Patterns Of Progression Research Articles

Autoencoder to Identify Sex-Specific Sub-phenotypes in Alzheimer's Disease Progression Using Longitudinal Electronic Health Records.

Alzheimer's Disease (AD) is a complex neurodegenerative disorder significantly influenced by sex differences, with approximately two-thirds of AD patients being women. Characterizing the sex-specific AD progression and identifying its progression trajectory is a crucial step to developing effective risk stratification and prevention strategies. In this study, we developed an autoencoder to uncover sex-specific sub-phenotypes in AD progression leveraging longitudinal electronic health record (EHR) data from OneFlorida+ Clinical Research Consortium. Specifically, we first constructed temporal patient representation using longitudinal EHRs from a sex-stratified AD cohort. We used a long short-term memory (LSTM)-based autoencoder to extract and generate latent representation embeddings from sequential clinical records of patients. We then applied hierarchical agglomerative clustering to the learned representations, grouping patients based on their progression sub-phenotypes. The experimental results show we successfully identified five primary sex-based AD sub-phenotypes with corresponding progression pathways with high confidence. These sex-specific sub-phenotypes not only illustrated distinct AD progression patterns but also revealed differences in clinical characteristics and comorbidities between females and males in AD development. These findings could provide valuable insights for advancing personalized AD intervention and treatment strategies.

A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes

Uric acid has been linked to various disease outcomes. However, it remains unclear whether uric acid-lowering therapy could be repurposed as a treatment for conditions other than gout. We first performed both observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to identify associations of uric acid levels with a wide range of disease outcomes. Then, trajectory analysis was conducted to explore temporal progression patterns of the observed disease outcomes. Finally, we investigated whether uric acid-lowering drugs could be repurposed using a factorial Mendelian randomization (MR) study design. A total of 41 overlapping phenotypes associated with uric acid levels were identified by both Obs- and PRS- PheWASs, primarily cardiometabolic diseases. The trajectory analysis illustrated how elevated uric acid levels contribute to cardiometabolic diseases, and finally death. Meanwhile, we found that uric acid-lowering drugs exerted a protective role in reducing the risk of coronary atherosclerosis (OR = 0.96, 95%CI: 0.93, 1.00, P = 0.049), congestive heart failure (OR = 0.64, 95%CI: 0.42, 0.99, P = 0.043), occlusion of cerebral arteries (OR = 0.93, 95%CI: 0.87, 1.00, P = 0.044) and peripheral vascular disease (OR = 0.60, 95%CI: 0.38, 0.94, P = 0.025). Furthermore, the combination of uric acid-lowering therapy (e.g. xanthine oxidase inhibitors) with antihypertensive treatment (e.g. calcium channel blockers) exerted additive effects and was associated with a 6%, 8%, 8%, 10% reduction in risk of coronary atherosclerosis, heart failure, occlusion of cerebral arteries and peripheral vascular disease, respectively. Our findings support a role of elevated uric acid levels in advancing cardiovascular dysfunction and identify potential repurposing opportunities for uric acid-lowering drugs in cardiovascular treatment.

Clinicopathological Appearance of Epidermal Growth-Factor-Containing Fibulin-like Extracellular Matrix Protein 1 Deposition in the Lower Gastrointestinal Tract: An Autopsy-Based Study.

This study examined the patterns of epidermal growth-factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) deposition in the small intestine and colon to evaluate the association between the histopathological severity of EFEMP1 deposition and constipation and determine the colocalization of amyloid transthyretin (ATTR) and EFEMP1 deposits. In 40 older cases (≥80 years of age), EFEMP1 deposition in the small intestine initiated in the submucosal and subserous vessels, subserous interstitium, and serosa (early stage), progressing to the muscularis propria and peri-Auerbach plexus area (intermediate stage), and finally spreading diffusely to other areas, excluding the mucosa and muscularis mucosa (advanced stage). The colon had a similar pattern of progression. During the middle-to-advanced stages, amyloid formation was observed in some vascular and serous deposits. A subgroup of cases was identified in which EFEMP1 deposition was the only presumed cause of constipation. Additionally, we demonstrated the colocalization of ATTR and EFEMP1 deposition. Apple-green birefringence was detected under polarized light only in approximately one-half of the cases in the small intestine and one-third of the cases in the colon. These findings strongly suggest that EFEMP1 deposits are correlated with pathological conditions of the lower gastrointestinal tract. As the histopathological diagnosis using Congo red-stained specimens is challenging, the combined use of elastic fiber staining and EFEMP1 immunohistochemistry is recommended to identify EFEMP1 deposition.

