Heterogeneous Cohort Research Articles

Very low urinary marinobufagenin excretion reflects a high risk of disease progression in non-advanced CKD

BackgroundChronic kidney disease (CKD) has now reached pandemic proportions but risk prediction towards end-stage kidney disease (ESKD) remains challenging. Kidney fibrosis is a key determinant in the transition from CKD to ESKD. In this prospective study, we investigated the prognostic significance of urinary Marinobufagenin (uMBG), a cardiotonic steroid with acknowledged pro-fibrotic activity, for stratifying the risk of CKD progression in individuals with non-advanced renal disease.MethodsAfter baseline uMBG measurements, 108 CKD patients (eGFR 40.54 ± 17 mL/min/1.73 m2) were prospectively followed up to 24 months. The study (renal) endpoint was a composite of serum creatinine doubling, eGFR decline >25% from baseline values, or ESKD requiring chronic renal replacement therapy.ResultsDuring follow-up (mean 21 months), 32.4% of patients had progressive CKD. These individuals displayed almost halved baseline uMBG excretion as compared to others (p < 0.0001). At ROC analysis uMBG showed a remarkable diagnostic capacity on CKD progression (AUC 0.898) and patients with uMBG ≤310 pmol/L (Best ROC-derived cut-off) had a significantly faster progression to the endpoint (Log-rank 57.9; p < 0.0001). Restricted cubic splines fitting logistic and Cox-regression analyses revealed that the risk association between uMBG and CKD progression was best described by a curvilinear, inverse J-shaped trend, the highest risk associated with very low uMBG levels. This trend remained unaffected by adjustment for age, baseline eGFR, and 24 h-proteinuria.ConclusionIn individuals with non-advanced CKD, very low urinary excretion of MBG reflects a more sustained risk of CKD progression over time. Validation studies are needed to generalize these findings in larger heterogeneous cohorts.

Characteristics of older patients undergoing surgery in the UK: SNAP-3, a snapshot observational study.

Frailty and multimorbidity are common in older adults, but the prevalence and interaction of these conditions in surgical patients remain unclear. This study describes the clinical characteristics of a heterogeneous cohort of older UK surgical patients. We conducted a prospective observational cohort study during 5 days in March 2022, aiming to recruit all UK patients aged 60 yr and older undergoing surgery, excluding minor procedures (e.g. cataract surgery). Data were collected on patient characteristics, clinical care, frailty, and multimorbidity measures. A total of 7134 patients from 214 NHS hospitals were recruited, with a mean (sd) age of 72.8 (8.1) yr. Of all operations, 69% (95% confidence interval [CI] 67.9-70.1%) were elective, and 34% (95% CI 32.7-34.8%) were day cases. Of the patients, 19% (95% CI 18.3-20.1%) were living with frailty (Clinical Frailty Score ≥5), and 63.1% (95% CI 62.0-64.3%) were living with multimorbidity (count of ≥2 comorbidities). Those living with frailty, multimorbidity, or both were typically older, were from lower socioeconomic backgrounds, and experienced greater polypharmacy and reduced independence. Patients living with frailty were less likely to undergo elective and day-case surgeries. Four out of five (78.8% [1079/1369]) of those who were living with frailty were also living with multimorbidity; 27.1% (1079/3978) of those who were living with multimorbidity were also living with frailty. In the UK, one in five older patients undergoing surgery is living with frailty, and almost two-thirds of older patients are living with multimorbidity. These data highlight the importance of frailty screening. In addition, they can serve to guide resource allocation and provide comparative estimates for future research.

Non-Traumatic Intracranial Hemorrhage and Risk of Incident Dementia in U.S. Medicare Beneficiaries.

