective cohort study included patients aged 18-50 presenting with AIS from January 2017 to December 2021 within our multi-center stroke network. Patients with LVO on CTA/MRA at presentation were included. We assessed demographics, stroke etiology (TOAST classification), and treatment-related outcomes. Based on intervention received, patients were divided into 5 groups [IV-thrombolysis (IVT) only, Mechanical Thrombectomy (MT) only, IVT+MT, no treatment, unsuccessful MT]. RESULTS: Among 1210 AIS patients, 220 with LVO were included. The median age was 42 (36, 46). 75 (34.1%) patients underwent successful MT (46.7% received IVT+MT). 26 (11.8%) received IVT only, 110 (50%) received neither intervention, and 9 (4.1%) underwent unsuccessful MT. Per TOAST, 17.4% had large artery atherosclerosis (LAA), 19.2% cardio-embolism, 28.6% stroke of other etiology, and 34.7% had undetermined etiology. Favorable thrombectomy outcomes (TICI 2b/2c/3) were observed in 87.2%. Discharge NIH Stroke Scale (NIHSS) scores improved for patients with IVT+MT in all TOAST categories except LAA. CONCLUSIONS: Young adults with LVO-AIS had good outcomes irrespective of stroke etiology, except LAA, which was associated with a higher discharge NIHSS. Moreover, 50% of young adults in our study received no intervention, a quarter of those owing to delayed presentation. Further studies are needed to identify barriers in seeking acute treatment in young adults with LVO-AIS.
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BACKGROUND: Intracranial compliance refers to the relationship between changes in volume and the resultant changes in intracranial pressure (ICP). This study aimed to assess the agreement of a noninvasive ICP waveform device for the estimation of compliance compared with invasive ICP monitoring employing three distinct methods. METHODS: We conducted a retrospective analysis of ICP waveform morphology recorded through both invasive (external ventricular drain) and noninvasive (mechanical extensometer) methods in adult patients with acute brain injury admitted to a neurointensive care unit between August 2021 and August 2022. Compliance was calculated as the amplitude of the fundamental component of cerebral arterial blood volume (estimated with concurrent Transcranial Doppler [TCD] recordings), divided by the amplitude of the fundamental component of the invasive and noninvasive ICP waveforms. Subsequently, we assessed the agreement between invasive and noninvasive intracranial compliance by repeated measures correlation coefficient analysis using three methods: TCD-derived, P2/P1 ratio, and time-to-peak (TTP). A linear mixed-effects model was used to compute the concordance correlation coefficient, total deviation index, and coefficient of individual agreement. Coverage probability plot was calculated to estimate the percent of observations within different cut points for each of the three methods. RESULTS: A total of 21 patients were identified for this study. Repeated measures correlation analysis showed a strong correlation (R = 0.982, 95% confidence interval [0.980-0.984], p < 0.0001) between log-transformed noninvasive and invasive compliance. Agreement statistics for TCD, P2/P1 ratio, and TTP indicated that although the concordance correlation coefficient was highest for log(TCD) values, TTP and P2:P1 ratio measures had better agreement with total deviation index and coverage probability plot analyses. CONCLUSIONS: Repeated measures correlations suggest that ICP waveform analyses may offer a more accurate estimate of compliance than TCD-derived methods for noninvasive ICP monitoring. Further validations studies are warranted to confidently establish this method as an indicator of intracranial compliance.
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SUMMARYInfective endocarditis (IE) is a life-threatening infection that has nearly doubled in prevalence over the last two decades due to the increase in implantable cardiac devices. Transcatheter aortic valve implantation (TAVI) is currently one of the most common cardiac procedures. TAVI usage continues to exponentially rise, inevitability increasing TAVI-IE. Patients with TAVI are frequently nonsurgical candidates, and TAVI-IE 1-year mortality rates can be as high as 74% without valve or bacterial biofilm removal. Enterococcus faecalis, a historically less common IE pathogen, is the primary cause of TAVI-IE. Treatment options are limited due to enterococcal intrinsic resistance and biofilm formation. Novel approaches are warranted to tackle current therapeutic gaps. We describe the existing challenges in treating TAVI-IE and how available treatment discovery approaches can be combined with an in silico "Living Heart" model to create solutions for the future.