Identification of Parkinson’s disease PACE subtypes and repurposing treatments through integrative analyses of multimodal data

Parkinson’s disease (PD) is a serious neurodegenerative disorder marked by significant clinical and progression heterogeneity. This study aimed at addressing heterogeneity of PD through integrative analysis of various data modalities. We analyzed clinical progression data (≥5 years) of individuals with de novo PD using machine learning and deep learning, to characterize individuals’ phenotypic progression trajectories for PD subtyping. We discovered three pace subtypes of PD exhibiting distinct progression patterns: the Inching Pace subtype (PD-I) with mild baseline severity and mild progression speed; the Moderate Pace subtype (PD-M) with mild baseline severity but advancing at a moderate progression rate; and the Rapid Pace subtype (PD-R) with the most rapid symptom progression rate. We found cerebrospinal fluid P-tau/α-synuclein ratio and atrophy in certain brain regions as potential markers of these subtypes. Analyses of genetic and transcriptomic profiles with network-based approaches identified molecular modules associated with each subtype. For instance, the PD-R-specific module suggested STAT3, FYN, BECN1, APOA1, NEDD4, and GATA2 as potential driver genes of PD-R. It also suggested neuroinflammation, oxidative stress, metabolism, PI3K/AKT, and angiogenesis pathways as potential drivers for rapid PD progression (i.e., PD-R). Moreover, we identified repurposable drug candidates by targeting these subtype-specific molecular modules using network-based approach and cell line drug-gene signature data. We further estimated their treatment effects using two large-scale real-world patient databases; the real-world evidence we gained highlighted the potential of metformin in ameliorating PD progression. In conclusion, this work helps better understand clinical and pathophysiological complexity of PD progression and accelerate precision medicine.

Temporal stratification of amyotrophic lateral sclerosis patients using disease progression patterns

Identifying groups of patients with similar disease progression patterns is key to understand disease heterogeneity, guide clinical decisions and improve patient care. In this paper, we propose a data-driven temporal stratification approach, ClusTric, combining triclustering and hierarchical clustering. The proposed approach enables the discovery of complex disease progression patterns not found by univariate temporal analyses. As a case study, we use Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease with a non-linear and heterogeneous disease progression. In this context, we applied ClusTric to stratify a hospital-based population (Lisbon ALS Clinic dataset) and validate it in a clinical trial population. The results unravelled four clinically relevant disease progression groups: slow progressors, moderate bulbar and spinal progressors, and fast progressors. We compared ClusTric with a state-of-the-art method, showing its effectiveness in capturing the heterogeneity of ALS disease progression in a lower number of clinically relevant progression groups.

Midline structures and cortical development in late-onset fetal growth restriction according to Doppler status: prospective study.