Background: To study the risk of incident dementia after a non-traumatic intracranial hemorrhage in a diverse US population, and evaluate if this risk is different for the subtypes of intracranial hemorrhage. Methods: We performed a retrospective cohort study using both inpatient and outpatient claims data on Medicare beneficiaries between January 1, 2008 and December 31, 2018. The exposure was a new diagnosis of non-traumatic intracranial hemorrhage, defined as a composite of intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and subdural hemorrhage (SDH). The outcome was a first-ever diagnosis of dementia. The exposure and outcomes were identified using validated ICD-9 and ICD-10-CM diagnosis codes. We excluded patients who had prevalent intracranial hemorrhage or dementia, to ensure that only incident cases were counted in our analyses. In the primary analysis, we used Cox regression to study the risk of dementia after intracranial hemorrhage, after adjusting for demographics and comorbidities. In secondary analyses, the risks of dementia in different subtypes of intracranial hemorrhage were studied. Results: Among 2.1 million patients, 14,775 had a diagnosis of intracranial hemorrhage. During a median follow up of 5.6 years (IQR, 3.0-9.1), incident dementia was diagnosed in 2527 (17.1%) patients with an intracranial hemorrhage and 260,691 (12.8%) in those without intracranial hemorrhage. The cumulative incidence rate of dementia was 8.6% (IQR, 8.1-8.9) among patients with an intracranial hemorrhage, and 2.2% (2.0-2.4) in patients without intracranial hemorrhage. In adjusted Cox regression analysis, intracranial hemorrhage was associated with an increased risk of incident dementia (HR, 2.0; CI, 1.9-2.2). In secondary analyses, a higher risk of incident dementia was observed with ICH (HR, 2.4; CI, 2.2-2.5), SAH (HR, 1.99; CI, 1.7-2.2), and SDH (HR, 1.6; CI, 1.4-1.7). Conclusion: In a large heterogeneous cohort of elderly US participants, intracranial hemorrhage was independently associated with a 2-fold increased risk of incident dementia. This elevated risk was consistently observed across subtypes of intracranial hemorrhage.

Simple exercise echocardiography parameters can enhance diagnosis of early heart failure with preserved ejection fraction (HFpEF)

Abstract Background Early heart failure with preserved ejection fraction (HFpEF) is characterised by exertional dyspnoea or intolerance. The non-specific nature of these symptoms and a lack of accurate diagnostic tools leave many undiagnosed and untreated. Whilst exercise right heart catheterisation is the recommended gold-standard, it is not widely available owing to technical challenges and its invasive nature. Exercise echocardiography offers a pragmatic compromise but its evidence-base in HFpEF diagnosis remains scarce, with significant variation in exercise protocols and assessment criteria. Purpose Using multimodality exercise imaging, the study aims to (1) correlate current recommended echocardiographic parameters at rest and exercise with functional capacity, symptom burden and adverse haemodynamic features (2) identify other echocardiographic parameters that interrogate mechanisms of exertional dyspnoea, thus improving early HFpEF diagnosis. Method Symptomatic patients with confirmed HFpEF or intermediate (INT) risk of HFpEF (as defined by the HFA-PEFF diagnostic algorithm) were prospectively enrolled alongside age-matched healthy control subjects. All participants underwent rest and 35W exercise echocardiography, exercise cardiac magnetic resonance imaging (e-CMR), 6-minute walk test (6MWT) and a Kansas City Cardiomyopathy Questionnaire (KCCQ-CSS). Results 46 HFpEF patients, 39 INT and 19 controls were recruited. The HFpEF and INT groups had similarly reduced functional capacity (6MWT HFpEF 363 vs. INT 384 vs. Control 492m) and worse patient-reported outcomes (KCCQ-CSS HFpEF 70 vs. INT 73 vs. Control 97) compared to age-matched controls. Despite more favourable serum NTproBNP, rest and stress E/e’ in the INT group, cardiac output augmentation during 35W exercise (ΔCI) on e-CMR was similarly blunted when compared to the HFpEF cohort (Table 1). Importantly, echocardiographic parameters in the current HFpEF diagnostic algorithm such as E/e’ and indexed left atrial volume (LAVI) do not correlate with 6MWT distance, KCCQ-CSS or ΔCI after adjusting for age, hypertension and body mass index (Figure A). Across this heterogeneous study cohort, rest and exercise LV septal S’ and RV S’ better correlated with 6MWT distance, KCCQ-CSS score and adverse haemodynamic features (ΔCI and right ventricular-pulmonary artery coupling) (Figures B-C). Conclusion Symptomatic patients at intermediate-risk of HFpEF share adverse haemodynamic features and functional impairment to those with diagnosed HFpEF. Using multimodality exercise imaging, we propose simple tissue doppler imaging parameters and assessment of cardiac reserve during exercise echocardiography better elicit mechanisms of exertional dyspnoea, beyond current recommendations. Further validation studies exploring these parameters are needed to advance the role of non-invasive imaging in early HFpEF diagnosis. Table 1 Figure 2

Multicenter validation of secondary hemophagocytic lymphohistiocytosis diagnostic criteria.