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Although neurofilament light chain is a well-known marker of neuronal damage, its characterization at the proteoform level is underdeveloped. Here, we describe a new method to profile and quantify neurofilament light chain in plasma at the peptide level, using three in-house monoclonal antibodies targeting distinct protein domains and nano-liquid chromatography coupled to high-resolution tandem mass spectrometry. This study profiled and compared plasma neurofilament light chain to CSF in 102 older individuals (73.9 ± 6.3 years old), 37 of which had a clinical dementia rating greater than 0. We observed elevated neurofilament light chain in preclinical Alzheimer's disease plasma for two measures (NfL101 and NfL324) and CSF for seven measures (NfL92, NfL101, NfL117, NfL137, NfL148, NfL165 and NfL530). We found five plasma peptides (NfL92, NfL101, NfL117, NfL324 and NfL530) significantly associated with age and two (NfL148 and NfL324) with body mass index.
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Understanding the interplay of interaction and disorder in quantum transport poses long-standing scientific challenges for theory and experiment. While highly controlled ultracold atomic platforms combining atomic interactions with spatially disordered lattices have led to remarkable advances, the extension of such controlled studies to phenomena in high-dimensional disordered systems, such as the three-dimensional Anderson metal-insulator transition has been limited. Kicked quantum gases provide an alternate experimental platform that captures the Anderson model in momentum space and features dynamical localization as the analog of Anderson localization. Here, we utilize a momentum space lattice platform using quasiperiodically kicked ultracold atomic gases to experimentally investigate interaction effects on the three-dimensional dynamical Anderson metal-insulator transition. We observe interaction-driven subdiffusion and a divergence of delocalization onset time on approaching the phase boundary. Mean-field numerical simulations show qualitative agreement with experimental observations, but with significant quantitative deviations.
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PURPOSE: Seizures are a common clinical occurrence in high-grade glioma (HGG). While many studies have explored seizure incidence and prevalence in HGG, limited studies have examined the prognostic effect of seizures occurring in the post-diagnosis setting. This study aims to assess the impact of seizure presentation on HGG survival outcomes. METHODS: Single-center retrospective review identified 950 patients with histologically-confirmed high-grade glioma. Seizure presentation was determined by clinical history and classified as early onset (occurring within 30 days of HGG presentation) or late onset (first seizure occurring after beginning HGG treatment). The primary outcome, hazard ratios for overall survival and progression-free survival, was assessed with multivariable Cox proportional-hazards models. IDH1 mutation status (assessed through immunohistochemistry) was only consistently available beginning in 2015; subgroup analyses were performed in the subset of patients with known IDH1 status. RESULTS: Epileptic activity before (HR = 0.81, 95% CI = 0.68-0.96, P = 0.017) or after (HR = 0.74, 95% CI = 0.60-0.91, P = 0.005) HGG diagnosis associated with improved overall survival. Additionally, late seizure onset significantly associated with lower odds of achieving partial (OR = 0.25, 95% CI = 0.12-0.53, P = < 0.001) or complete (OR = 0.30, 95% CI = 0.18-0.50, P < 0.001) seizure control than patients with early seizure onset. CONCLUSIONS: Clinical seizures both at the time of diagnosis and later during the HGG treatment course are associated with improved overall survival. This association potentially persists for both IDH1-wildtype and IDH1-mutant patients, but further study is required.
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Thiosilvatins are a family of biologically active sulfenylated diketopiperazine natural products. The first members were reported over 40 years ago, but total synthesis of a thiosilvatin has remained elusive. Here, we describe the first, collective, synthesis of the parent epidithiodiketopiperazine (-)-dithiosilvatin and ten related thiosilvatins. Several of the targets are structurally revised. A catalytic asymmetric sulfenylation of triketopiperazines efficiently controls absolute configuration at the thioaminal units. Further synthetic highlights include a diastereoconvergent installation of the requisite cis-orientation of the sulfur atoms and a tandem epidisulfide formation/O-prenylation under mild Mitsunobu conditions. The described methods for late-stage diversification of sensitive bis(methylthio)diketopiperazines offer a blueprint for systematically exploring this interesting 3D-pharmacophore in stereochemically pure form.