Fetuses with late-onset growth restriction (FGR) have a higher risk of suboptimal neurocognitive performance after birth. Previous studies have reported that impaired brain and cortical development can start in utero. The primary aim of this study was to report midline structure growth and cortical development in fetuses with late-onset FGR according to its severity; the secondary aim was to elucidate whether the severity of FGR, as defined by the presence of abnormal Doppler findings, plays a role in affecting brain growth and maturation. This was a prospective observational study that included fetuses with late-onset FGR (defined according to the Delphi FGR criteria) undergoing neurosonography between 32 and 34 weeks' gestation. Midline structure (corpus callosum (CC) and cerebellar vermis (CV)) length and cortical development, including the depth of the Sylvian (SF), parieto-occipital (POF) and calcarine (CF) fissures, were compared between late-onset FGR, small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) fetuses. Subgroup analysis according to the severity of FGR (normal vs abnormal fetal Doppler) was also performed. Univariate analysis was used to analyze the data. A total of 52 late-onset FGR fetuses with normal Doppler findings, 60 late-onset FGR fetuses with abnormal Doppler findings, 64 SGA fetuses and 100 AGA fetuses were included in the analysis. When comparing AGA controls with SGA fetuses, late-onset FGR fetuses with normal Doppler findings and late-onset FGR fetuses with abnormal Doppler findings, there was a progressive and significant reduction in the absolute values of the following parameters: CC length (median (interquartile range (IQR)), 43.5 (28.9-56.1) mm vs 41.9 (27.8-51.8) mm vs 38.5 (29.1-50.5) mm vs 31.7 (23.8-40.2) mm; K = 26.68; P < 0.0001), SF depth (median (IQR), 14.5 (10.7-16.8) mm vs 12.7 (9.8-15.1) mm vs 11.9 (9.1-13.4) mm vs 8.3 (6.7-10.3) mm; K = 75.82; P < 0.0001), POF depth (median (IQR), 8.6 (6.3-11.1) mm vs 8.1 (5.6-10.4) mm vs 7.8 (6.1-9.3) mm vs 6.6 (4.2-8.0) mm; K = 45.06; P < 0.0001) and CF depth (median (IQR), 9.3 (6.7-11.5) mm vs 8.2 (5.7-10.7) mm vs 7.7 (5.2-9.4) mm vs 6.3 (4.5-7.2) mm; K = 46.14; P < 0.0001). Absolute CV length was significantly higher in AGA fetuses compared with all other groups, although the same progressive pattern was not noted (median (IQR), 24.9 (17.6-29.2) mm vs 21.6 (15.2-26.1) mm vs 19.1 (13.8-25.9) mm vs 21.0 (13.5-25.8) mm; K = 16.72; P = 0.0008). When the neurosonographic variables were corrected for fetal head circumference, a significant difference in the CC length and SF, POF and CF depths, but not CV length, was observed only in late-onset FGR fetuses with abnormal Doppler findings when compared with AGA and SGA fetuses. Fetuses with late-onset FGR had shorter CC length and delayed cortical development when compared with AGA fetuses. After controlling for fetal head circumference, these differences remained significant only in late-onset FGR fetuses with abnormal Doppler. These findings support the existence of a link between brain development and impaired placental function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

P-377 Understanding the interplay between multiple sclerosis patterns and ovarian reserve, which influences the other?

Abstract Study question Is multiple sclerosis (MS) associated with diminished ovarian reserve in women? Does ovarian reserve influence multiple sclerosis progression patterns? Summary answer AntiMüllerian Hormone (AMH) is not diminished in MS patients compared to healthy matched controls. Ovarian reserve predicts multiple sclerosis patterns independently from chronological age. What is known already Population registries indicate increased childlessness in individuals with MS, but the influence of MS on ovarian reserve and the need for fertility preservation counseling are topics of ongoing debate. Notably, MS research highlights the concept of immunosenescence: with age the disease shifts from high relapse rates to disability accumulation and fewer relapses. It is uncertain whether ovarian aging, assessed through AMH, could serve as a marker of immunosenescence, offering more precise predictions of MS patterns compared to chronological age alone. Study design, size, duration This prospective observational study enrolled all female MS patients aged 18 to 50 presenting to the neurology service between June and November 2023, matching them in a 1:2 ratio with controls of similar age and BMI. The controls were healthy females, without known causes of female infertility. Exclusion criteria were: postmenopausal state, prior neoplasm requiring gonadotoxic therapy or prior hematopoietic stem cell transplantation. Participants/materials, setting, methods The study was conducted in an academic hospital, regional referral for neurology and fertility preservation. Detailed neurological and gynecological anamnesis was collected for 73 patients and 146 controls. AMH measurements were performed by the same laboratory with the Roche Elecsys AMH system. Multiple generalized linear models were carried out to explore the correlation between AMH and neurological data. All results were adjusted for age and use of hormonal contraception. Bonferroni corrected post-hoc analyses were performed. Main results and the role of chance Cases and controls were matched for age (33.6±6.1 vs. 34.4±4.5 years) and BMI (22.3±3.4 vs. 22.2±3.5 Kg/m2). The AMH values were not significantly different between cases and controls (2.7±3.5 vs. 2.7±1.6 ng/ml, p = 0.7) and showed no correlation with MS duration (p = 0.3) and disability measured with EDSS score (p = 0.9). Interestingly, higher AMH levels correlated with both having relapsed in the prior year (yes: 4.9±5.3 vs. no: 1.7±1.6 p = 0.008) and with the number of relapses in the 2 previous years (zero: 1.9±1.8, one: 2.3±2.9, more than 2: 5.8±6.2 ng/ml, p = 0.02). Consequently, patients with “No Evidence of Disease Activity”(NEDA) in the previous year showed lower AMH levels (1.68±1.3 vs. 4.1±4.7 ng/ml, p = 0.01), since absence of relapses is one of the components to define NEDA. In summary, patients with higher ovarian reserve showed a MS pattern typical of young age (higher relapse rates) independently from the actual chronological age. Limitations, reasons for caution The results should be confirmed by larger/multicenter datasets, powered to properly assess the possible influence of the different disease modifying therapies. Further research is warranted to understand the biological link behind the observed results. Wider implications of the findings Ovarian aging, measured through AMH, may provide a better indicator of a patient’s biological age than chronological age only. This may help neurologists in predicting MS patterns and treating it accordingly, providing a unique perspective on the mechanisms that link immunosenescence to the ovarian reserve reduction. Trial registration number Not Applicable