Five fulfilled hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, and the HScore are widely used and recommended by international expert consensus to diagnose secondary HLH. Both diagnostic scores have never been validated in heterogeneous patient cohorts of secondary HLH patients. We aimed to systematically optimize and validate diagnostic criteria of secondary HLH using a multicenter approach. We developed optimized criteria in our cohort of critically ill patients as a first step. We next validated these new criteria together with the original and modified HLH-2004 criteria as well as the HScore using original data of 13 published cohorts, which were identified by a systematic literature search. The best performing HLH diagnostic criteria sets over all 13 validation cohorts were the original HLH-2004 criteria with a decreased cut-off (cut-off 4, mean sensitivity 86.5%, mean specificity 86.1%), followed by the revised HLH-2004 criteria (natural killer cell activity removed; cut-off 4, mean sensitivity 83.8%, mean specificity 87.8%) and the HScore (cut-off 169, mean sensitivity 82.4%, mean specificity 87.6%). Our newly developed HLH diagnostic criteria showed inferior performance. Ferritin ≥500µg/L had 94.0% mean sensitivity over all cohorts. In this first multicenter validation study, four fulfilled HLH-2004 criteria and an HScore of 169 were suitable to diagnose secondary HLH, which will lead to rapid diagnosis and improved patient outcomes. Ferritin proved as a reliable HLH screening marker. Our results should be taken into account in clinical recommendations and in designing new studies.

"Synthetic" DSC Perfusion MRI with Adjustable Acquisition Parameters in Brain Tumors Using Dynamic Spin-and-Gradient-Echo Echoplanar Imaging.

Normalized relative cerebral blood volume (nrCBV) and percentage of signal recovery (PSR) computed from dynamic susceptibility contrast (DSC) perfusion imaging are useful biomarkers for differential diagnosis and treatment response assessment in brain tumors. However, their measurements are dependent on DSC acquisition factors, and CBV-optimized protocols technically differ from PSR-optimized protocols. This study aimed to generate "synthetic" DSC data with adjustable synthetic acquisition parameters using dual-echo gradient-echo (GE) DSC datasets extracted from dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI). Synthetic DSC was aimed at: 1) simultaneously create nrCBV and PSR maps using optimal sequence parameters, 2) compare DSC datasets with heterogeneous external cohorts, and 3) assess the impact of acquisition factors on DSC metrics. Thirty-eight patients with contrast-enhancing brain tumors were prospectively imaged with dynamic SAGE-EPI during a non-preloaded single-dose contrast injection and included in this cross-sectional study. Multiple synthetic DSC curves with desired pulse sequence parameters were generated using the Bloch equations applied to the dual-echo GE data extracted from dynamic SAGE-EPI datasets, with or without optional preload simulation. Dynamic SAGE-EPI allowed for simultaneous generation of CBV-optimized and PSR-optimized DSC datasets with a single contrast injection, while PSR computation from guideline-compliant CBV-optimized protocols resulted in rank variations within the cohort (Spearman's ρ = 0.83-0.89, i.e. 31%-21% rank variation). Treatment-naïve glioblastoma exhibited lower parameter-matched PSR compared to the external cohorts of treatment-naïve primary CNS lymphomas (PCNSL) (p<0.0001), supporting a role of synthetic DSC for multicenter comparisons. Acquisition factors highly impacted PSR, and nrCBV without leakage correction also showed parameter-dependence, although less pronounced. However, this dependence was remarkably mitigated by post-hoc leakage correction. Dynamic SAGE-EPI allows for simultaneous generation of CBV-optimized and PSR-optimized DSC data with one acquisition and a single contrast injection, facilitating the use of a single perfusion protocol for all DSC applications. This approach may also be useful for comparisons of perfusion metrics across heterogeneous multicenter datasets, as it facilitates post-hoc harmonization.

Matching Heterogeneous Cohorts by Projected Principal Components Reveals Two Novel Alzheimer's Disease-Associated Genes in the Hispanic Population.

Alzheimer's disease (AD) is the most common form of dementia in elderly, affecting 6.9 million individuals in the United States. Some studies have suggested the prevalence of AD is greater in individuals who self-identify as Hispanic. Focused results are relevant for personalized and equitable clinical interventions. Ethnicity as a stratifying tool in genetic studies is often accompanied by genomic inflation due to heterogeneity. In this study, we report GWAS and meta-analyses conducted among NIAGADS subjects who self-identified as Hispanic and All of Us (AoU) sub-cohorts matched to that cohort, using projected genetically-derived principal components, with and without age and sex. In Hispanic NIAGADS subjects, we identified a common variant in PIEZO2 that was protective for AD with a p-value just beyond genome-wide significance (p = 5.4 * 10 -8 ). Meta-analyses with genetically-matched AoU participants yielded three (two novel) genome-wide significant AD-associated loci based on rare lead variants: rs374043832 ( RGS6/PSEN1 ), rs192423465 ( ASPSCR1 ), and rs935208076 ( GDAP2 ), which were also nominally significant in AoU sub-cohorts. We also show how genomic inflation can be mitigated in heterogeneous populations while increasing sample size and result generalizability.