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Background: The proposed research aims to test the effects and mechanisms of a six-month yoga-based intervention as an add-on to standard treatment in opioid use disorder (OUD) by conducting a randomized controlled study with the following primary outcome variables: 1) clinical: abstinence (opioid negative urine test), and reductions in pain and craving, and 2) mechanisms: reward circuit activation in response to opioid visual cue craving paradigm, activation in response to a cognitive control task, and resting state functional connectivity through fMRI, and plasma beta-endorphin levels. Secondary outcome variables are perceived stress, anxiety, sleep quality, cognitive performance, pain threshold, buprenorphine dosage and side effects, withdrawal symptoms, socio-occupational functioning, vedic personality traits, heart rate variability, serum cortisol, and brain GABA levels through magnetic resonance spectroscopy (MRS). Methods: In this single-blinded, randomized, controlled, parallel-group superiority trial with 1:1 allocation ratio, 164 patients with OUD availing the outpatient/ inpatient clinical services at a tertiary mental healthcare hospital in India will be enrolled after giving informed consent. Consecutive consenting patients will be randomly allotted to one of the two groups - yoga arm (standard treatment + yoga-based intervention), or waitlist group (standard treatment alone). Allocation concealment will be followed, the clinicians, outcome assessors and data analysts will remain blind to subject-group allocation. A validated and standardized yoga program for OUD will be used as an intervention. Participants in the yoga arm will receive 10 supervised in-person sessions of yoga in the initial two weeks followed by tele-yoga sessions thrice a week for the next 22 weeks. The wait-list control group will continue the standard treatment alone for 24 weeks. Assessments will be done at baseline, two weeks, 12 weeks, and 24 weeks. Data from all randomized subjects will be analysed using intent-to-treat analysis and mixed model multivariate analysis. Dissemination: Findings will be disseminated through peer-reviewed publication, conference presentations, and social media. Trial registration number: The trial has been registered under Clinical Trials Registry-India with registration number CTRI/2023/03/050737.
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BACKGROUND: While sleep disorders are implicated in atrial fibrillation (AF), the interplay of physiologic alterations and symptoms remains unclear. Sleep-based phenotypes can account for this complexity and translate to actionable approaches to identify at-risk patients and therapeutic interventions. OBJECTIVES: This study hypothesized discrete phenotypes of symptoms and polysomnography (PSG)-based data differ in relation to incident AF. METHODS: Data from the STARLIT (sleep Signals, Testing, And Reports LInked to patient Traits) registry on Cleveland Clinic patients (≥18 years of age) who underwent PSG from November 27, 2004, to December 30,2015, were retrospectively examined. Phenotypes were identified using latent class analysis of symptoms and PSG-based measures of sleep-disordered breathing and sleep architecture. Phenotypes were included as the primary predictor in a multivariable-adjusted Cox proportional hazard models for incident AF. RESULTS: In our cohort (N = 43,433, age 51.8 ± 14.5 years, 51.9% male, 74.9% White), 7.3% (n = 3,166) had baseline AF. Over a 7.6- ± 3.4-year follow-up period, 8.9% (n = 3,595) developed incident AF. Five phenotypes were identified. The hypoxia subtype (n = 3,245) had 48% increased incident AF (HR: 1.48; 95% CI: 1.34-1.64), the apneas + arousals subtype (n = 4,592) had 22% increased incident AF (HR: 1.22; 95% CI: 1.10-1.35), and the short sleep + nonrapid eye movement subtype (n = 6,126) had 11% increased incident AF (HR: 1.11; 95% CI: 1.01-1.22) compared with long sleep + rapid eye movement (n = 26,809), the reference group. The hypopneas subtype (n = 2,661) did not differ from reference (HR: 0.89; 95% CI: 0.77-1.03). CONCLUSIONS: Consistent with prior evidence supporting hypoxia as an AF driver and cardiac risk of the sleepy phenotype, this constellation of symptoms and physiologic alterations illustrates vulnerability for AF development, providing potential value in enhancing our understanding of integrated sleep-specific symptoms and physiologic risk of atrial arrhythmogenesis.
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Background: There is an urgent need for pharmacological treatment for cocaine (COC) use disorder (CUD). Glutamatergic transmission in the prefrontal cortex is affected by addictive behaviors. Clavulanic acid (CLAV), a glutamate transporter GLT-1 (excitatory amino acid transporter) activator, is a clinical-stage medication that has potential for treating CUD. Methods: In a pilot study, nine participants with CUD received 500 mg CLAV with dose escalations to 750 mg and 1000 mg over 10 days. In 5 separate magnetic resonance imaging (MRI) sessions, brain anterior cingulate cortex (ACC) glutamate level and resting state network (RSN) functional connectivity (FC) were assessed using MR spectroscopy and functional MRI. Craving was assessed at the same time points, between baseline (before CLAV), 6 days, and 10 days of CLAV. Independent component analysis with dual regression was used to identify RSN FC changes from baseline to Days 6 and 10. Relationships among glutamate, craving, and resting state FC values were analyzed. Results: Participants who achieved high ACC glutamate levels after CLAV treatment had robust decreases in COC craving (râ¯=â¯-0.90, Pâ¯=â¯0.0009, nâ¯=â¯9). The salience network (SN) and executive control network (ECN) demonstrated an association between increased FC after CLAV treatment and low baseline ACC Glu levels (SN CLAV 750 mg, râ¯=â¯-0.82, Pâ¯=â¯0.007) (ECN CLAV 1000 mg, râ¯=â¯-0.667, Pâ¯=â¯0.050; nâ¯=â¯9). Conclusions: Glutamate associated changes in craving and FC of the salience and executive control brain networks support CLAV as a potentially efficacious pharmacological treatment for CUD.