Neurological Complications of COVID-19 Infection: A Comprehensive Review.

The COVID-19 pandemic is well on its way to reaching endemic status across the globe. While the medical community's understanding of the respiratory complications induced by COVID-19 is improving, there is still much to be learned about the neurological manifestations associated with COVID-19 infection. This review aimed to compile relevant, available evidence of COVID-19-induced neurological complications and to provide information for each complication regarding symptomology, progression patterns, demographic risk factors, treatment, and causative mechanism of action when available. Data for this review was collected using a confined search on PubMed using the keywords ["COVID-19" OR "SARS-CoV-2"] AND ["neurological complications" OR "olfactory symptoms" OR "gustatory symptoms" OR "myalgia" OR "headache" OR "dizziness" OR "stroke" OR "seizures" OR "meningoencephalitis" OR "cerebellar ataxia" OR "acute myelitis" OR "Guillain Barré Syndrome" OR "Miller Fisher Syndrome" OR "Posterior Reversible Encephalopathy Syndrome"] between 2019 and 2023. A wide range of neurological manifestations impact a significant percentage of COVID-19 patients, and a deeper understanding of these manifestations is necessary to ensure adequate management. The most common neurological complications identified consist of olfactory and gustatory dysfunctions, myalgia, headache, and dizziness, while the most severe complications include stroke, seizures, meningoencephalitis, Guillain-Barré syndrome, Miller Fisher syndrome, acute myelitis, and posterior reversible encephalopathy syndrome. While this review effectively provides a roadmap of the neurological risks posed to COVID-19 patients, further research is needed to clarify the precise incidence of these complications and to elucidate the mechanisms responsible for their manifestation.

Deep Learning‐Enabled Vasculometry Depicts Phased Lesion Patterns in High Myopia Progression

PurposeTo investigate the potential phases in myopic retinal vascular alterations for further elucidating the mechanisms underlying the progression of high myopia (HM). MethodsFor this retrospective study, participants diagnosed with high myopia at Beijing Tongren Hospital were recruited. Based on bionic mechanisms of human vision, an intelligent image processing model was developed and utilized to extract and quantify the morphological characteristics of retinal vasculatures in different regions measured by papilla-diameter (PD), including vascular caliber, arteriole-to-venule ratio (AVR), tortuosity, the angle of the vascular arch (AVA), the distance of the vascular arch (DVA), density, fractal dimension, and venular length. In addition, the optic disc and the area of peripapillary atrophy (PPA) were also quantified. The characteristics of the overall population, as well as patients aged less than 25 years old, were compared by different genders. Univariate and multiple linear regression analyses were conducted to investigate the correlation of retinal vasculature parameters with PPA width, and detailed trends of the vascular indicators were analyzed to explore the potential existence of staged morphological changes. FindingsThe study included 14,066 fundus photographs of 5775 patients (aged 41.2 ± 18.6 years), of whom 7379 (61.2 %) were female. The study included 12,067 fundus photographs of 5320 patients (aged 41.2 ± 18.6 years). Significant variations in the morphological parameters of retinal vessels were observed between males and females. After adjusting for age and sex, multiple linear regression analysis showed that an increased PPA width ratio was associated with lower AVA (1PD), DVA (1PD), vascular caliber (0.5–1.0 PD), tortuosity (0.5–1.0 PD), density and fractal dimension (all P < 0.001, Spearman’s ρ < 0). Overall, the changes in retinal vascular morphology showed two phases: tortuosity (0.5–1.0PD) and AVA (1PD) decreased rapidly in the first stage but significantly more slowly in the second stage, while vascular density and fractal dimension showed a completely opposite trend with an initial slow decline followed by a rapid decrease. ConclusionsThis study identified two distinct phases of retinal vascular morphological changes during the progression of HM. Traction lesions were predominant in the initial stage, while atrophic lesions were predominant in the later stage. These findings provide further insight into the development mechanism of HM from the perspective of retinal vasculature.