Novel, standardized sample collection from the brain-nose interface.

Diagnostics for neurodegenerative diseases lack non-invasive approaches suitable for early-stage biochemical screening and routine examination of neuropathology. Biomarkers of neurodegenerative diseases pass through the brain-nose interface (BNI) and accumulate in nasal secretion. Sample collection from the brain-nose interface presents a compelling prospect as basis for a non-invasive molecular diagnosis of neuropathologies. Here, we evaluated a novel medical device (nosecollect) that is tailored for the standardized collection of nasal secretion samples from BNI, focusing on its sample collection safety and efficiency. A class I medical device (nosecollect) was developed, to enable the standardized collection of nasal secretion exclusively from BNI in a user-friendly, safe, and comfortable manner. We performed a clinical study to test the collection device on a heterogenous cohort (n=923) at 8 study centers and evaluated its performance to collect sufficient sample volume from the targeted BNI area, its safety and tolerability. Samples were collected by trained medical personnel (medical doctors and nurses). Nosecollect gathered a mean volume of 452±317μl from the BNI. Successful positioning of the absorption material (AM) in the BNI was observed in 95% of the cases. Pain level/level of discomfort and occurrences of adverse events remained minimal (visual analogue scale (VAS)=1.97±1.99 (range 0-10), adverse events: 1%, no serious adverse events). Analysis of the nasal secretion sample identified detectable levels of CNS biomarkers in it. The precision and ergonomic design of nosecollect ensures a standardized, targeted and safe collection of non-diluted nasal secretion samples from BNI, thus outperforming traditional methods such as swabs, lavage etc which are not customized for accessing undiluted samples from BNI. In addition, the device offers a non-invasive and accessible approach for the acquisition of nasal secretion samples from BNI, signifying a crucial step in the future development of a BNI-based non-invasive diagnostic platform for neurodegenerative diseases.

Transfusion in trauma: empiric or guided therapy?

A state of the art lecture titled "Transfusion therapy in trauma-what to give? Empiric vs guided" was presented at the International Society on Thrombosis and Haemostasis Congress in 2024. Uncontrolled bleeding is the commonest preventable cause of death after traumatic injury. Hemostatic resuscitation is the foundation of contemporary transfusion practice for traumatic bleeding and has 2 main aims: to immediately support the circulating blood volume and to treat/prevent the associated trauma-induced coagulopathy. There are 2 broad types of hemostatic resuscitation strategy: empiric ratio-based therapy, often using red blood cells and fresh frozen plasma in a 1:1 ratio, and targeted therapy where the use of platelets, plasma, or fibrinogen is guided by laboratory or viscoelastic hemostatic tests. There are benefits, and limitations, to each strategy and neither approach has yet been shown to improve outcomes across all patient groups. Questions remain, and future directions for improving transfusion therapy are likely to require novel approaches that have greater flexibility to evaluate and treat heterogeneous trauma cohorts. Such approaches may include the integration of machine learning technologies in clinical systems, with real-time linkage of clinical and laboratory data, to aid early recognition of patients at the greatest risk of bleeding and to direct and individualize transfusion therapies. Greater mechanistic understanding of the underlying pathobiology of trauma-induced coagulopathy and the direct effects of common treatments on this process will be of equal importance to the development of new treatments. Finally, we summarize relevant new data on this topic presented at the 2024 ISTH Congress.

Stratified Medicine Paediatrics: Cell free DNA and serial tumour sequencing identifies subtype specific cancer evolution and epigenetic states.

We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.

SegcsvdWMH: A Convolutional Neural Network-Based Tool for Quantifying White Matter Hyperintensities in Heterogeneous Patient Cohorts.