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Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarkers for reliable detection of Alzheimer's disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-ß (Aß)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests. Samples from 998 individuals (mean[range] age 68.5[20.0-92.5], 53% female) from the Swedish BioFINDER-2 cohort were analyzed. Plasma p-tau217 was measured with mass spectrometry (MS) assays (the ratio between phosphorylated and non-phosphorylated [%p-tau217WashU]and ptau217WashU) as well as with immunoassays (p-tau217Lilly, p-tau217Janssen, p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, and the FDA-approved p-tau181/Aß42Elecsys and p-tau181Elecsys. All plasma p-tau217 tests exhibited high ability to detect abnormal Aß-PET (AUC range: 0.91-0.96) and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (P diff<0.007). For detecting Aß-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 91% (immunoassays: 84-87%), and a specificity of 94% (immunoassays: 85-89%). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aß-PET status (P diff<0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (P diff=0.025). Plasma %p-tau217WashU exhibited higher associations with all PET load outcomes compared to immunoassays; baseline Aß-PET load (R2: 0.72; immunoassays: 0.47-0.58; Pdiff<0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38-0.45; Pdiff<0.001), longitudinal Aß-PET load (R2: 0.53; immunoassays: 0.31-0.38; Pdiff<0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35-0.43; Pdiff<0.014). Among immunoassays, plasma p-tau217Lilly was more strongly associated with Aß-PET load than plasma p-tau217Janssen (P diff<0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all P diff<0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination[MMSE]) than all immunoassays (R2 %p-tau217WashU: 0.33; immunoassays: 0.27-0.30; P diff<0.024). The main results were replicated in an external cohort from Washington University in St Louis (n =219). Finally, p-tau217Nulisa showed similar performance to other immunoassays in subsets of both cohorts. In summary, both MS- and immunoassay-based p-tau217 tests generally perform well in identifying Aß-PET, tau-PET, and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for AD pathology, while some immunoassays might be better suited as triage tests where positive results are confirmed with a second test.
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Importance: Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain ß-amyloid (Aß) levels who are at high risk of accumulating Aß. Objective: To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aß pathology in CU individuals with subthreshold brain Aß levels (defined as Aß levels <40 Centiloids) at baseline. Design, Setting, and Participants: This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aß42/40 assessments and Aß assessments with positron emission tomography (Aß-PET) or cerebrospinal fluid (CSF) Aß42/40. Data were analyzed between April 2023 and May 2024. Exposures: Baseline plasma levels of Aß42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Main Outcomes and Measures: Cross-sectional and longitudinal PET and CSF measures of brain Aß pathology. Results: This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aß-status, a combination of plasma %p-tau217 and Aß42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aß-PET, baseline plasma %p-tau217 and Aß42/40 levels were significantly associated with baseline Aß-PET (n = 384) and increases in Aß-PET over time (n = 224). Associations of plasma %p-tau217 and Aß42/40 and their interaction with baseline Aß-PET (%p-tau217: ß = 2.77; 95% CI, 1.84-3.70; Aß42/40: ß = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aß42/40: ß = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal Aß-PET (%p-tau217: ß = 0.67; 95% CI, 0.48-0.87; Aß42/40: ß = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aß42/40: ß = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aß42/40 were independently associated with longitudinal Aß-PET in Knight ADRC (%p-tau217: ß = 0.71; 95% CI, 0.26-1.16; P = .002; Aß42/40: ß = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF Aß42/40 in BioFINDER-1 (p-tau217: ß = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; Aß42/40: ß = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aß levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Conclusions and Relevance: Results of this cohort study suggest that combining plasma p-tau217and Aß42/40 levels could be useful for predicting development of Aß pathology in people with early stages of subthreshold Aß accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.