A three-dimensional CFD simulation of corium jet breakup in intensive vapor generation condition

The complexity of ex-vessel phenomena during a severe accident limits the most previous CFD applications only to hydrodynamic aspects. The present study performs numerical analysis of jet breakup and debris bed formation under intensive steam generation using the STAR-CCM + code. The CFD prediction of the MATE06 experiment demonstrates jet breakup progression patterns consistent to the experiment results. The predicted jet breakup lengths are in good agreement with the MATE 06 data in earlier stage. However, some disparities of the leading-edge position between the MATE 06 and the simulation are predicted in late stage. This is attributed to non-periodic repetitions of the detachment and reattachment of some fragmented segments to the jet column. The difference of frictional force or shear stress between the experiment and CFD simulation also causes uncertainty in the amount of steam generation. In overall, the present study becomes significant to simulate successfully the series of jet breakup process and debris bed formation under intensive steam generation condition. In future studies, it is required to upgrade the current model through more evaluation of experiments and to develop much sophisticated models which provide an enhanced realistic simulation of ex-vessel phenomena.

Damaged mortise–tenon joint strengthened using an assembled spring–steel hoop based on a design of similar rotational stiffness

The excessive enhancement of rotational stiffness leads to an uneven distribution of rotational stiffness across the entire timber frame. This uneven distribution concentrates the load effect on the strengthened mortise–tenon joints (MJs), causing localized failure in advance. To address this issue, a reversible and non-destructive strengthening method for the damaged MJs is devised, involving the utilization of an assembled spring-steel hoop. The rotational stiffness of a strengthened MJ is derived from the springs that link the steel hoop of the beam and column, resembling the rotational stiffness of an intact MJ. A comparison of the measured moment-rotation curves of various types of MJ reveals that the rotational stiffness similarity necessitates the strengthened MJ's yield moment and ultimate moment, along with the associated rotation angles, to closely resemble those of the intact MJ. Secondly, a design methodology is developed for the assembled spring-steel hoop, which involves determining the parameters of the connecting spring. The comparative analysis of the hysteretic test results on multiple strengthened and intact MJs indicates that the strengthened MJs exhibit rotational stiffness deviations of less than 12.2 % during the elasticity stage and 6.6 % during the plasticity stage, in comparison to the intact MJs. A spring exhibits a lower ultimate extension compared to timber, leading to a maximum discrepancy of 37.5 % in the ductility coefficients between the strengthened MJs and intact MJs. The strengthened and intact MJs display similar patterns of stiffness reduction and energy dissipation progression.

Identifying chronic kidney disease stage 3 with excess disease burden.

Chronic kidney disease (CKD) is a widely prevalent disease with heterogeneous disease progression. Prior study findings suggest that early referral to nephrologists can improve health outcomes for patients with CKD. Current practice guidelines recommend nephrology referral when patients are diagnosed with CKD stage 4. We tested whether a subset of patients with CKD stage 3 and common medical comorbidities demonstrates disease progression, cost, and utilization patterns that would merit earlier referral. Retrospective study of Medicare fee-for-service beneficiaries with CKD stages 3 through 5 and end-stage kidney disease. We identified 7 comorbidities with high prevalence in patients with progressive CKD and segmented beneficiaries with CKD stage 3 based on the presence of these comorbidities. Outcomes including costs, utilization, and disease progression were then compared across beneficiaries with different stages of CKD. We identified that beneficiaries with CKD stage 3 and at least 1 of the selected comorbidities (CKD stage 3-plus) represented 35.4% of all beneficiaries with CKD stage 3. The CKD stage 3-plus cohort had cost and utilization patterns that were more similar to beneficiaries with CKD stages 4 and 5 than to beneficiaries with CKD stage 3 without the selected comorbidities. Our findings demonstrate the use of a claims-based algorithm to identify patients with CKD stage 3 who have high costs and are at risk of disease progression, highlighting a potential subset of patients who might benefit from earlier nephrology intervention.