White matter hyperintensities (WMH) of presumed vascular origin are a magnetic resonance imaging (MRI)-based biomarker of cerebral small vessel disease (CSVD). WMH are associated with cognitive decline and increased risk of stroke and dementia, and are commonly observed in aging, vascular cognitive impairment, and neurodegenerative diseases. The reliable and rapid measurement of WMH in large-scale multisite clinical studies with heterogeneous patient populations remains challenging, where the diversity of imaging characteristics across studies adds additional complexity to this task. We present segcsvdWMH, a convolutional neural network-based tool developed to provide reliable and accurate WMH quantification across diverse clinical datasets. segcsvdWMH was developed using a large dataset consisting of over 700 fluid-attenuated inversion recovery MRI scans from seven multisite studies, spanning a wide range of clinical populations, WMH burdens, and imaging protocols. Model training incorporated anatomical information through a novel hierarchical segmentation approach, together with extensive data augmentation techniques to improve performance across varied imaging conditions. Benchmarked against three widely available segmentation tools, segcsvdWMH demonstrated superior accuracy, achieving mean Dice score improvements of 7.8% ± 9.7% over HyperMapp3r, 21.8% ± 8.6% over SAMSEG, and 43.5% ± 7.1% over WMH-SynthSeg across four diverse test datasets. segcsvdWMH also maintained consistently high Dice scores across these test datasets (mean DSC = 0.86 ± 0.08), and exhibited strong, stable correlations with periventricular, deep, and total WMH ground truth volumes (mean r = 0.99 ± 0.01). Additionally, segcsvdWMH was robust to low and moderate levels of simulated MRI spike noise artifacts and maintained strong performance across a range of binary segmentation thresholds and WMH burden levels. These findings suggest that segcsvdWMH may provide more accurate and robust WMH segmentation performance for heterogeneous clinical datasets characterized by varying degrees of CSVD severity.

Strong diagnostic performance of plasma ptau217 for CSF biomarker-defined young-onset Alzheimer disease in a diagnostically heterogeneous clinical cohort.

We investigated diagnostic utility of phosphorylated tau 217 and 181 (ptau217, ptau181), glial fibrillary acidic protein (GFAP), amyloid beta 42 and 40 (Aβ42, Aβ40), and neurofilament light (NfL) to distinguish biomarker-defined Alzheimer disease (AD) from non-AD conditions, in a heterogenous clinical cohort of younger people. Plasma biomarkers were analysed using ultrasensitive technology, and compared in patients with CSF Alzheimer disease profiles (A+T+) to other CSF profiles (Other). Seventy-nine patients were included, median age 60.8years: 16 A+T+, 63 Other. Ptau217, ptau181, GFAP were significantly elevated in A+T+ compared to Other (3.67 vs 1.12pg/mL, 3.87 vs 1.79pg/mL, 189 vs 80pg/mL, respectively). ptau217 distinguished AD from Other with 90% accuracy (88% specificity, 100% sensitivity). ptau217 also demonstrated strong diagnostic performance for clinically diagnosed AD. Plasma ptau217 has strong diagnostic performance in distinguishing CSF biomarker-defined AD in a clinically relevant, younger cohort of people with symptoms, adding further weight for a simple diagnostic blood test for AD as a cause of a patient's symptoms.

The PAUL Glaucoma Implant in the management of uveitic glaucoma-3-year follow-up.

Evaluate the mid-term outcomes of the PAUL Glaucoma Implant (PGI) in the management of uveitic glaucoma. This was a single-centre, multi-surgeon, retrospective analysis of 50 consecutive cases of PGI for uveitic glaucoma performed between April 2019 and August 2021. Primary outcomes include: complete and qualified success (IOP ≥5 mmHg to ≤21 mmHg with ≥20% IOP reduction) or failure (IOP exceeding the success criteria, additional glaucoma procedures, no perception of light vision). Secondary outcomes included: visual acuity, IOP, medications, complications and intraluminal stent removal. We included 50 eyes of 41 patients. Mean age was 45.8 ± 19.8 years (range 6-81 years) in this heterogenous and complex cohort. Mean pre-op IOP was 30.6 ± 9.8 mmHg on 3.9 ± 0.9 medications. In total, 62% of patients were on acetazolamide, and 64% required systemic immunosuppression. At final follow-up (mean: 35.8 ± 9.8 months, range 5-58 months), IOP and medications were significantly reduced (12.2 ± 4.4 mmHg, requiring 1.1 ± 1.3 medications, p < 0.0001). Resulting in 48% complete and 92% qualified success rates. Failure occurred in 8% of cases, 6% due to hypertension but only one case of prolonged hypotony (2%). To date, this study represents the first publication looking specifically at the efficacy and safety of the PGI in the management of complex uveitic glaucoma. With an average follow-up of 3 years, it shows high levels of complete and qualified success with few complications.

Video game-based application for fall risk assessment: a proof-of-concept cohort study

Fall(s) are a significant cause of morbidity and mortality especially amongst elderly with polyneuropathy and cognitive decline. Conventional fall risk assessment tools are prone to low predictive values and do not address specific vulnerabilities. This study seeks to advance the development of an innovative, engaging fall prediction tool for a high-risk cohort diagnosed with diabetes. In this proof-of-concept cohort study, between July 01, 2020, and May 31, 2022, 152 participants with diabetes performed clinical examinations to estimate individual risks of fall (timed "up and go" (TUG) test, dynamic gait index (DGI), Berg-Balance-Scale (BBS)) and participated in a video game-based fall risk assessment with sensor-equipped insoles as steering units. The participants engaged in four distinct video games, each designed to address capabilities pertinent to prevent fall(s): skillfulness, reaction time, sensation, endurance, balance, and muscle strength. Data were collected during both, seated and standing gaming sessions. By data analyses using binary machine learning models a classification of participants was achieved and compared with actual fall events reported for the past 24 months. Overall 22 out of 152 participants (14.5%) underwent at least one episode of fall during the past 24 months. Adjusted risk classification accuracies of TUG, DGI, and BBS reached 58.7%, 58.3%, and 47.5%, respectively. Data analyses from gaming sessions in seated and standing positions yielded two models with six predictors from the four games with accuracies of 82.8% and 88.6% (area under the receiver-operating-characteristic curve 0.84 (95% confidence interval (CI): 0.77-0.91) and 0.91 (95% CI: 0.85-0.97), respectively). Key capabilities that were distinctly different between the groups related to endurance (0.6±0.1 vs. 0.5±0.2; p=0.03) and balance (0.7±0.2 vs. 0.6±0.2; p=0.05). The AI-driven analysis allowed to extract a list of game features that showed highly significant predictive values, e.g., reaction times in specific task, deviation from ideal steering routes in parcours and pressure-related parameters. Thus, video game-based assessment of fall risk surpasses traditional clinical assessment tools and scores (e.g., TUG, DGI, and BBS) and may open a novel resource for patient evaluation in the future. Further research with larger, heterogeneous cohorts is needed to validate these findings and especially predict future fall risk probabilities in clinical as well as outpatient settings. This project was funded by the Ministry of Science, Economics, and Digitalization of the State of Saxony-Anhalt and the European Fund for Regional Development under the Autonomy in Old Age Program (Funding No: ZS/2016/05/78615, ZS/2018/12/95325) and Healthy Cognition and Nerve function (HeyCoNer, ZS/2023/12/183088).

Voxel‐wise Florzolotau (APN‐1607) Tau PET Covariance Patterns in Alzheimer’s Disease and Progressive Supranuclear Palsy

AbstractBackgroundFlorzolotau (APN‐1607) tau‐PET has shown distinct patterns of binding in patients with AD and 4‐repeat tauopathies. We aimed to establish disease‐specific tau covariance patterns in AD and PSP/CBS and validate them as user‐independent quantitative biomarkers for reference‐region‐free evaluation of tau‐PET in an independent clinical cohort.MethodWe analyzed Florzolotau PET data from four different cohorts. The derivation dataset included 30 Aβ‐ healthy controls (HC) and 30 patients each with Aβ+ AD and PSP with Richardson’s syndrome (PSP‐RS). The validation dataset included 44, 51, 6, 15, and 17 patients with AD, PSP/CBS, MSA, LBD, and FTD, respectively. First, we applied scaled sub‐profile modelling principal components analysis to the derivation dataset to define the AD‐ and PSP‐RS‐related covariance patterns. Second, the topographic profile rating algorithm was applied to each scan to calculate AD‐ and PSP‐RS‐related pattern scores.ResultThe AD‐ and PSP‐RS‐related patterns are described in Figures 1 and 2. In the derivation dataset, the AD‐ and PSP‐RS‐scores showed strong increases compared to HC (both p&lt;0.001, AUC‐ROC=0.994 and 0.898, respectively). AD‐scores showed a significant negative association with age (r=‐0.66, p&lt;0.001) and MMSE (r=‐0.64, p&lt;0.001) in AD, while PSP‐RS‐scores correlated with the PSP rating scale (r=0.43, p=0.018) in PSP‐RS. In the validation dataset (Figure 3), AD‐scores were highest in AD (p&lt;0.001 vs. all other, AUC‐ROC[AD vs. all other]=0.946) and were negatively associated with age and MMSE in AD (r=‐0.62, p&lt;0.001 and r=‐0.49, p=0.002, respectively). PSP‐RS‐scores were highest in the PSP/CBS (p&lt;0.001 vs. all other [at least p&lt;0.05 vs. each group], AUC‐ROC[PSP/CBS vs. all other]=0.734), though also relatively increased in FTD and MSA. UPDRS‐III scores (off‐state) were available in 23 PSP/CBS patients and significantly associated with PSP‐RS‐scores (r=0.60, p=0.002).ConclusionModelling with principal components analysis allows for reference‐region‐free quantification of tau imaging data by constructing disease‐specific covariance patterns. When applied to Florzolotau, AD‐ and PSP‐RS‐related patterns showed high discrimination power in both the derivation and the clinically heterogeneous validation cohorts. PSP‐RS‐related pattern expression in FTD and MSA may be related to PSP pathology and known striatal off‐target binding, respectively. Strong association with respective disease severity scores further advocates for use of AD‐ and PSP‐RS‐related patterns as potential quantitative biomarkers of tau pathology.

Functional Connectivity of the Affective Blindsight Pathway in Atypical Alzheimer’s Disease

AbstractBackgroundAffective cognition and emotion processing is impaired in amnestic Alzheimer’s disease (AD), although less is known about atypical (AT) variants such as logopenic variant primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA). The affective blindsight pathway bypasses V1 via the superior colliculus‐pulvinar route to activate the amygdala in cases of occipital lesioning and may explain maintenance of emotion identification and visual information processing in non‐amnestic AD despite atrophy in visuospatial regions. We sought to characterize functional connectivity from key regions along the affective blindsight pathway in a clinically heterogeneous AD cohort.MethodWe collected structural, resting‐state, and task functional MRI scans where participants viewed affective face and neutral scene images, and neuropsychological data in individuals with clinically heterogeneous AD (8 lvPPA, 9 PCA) and age‐matched healthy controls (24 HC). We assessed connectivity from 4mm radius seeds located along the affective blindsight pathway (superior colliculus, medial pulvinar, and amygdala) using CONN toolbox. Two‐sample t‐tests were used to compute group‐level differences (AT &gt; HC; p &lt; 0.05/0.05), using w‐scores to correct for atrophy.ResultAs expected, AT participants performed significantly worse on visuospatial tasks outside the scanner (WAIS‐III Blocks Design, Benson Complex Figure Copy immediate recall; p &lt; 0.01). During resting state scans, the AT group had relatively lower connectivity to visuospatial regions including the lateral occipital cortex, angular gyrus, and precuneus from the superior colliculus and medial pulvinar seeds. During the scenes/faces task, they displayed relatively higher connectivity to those same visuospatial regions. From the amygdala seed, the AT group had higher connectivity to area V1 during the resting state scan and lower connectivity to frontal lobe regions during scenes/faces.ConclusionWe explored functional connectivity of the affective blindsight pathway in a clinically heterogeneous AD cohort. Connectivity was relatively higher in the AT group from the superior colliculus, medial pulvinar, and amygdala to occipital lobe regions commonly atrophied in PCA and lvPPA, suggesting a function of this pathway may be to compensate for disease‐related atrophy. While preliminary, these findings hint that the blindsight pathway may serve a compensatory function in atypical AD.

Prognostic role of extent of resection and adjuvant radiotherapy in de novo anaplastic meningiomas.

Grade 3 meningiomas, although rare, are associated with high morbidity and mortality. The respective impacts of extent of surgical resection and adjuvant radiotherapy are still debated. Moreover, anaplastic meningiomas are studied in heterogenous cohort of de novo and progressive anaplastic tumors. We conducted a retrospective multicentric study on patients operated from a de novo anaplastic meningioma between 1999 and 2021. A centralized pathological review using 2016 WHO criteria was performed for all cases. Patients with history of radiotherapy or NF2-related Schwannomatosis were excluded. Sixty-five patients were included in the study. Median progression free survival was 23months and median overall survival was 2years. Neither quality of resection nor adjuvant radiotherapy alone were predictive of better overall survival. Progression free survival were impacted by combination of gross-total resection and adjuvant radiotherapy (HR = 0.47 CI95% = [0.24-0.92], p = 0.027) and age at diagnosis (HR = 2.92 CI95% = [1.38-6.21], p = 0.005) in univariate analyses. Within anaplastic tumors, those graded on mitosis number had a poorer prognosis than those graded on overt anaplasia. Among anaplastic tumors with high mitotic score (> 20/10HPF), progression free survival were impacted by postoperative radiotherapy (HR = 0.44 CI95% = [0.22-0.88], p = 0.020) and gross total resection and adjuvant radiotherapy association (HR = 0.44 CI95% = [0.21-0.90], p = 0.024) in univariate analyses. Simpson grade didn't show any impact on overall survival. Gross total resection + adjuvant radiotherapy favorably impacted progression free survival in our cohort of de novo anaplastic meningiomas.

Empowering Managers to Adopt Multimethodological Intervention Strategies to Address Complex Problematic Situations

ABSTRACTMichael Jackson's early work on the development of the Systems of System Methodologies recognised that problem situations can be complex, across both decision‐makers and systems. Jackson later advocated for methodological complementarity in his works on critical systems thinking, suggesting that ‘hard’, ‘soft’ and ‘emancipatory’ approaches may all have a role to play depending on the complexities of a problem situation. We used Jackson's ideas to develop a post‐graduate systems thinking subject for managers at an Australian university. The constraints of delivering this learning experience within a 4‐day workshop to an increasingly heterogenous student cohort created forces of natural selection that drove an evolution in the format and content of the subject. In this paper, we will explain how the subject is currently being offered. We also illustrate how we used one instance of the subject to investigate a complex problem facing the Australian construction sector.

C-C motif chemokine ligand 14 characterization for prediction of persistent severe AKI in post-cardiac surgery children.

We evaluate the association of early postoperative urinary c-c motif chemokine ligand 14 (CCL14) and persistent severe acute kidney injury (AKI) in pediatric post-cardiac surgery patients. This is a retrospective single-center cohort study of patients < 18 years of age undergoing cardiac surgery who provided a biorepository urine sample within the first 24 postoperative hours. Persistent severe AKI was defined as any AKI stage lasting for ≥ 72 h with at least one time point of AKI stage 2 or 3 during that time frame. Patients with persistent severe AKI were matched 2:1 with non-AKI patients on age and sex. Urine samples were measured for CCL14 concentration. Logistic regression was used to evaluate associations between CCL14 and persistent severe AKI. Persistent severe AKI occurred in 14 (5.4%) patients and was more common in patients with higher surgical complexity and longer cardiopulmonary bypass and cross-clamp duration. Patients with persistent severe AKI had longer median cardiac intensive care unit (CICU) (5 [3, 10] vs. 2 [1.5, 5.5], p-value = 0.039) and hospital length of stays (13.5 [7.8, 16.8] vs. 6 [4,8], p-value = 0.009). There was no difference in CCL14 levels between patients with and without persistent severe AKI (46.7 pg/ml [31.0, 82.9] vs. 44.2 pg/ml [25.1, 74.9], p-value = 0.49) in univariable and logistic regression. In this heterogenous cohort of children undergoing cardiac surgery, CCL14 was not associated with persistent severe AKI. Future studies are needed to evaluate the use of CCL14 for predicting persistent severe AKI in children.

Is an earlier onset of focal epilepsy associated with atypical language lateralization? A systematic review, meta-analysis and new data.

Right and bilateral language representation is common in focal epilepsy, possibly reflecting the influence of epileptogenic lesions and/or seizure activity in the left hemisphere. Atypical language lateralization is assumed to be more likely in cases of early seizure onset, due to greater language plasticity in childhood. However, evidence for this association is mixed, with most research based on small samples and heterogenous cohorts. In this preregistered meta-analysis we examined the association between age at seizure onset and fMRI-derived language lateralization in individuals with focal epilepsy. The pooled effect size demonstrated a correlation between an earlier onset and rightward language lateralization in the total sample (r=0.1, p=.005, k=58, n=1240), with no difference in the correlation between left and right hemisphere epilepsy samples (Q=62.03, p=.302). In exploratory analyses of the individual participant data (n=1157), we demonstrated strong evidence that a logarithmic model fits the data better than a linear (BF=350) or categorical model with 6 years of age as a cut-off (BF=36). These findings indicate that there is a small but significant relationship between age at seizure onset and language lateralization. The relationship was consistent with theories of language plasticity proposing an exponential decline in plasticity over early childhood. However, given that this effect was subtle and only found in larger sample sizes, an early age at seizure onset would not serve as a good indicator of atypical language lateralization on the individual patient level.