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Péptidos beta-Amiloides , Biomarcadores , Encéfalo , Fragmentos de Péptidos , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/metabolismo , Proteínas tau/sangre , Femenino , Masculino , Anciano , Biomarcadores/sangre , Estudios Longitudinales , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeo , Persona de Mediana Edad , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Fosforilación , Anciano de 80 o más Años , Disfunción Cognitiva/sangreRESUMEN
Gut motility undergoes a switch from myogenic to neurogenic control in late embryonic development. Here, we report on the electrical events that underlie this transition in the enteric nervous system, using the GCaMP6f reporter in neural crest cell derivatives. We found that spontaneous calcium activity is tetrodotoxin (TTX) resistant at stage E11.5, but not at E18.5. Motility at E18.5 was characterized by periodic, alternating high- and low-frequency contractions of the circular smooth muscle; this frequency modulation was inhibited by TTX. Calcium imaging at the neurogenic-motility stages E18.5-P3 showed that CaV1.2-positive neurons exhibited spontaneous calcium activity, which was inhibited by nicardipine and 2-aminoethoxydiphenyl borate (2-APB). Our protocol locally prevented muscle tone relaxation, arguing for a direct effect of nicardipine on enteric neurons, rather than indirectly by its relaxing effect on muscle. We demonstrated that the ENS was mechanosensitive from early stages on (E14.5) and that this behaviour was TTX and 2-APB resistant. We extended our results on L-type channel-dependent spontaneous activity and TTX-resistant mechanosensitivity to the adult colon. Our results shed light on the critical transition from myogenic to neurogenic motility in the developing gut, as well as on the intriguing pathways mediating electro-mechanical sensitivity in the enteric nervous system. HIGHLIGHTS: What is the central question of this study? What are the first neural electric events underlying the transition from myogenic to neurogenic motility in the developing gut, what channels do they depend on, and does the enteric nervous system already exhibit mechanosensitivity? What is the main finding and its importance? ENS calcium activity is sensitive to tetrodotoxin at stage E18.5 but not E11.5. Spontaneous electric activity at fetal and adult stages is crucially dependent on L-type calcium channels and IP3R receptors, and the enteric nervous system exhibits a tetrodotoxin-resistant mechanosensitive response. Abstract figure legend Tetrodotoxin-resistant Ca2+ rise induced by mechanical stimulation in the E18.5 mouse duodenum.
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Canales de Calcio Tipo L , Calcio , Sistema Nervioso Entérico , Motilidad Gastrointestinal , Neuronas , Tetrodotoxina , Animales , Canales de Calcio Tipo L/metabolismo , Tetrodotoxina/farmacología , Sistema Nervioso Entérico/efectos de los fármacos , Sistema Nervioso Entérico/metabolismo , Sistema Nervioso Entérico/fisiología , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Motilidad Gastrointestinal/efectos de los fármacos , Motilidad Gastrointestinal/fisiología , Calcio/metabolismo , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Músculo Liso/fisiología , Ratones Endogámicos C57BL , Bloqueadores de los Canales de Calcio/farmacología , Femenino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Nicardipino/farmacología , Compuestos de BoroRESUMEN
Tropical stream ecosystems are under increasing human pressure, making the development of effective restoration approaches and expanding knowledge in this field urgent. This study evaluated the impact of riparian vegetation restoration and environmental context on stream ecosystem functioning by measuring key ecosystem functions - gross primary production (GPP), ecosystem respiration (ER), and nutrient uptake of ammonium and soluble reactive phosphorus - across ten tropical streams in southeastern Brazil. The streams represented a gradient from clearcut areas (impacted reaches) to relatively pristine conditions (reference reaches), including intermediate stages of vegetation recovery (restored reaches). In the short-term (~15-20 years after restoration), restoration led to reduced GPP akin to reference reaches. Yet, ER did not show the anticipated increase, suggesting a longer timeframe is necessary for restored streams to emulate the functional characteristics of reference reaches. Additionally, the restored reaches did not achieve the nutrient uptake efficiencies observed in both impacted and reference reaches, pointing to a partial recovery of ecosystem function. This study suggests that while riparian vegetation restoration contributes positively to certain aspects of stream function, environmental variables less related to this type of restoration, such as discharge and hydromorphology, significantly influence stream ecosystem functioning, highlighting the importance of considering environmental context in restoration efforts. A more holistic approach, possibly encompassing broader hydromorphological and habitat enhancements, is needed to fully restore ecological processes in these vital ecosystems. These insights are critical for informing future tropical stream restoration projects, advocating the use of ecosystem function metrics as comprehensive indicators of ecological recovery and restoration success.