Proteomic Analysis of Tears as a Promising Method for Diagnosing Dry Eye Syndrome

One of the most common diseases of the organ of vision, characterized by a loss of homeostasis of the tear film, with a violation of the stability of the tear film and its hyperosmolarity, is the dry eye syndrome (DES). The article presents a review of modern scientific literature, reflecting the prevalence and main factors of the pathogenesis of DES, as well as evaluating the prospects for the use of proteomic mapping, which provides significant assistance in studying the patterns of development and progression of the disease. The methodological foundations of tear collection for research are considered in detail, and current data on changes in the biochemical composition of tear fluid in DES are analyzed.

Multimodal subtypes identified in Alzheimer's Disease Neuroimaging Initiative participants by missing-data-enabled subtype and stage inference.

Alzheimer's disease is a highly heterogeneous disease in which different biomarkers are dynamic over different windows of the decades-long pathophysiological processes, and potentially have distinct involvement in different subgroups. Subtype and Stage Inference is an unsupervised learning algorithm that disentangles the phenotypic heterogeneity and temporal progression of disease biomarkers, providing disease insight and quantitative estimates of individual subtype and stage. However, a key limitation of Subtype and Stage Inference is that it requires a complete set of biomarkers for each subject, reducing the number of datapoints available for model fitting and limiting applications of Subtype and Stage Inference to modalities that are widely collected, e.g. volumetric biomarkers derived from structural MRI. In this study, we adapted the Subtype and Stage Inference algorithm to handle missing data, enabling the application of Subtype and Stage Inference to multimodal data (magnetic resonance imaging, positron emission tomography, cerebrospinal fluid and cognitive tests) from 789 participants in the Alzheimer's Disease Neuroimaging Initiative. Missing-data Subtype and Stage Inference identified five subtypes having distinct progression patterns, which we describe by the earliest unique abnormality as 'Typical AD with Early Tau', 'Typical AD with Late Tau', 'Cortical', 'Cognitive' and 'Subcortical'. These new multimodal subtypes were differentially associated with age, years of education, Apolipoprotein E (APOE4) status, white matter hyperintensity burden and the rate of conversion from mild cognitive impairment to Alzheimer's disease, with the 'Cognitive' subtype showing the fastest clinical progression, and the 'Subcortical' subtype the slowest. Overall, we demonstrate that missing-data Subtype and Stage Inference reveals a finer landscape of Alzheimer's disease subtypes, each of which are associated with different risk factors. Missing-data Subtype and Stage Inference has broad utility, enabling the prediction of progression in a much wider set of individuals, rather than being restricted to those with complete data.

Repeated HyperArc radiosurgery for recurrent intracranial metastases and dosimetric analysis of recurrence pattern to account for diffuse dose effect on microscopical disease

AimsEvaluate effectiveness and safety of multiple HyperArc courses and patterns of progression in patients affected by BMs with intracranial progression. Methods56 patients were treated for 702 BMs with 197 (range 2–8) HyperArc courses in case of exclusive intracranial progression. Primary end-point was the overall survival (OS), secondary end-points were intracranial progression-free survival (iPFS), toxicity, local control (LC), neurological death (ND), and whole-brain RT (WBRT)-free survival. Site of progression was evaluated against isodoses levels (0, 1, 2, 3, 5, 7, 8, 10, 13, 15, 20, and 24 Gy.). ResultsThe 1-year OS was 70 %, and the median was 20.8 months (17–36). At the univariate analysis (UVA) biological equivalent dose (BED) > 51.3 Gy and non-melanoma histology significantly correlated with OS. The median time to iPFS was 4.9 months, and the 1-year iPFS was 15 %. Globally, 538 new BMs occurred after the first HA cycle in patients with extracranial disease controlled. 96.4 % of them occurred within the isodoses range 0–7 Gy as follows: 26.6 % (0 Gy), 16.5 % (1 Gy), 16.5 % (2 Gy), 20.1 % (3 Gy), 13.1 % (5 Gy), 3.4 % (7 Gy) (p = 0.00). Radionecrosis occurred in 2 metastases (0.28 %). No clinical toxicity of grade 3 or higher occurred during follow-up. One- and 2-year LC was 90 % and 79 %, respectively. At the UVA BED > 70 Gy and non-melanoma histology were significant predictors of higher LC. The 2-year WBRT-free survival was 70 %. After a median follow-up of 17.4 months, 12 patients deceased by ND. ConclusionIntracranical relapses can be safely and effectively treated with repeated HyperArc, with the aim to postpone or avoid WBRT. Diffuse dose by volumetric RT might reduce microscopic disease also at relatively low levels, potentially acting as a virtual CTV. Neurological death is not the most common cause of death in this population, which highlights the impact of extracranial disease on overall survival.

Spatiotemporal dynamics and influencing factors of CO2 emissions under regional collaboration: Evidence from the Beijing-Tianjin-Hebei region in China

Against the backdrop of global climate change and the “dual carbon” target, cities have a significant responsibility to achieve carbon reduction targets. As a crucial urban agglomeration in northern China, effectively balancing economic growth with CO2 emission reduction to achieve high-quality economic development remains a significant challenge that the Beijing-Tianjin-Hebei region should address both presently and in the future. The objective of this study is to utilize nighttime lighting data and energy consumption information to quantify the CO2 emissions of diverse cities within the Beijing-Tianjin-Hebei region spanning from 2006 to 2020. The research aims to analyze the spatial progression patterns of CO2 emissions across these urban centers, identify key determinants and their interrelations, and delve into the underlying mechanisms pivotal for advancing carbon mitigation strategies within urban agglomerations. The results indicate that: with an exception in Beijing where CO2 emissions slightly decreased compared to 2006, CO2 emissions increased across cities in the Beijing-Tianjin-Hebei region by 2020. High-value CO2 emission areas are primarily concentrated in central of the study area, exhibiting negative spatial correlation characteristics. Based on its urban development positioning, it is imperative for the Beijing-Tianjin-Hebei urban agglomeration to formulate and implement carbon reduction strategies on innovative development, industrial upgrading, and ecological protection among other aspects towards coordinated low-carbon development.

A multi-institutional series of a novel, recurrent TRIM24::MET fusion-driven infant-type hemispheric glioma reveals significant clinico-pathological heterogeneity

Within the past decade, incremental integration of molecular characteristics into the classification of central nervous system neoplasms increasingly facilitated precise diagnosis and advanced stratification, beyond potentially providing the foundation for advanced targeted therapies. We report a series of three cases of infant-type hemispheric glioma (IHG) involving three infants diagnosed with neuroepithelial tumors of the cerebral hemispheres harboring a novel, recurrent TRIM24::MET fusion. Histopathology showed glial tumors with either low-grade or high-grade characteristics, while molecular characterization found an additional homozygous CDKN2A/B deletion in two cases. Two patients showed leptomeningeal dissemination, while multiple supra- and infratentorial tumor manifestations were found in one case. Following subtotal resection (two cases) and biopsy (one case), treatment intensity of adjuvant chemotherapy regimens did not reflect in the progression patterns within the reported cases. Two patients showed progression after first-line treatment, of which one patient died not responding to tyrosine kinase inhibitor cabozantinib. As the detection of a recurrent TRIM24::MET fusion expands the spectrum of renowned driving fusion genes in IHG, this comparative illustration may indicate a distinct clinico-pathological heterogeneity of tumors bearing this driver alteration. Upfront clinical trials of IHG promoting further characterization and the implementation of individualized therapies involving receptor tyrosine kinase inhibition are required.

Progression patterns, resistant mechanisms and subsequent therapy for ALK-positive NSCLC in the era of second-generation ALK-TKIs

BackgroundIn the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and subsequent therapeutic approaches for ALK-positive (ALK+) non-small cell lung cancer (NSCLC).MethodsPatients with advanced ALK+ NSCLC were retrospectively selected from our center. Cohort 1 consisted of patients who experienced disease progression after receiving first-line alectinib treatment (n = 20), while Cohort 2 included patients who progressed following sequential treatment with crizotinib and second-generation ALK-TKIs (n = 53). Oligo-progression was defined as the occurrence of disease progression in no more than three lesions. Symptomatic progression was determined when patients developed new symptoms or experienced worsening of pre-existing symptoms during radiological progression.ResultsThe incidence of central nervous system (CNS) progression and symptomatic CNS progression was significantly lower in Cohort 1 compared to patients treated with crizotinib, with rates of 15.0% vs. 56.6% (p = 0.002) and 5.0% vs. 32.1% (p = 0.016), respectively. A total of 60.3% (44/73) patients underwent repeated biopsy and next-generation sequencing subsequent to the second-generation ALK-TKI resistance, with secondary mutation in ALK kinase domain emerging as the predominant mechanism of resistance (56.8%). Local therapy was applied to 50% of oligo-progression cases. Subsequent ALK-TKIs demonstrated significantly prolonged progression-free survival (PFS) (8.6 m vs. 2.7 m, p = 0.021, HR = 0.43, 95%CI: 0.15–0.85) and long-term overall survival (OS) (NA vs. 11.9 m, p = 0.132, HR = 0.50, 95%CI: 0.18–1.25) in patients harboring ALK resistance mutations, compared to those without such mutations. For patients without ALK-resistant mutations following progression on second-generation ALK-TKIs, there was no statistically significant difference in survival outcomes between subsequent chemotherapy or alternative ALK-TKI treatments.ConclusionsFirst-line alectinib demonstrated superior efficacy in protecting the CNS compared to crizotinib. For patients with ALK-resistant mutations following the resistance to second-generation ALK-TKIs, appropriate sensitive ALK-TKI should be administered; for those without such mutations, the selection of chemotherapy or third-generation ALK-TKI should be based on the patient’s overall physical health and personal preferences.

Nationwide Prevalence of Video Head Impulse Test Abnormality and its Risk Factors in South Korea.

To identify the prevalence of and relevant information for video head impulse test (vHIT) abnormality in a large population. A cross-sectional design. Korean National Health and Nutrition Examination Survey, 2021. The sample was representative of the Korean population, with 2237 participants aged ≥40 years. A vHIT was performed to evaluate vestibular function. The vestibulo-ocular reflex (VOR) gain and the presence of reproducible catch-up saccades was assessed in a vHIT. Participants also completed questionnaires for demographics, socioeconomic status, and basic information regarding systemic diseases and dizziness and underwent hearing tests with automated pure-tone audiometry. The prevalence of vHIT abnormality was 22.5%, with unilateral (14.3%) being more common than bilateral (8.2%). The prevalence of vHIT abnormality increased significantly with age, with the highest rate observed in individuals aged >70 years (42.5%). Both hearing and VOR gain deteriorated with age, but the patterns of age-related progression were different. While hearing loss (HL) deteriorated gradually and progressively throughout adulthood, VOR gain deterioration was markedly evident after 70 years of age. Considering the high prevalence of vHIT abnormality, appropriate social and medical policies are needed to prevent associated injuries and improve patients' quality of life. The distinct age-related changes in HL and objective findings of vestibular dysfunction indicate the need for different approaches to address these social problems in aging countries.

The influence of cross-border mobility on the COVID-19 epidemic in Nordic countries.

Restrictions of cross-border mobility are typically used to prevent an emerging disease from entering a country in order to slow down its spread. However, such interventions can come with a significant societal cost and should thus be based on careful analysis and quantitative understanding on their effects. To this end, we model the influence of cross-border mobility on the spread of COVID-19 during 2020 in the neighbouring Nordic countries of Denmark, Finland, Norway and Sweden. We investigate the immediate impact of cross-border travel on disease spread and employ counterfactual scenarios to explore the cumulative effects of introducing additional infected individuals into a population during the ongoing epidemic. Our results indicate that the effect of inter-country mobility on epidemic growth is non-negligible essentially when there is sizeable mobility from a high prevalence country or countries to a low prevalence one. Our findings underscore the critical importance of accurate data and models on both epidemic progression and travel patterns in informing decisions related to inter-country mobility restrictions.