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Ecosistema , Monitoreo del Ambiente , Restauración y Remediación Ambiental , Ríos , Brasil , Restauración y Remediación Ambiental/métodos , Fósforo/análisis , Clima Tropical , Conservación de los Recursos Naturales/métodosRESUMEN
INTRODUCTION: Cerebrospinal fluid (CSF) tau phosphorylation at multiple sites is associated with cortical amyloid and other pathologic changes in Alzheimer's disease. These relationships can be non-linear. We used an artificial neural network to assess the ability of 10 different CSF tau phosphorylation sites to predict continuous amyloid positron emission tomography (PET) values. METHODS: CSF tau phosphorylation occupancies at 10 sites (including pT181/T181, pT217/T217, pT231/T231 and pT205/T205) were measured by mass spectrometry in 346 individuals (57 cognitively impaired, 289 cognitively unimpaired). We generated synthetic amyloid PET scans using biomarkers and evaluated their performance. RESULTS: Concentration of CSF pT217/T217 had low predictive error (average error: 13%), but also a low predictive range (ceiling 63 Centiloids). CSF pT231/T231 has slightly higher error (average error: 19%) but predicted through a greater range (87 Centiloids). DISCUSSION: Tradeoffs exist in biomarker selection. Some phosphorylation sites offer greater concordance with amyloid PET at lower levels, while others perform better over a greater range. HIGHLIGHTS: Novel pTau isoforms can predict cortical amyloid burden. pT217/T217 accurately predicts cortical amyloid burden in low-amyloid individuals. Traditional CSF biomarkers correspond with higher levels of amyloid.
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Health expenditure data almost always include extreme values, implying that the underlying distribution has heavy tails. This may result in infinite variances as well as higher-order moments and bias the commonly used least squares methods. To accommodate extreme values, we propose an estimation method that recovers the right tail of health expenditure distributions. It extends the popular two-part model to develop a novel three-part model. We apply the proposed method to claims data from one of the biggest German private health insurers. Our findings show that the estimated age gradient in health care spending differs substantially from the standard least squares method.
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Gastos en Salud , Gastos en Salud/estadística & datos numéricos , Humanos , Alemania , Adulto , Persona de Mediana Edad , Masculino , Femenino , Anciano , Modelos Estadísticos , Adulto Joven , Adolescente , Seguro de Salud/estadística & datos numéricos , Modelos Econométricos , Revisión de Utilización de Seguros , Factores de EdadRESUMEN
Neurofilament light chain is an established marker of neuroaxonal injury that is elevated in CSF and blood across various neurological diseases. It is increasingly used in clinical practice to aid diagnosis and monitor progression and as an outcome measure to assess safety and efficacy of disease-modifying therapies across the clinical translational neuroscience field. Quantitative methods for neurofilament light chain in human biofluids have relied on immunoassays, which have limited capacity to describe the structure of the protein in CSF and how this might vary in different neurodegenerative diseases. In this study, we characterized and quantified neurofilament light chain species in CSF across neurodegenerative and neuroinflammatory diseases and healthy controls using targeted mass spectrometry. We show that the quantitative immunoprecipitation-tandem mass spectrometry method developed in this study strongly correlates to single-molecule array measurements in CSF across the broad spectrum of neurodegenerative diseases and was replicable across mass spectrometry methods and centres. In summary, we have created an accurate and cost-effective assay for measuring a key biomarker in translational neuroscience research and clinical practice, which can be easily multiplexed and translated into clinical laboratories for the screening and monitoring of neurodegenerative disease or acute brain injury.
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We formulate a new conceptual approach for one-shot complete polarization state measurement with nanostructured metasurfaces applicable to classical light and multiphoton quantum states by drawing on the principles of generalized quantum measurements based on positive operator-valued measures. Accurate polarization reconstruction from a combination of photon counts or correlations from several diffraction orders is robust with respect to even strong fabrication inaccuracies, requiring only a single classical calibration of the metasurface transmission. Furthermore, this approach operates with a single metagrating without interleaving, allowing for a reduction in metasurface size while preserving high transmission efficiency and output beam quality. We theoretically obtained original metasurface designs, fabricated the metasurface from amorphous silicon nanostructures deposited on glass, and experimentally confirmed accurate polarization reconstruction of laser beams. We also anticipate robust operation under changes in environmental conditions, opening new possibilities for space-based imaging and satellite optics.
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Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aß42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0-5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aß-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials.