Patterns Of Progression Research Articles

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: From monoclonal gammopathy to newly diagnosed multiple myeloma

Osteocytes are mechanosensitive, bone-embedded cells which are connected via dendrites in a lacuno-canalicular network and regulate bone resorption and formation balance. Alterations in osteocyte lacunar volume, shape and density have been identified in conditions of aging, osteoporosis and osteolytic bone metastasis, indicating patterns of impaired bone remodeling, osteolysis and disease progression. Osteolytic bone disease is a hallmark of the hematologic malignancy multiple myeloma (MM), in which monoclonal plasma cells in the bone marrow disrupt the bone homeostasis and induce excessive resorption at local and distant sites. Qualitative and quantitative changes in the 3D osteocyte lacunar morphometry have not yet been evaluated in MM, nor in the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). In this study, we characterized the osteocyte lacunar morphology in trabecular bone of the iliac crest at the ultrastructural level using high resolution microCT in human bone biopsy samples of three MGUS, two SMM and six newly diagnosed MM. In MGUS, SMM and MM we found a trend for lower lacunar density and a shift towards larger lacunae with disease progression (higher 50 % cutoff of the lacunar volume cumulative distribution) in the small osteocyte lacunae 20–900 μm3 range compared to control samples. In the larger lacunae 900–3000 μm3 range, we detected significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae density, volume and shape, which could be an indicator for osteolysis and disease progression. Future studies are needed to understand whether alterations of the lacunae architecture affect the mechanoresponsiveness of osteocytes, and ultimately bone adaptation and fracture resistance in MM and its precursors conditions.

The Theme Progression Patterns in Popular Science Book Writing: A Systemic Functional Linguistics Approach

Despite the proliferation of digital mediums such as documentary series, video essays, and science podcasts, popular science books are still the primary medium for promoting science to the public as an epistemic way to understanding and being aware of our natural world. That said, in the domain of systemic functional linguistics, there exists a dearth of studies investigating popular science books. Hence, this study aims to investigate the organization of popular science discourse from the perspective of Theme Progression. A 93,078-word corpus was collected and divided into two main science categories: hard and soft—three disciplines under each main category and six texts under each discipline. The analysis of the corpus followed a mixed-method design where a Theme-counting excel sheet, created by the researcher, was used to calculate the most occurring Theme patterns. The results of the analysis indicate that the hard science disciplines give a logical presentation of the scientific text that intends to unpack and explain the intricacy behind the scientific notion whereas the soft science disciplines focus on expository narrative to connect and relate the scientific text to the target reader. Given these writing behaviors between the two science categories, it is recommended that future SFL studies explore the potentially arising differences within the broader aspect of the popular science genre, for instance, to juxtapose books from articles in the way discoursal features (e.g., coherence and cohesion) are structured in the text.

Evolution of Movement Disorders in Patients With CLN2-Batten Disease Treated With Enzyme Replacement Therapy.

Neuronal ceroid lipofuscinosis type 2 (CLN2-disease) is an inherited childhood-onset neurodegenerative condition, with classical early features of speech delay, epilepsy, myoclonus, ataxia, and motor regression. This study aimed to better characterize the spectrum of movement disorders in CLN2-disease in a cohort of children receiving enzyme replacement therapy (ERT). A cohort of 18 children attending a single center for treatment with cerliponase alfa ERT was systematically assessed using a standardized structured history and a double-scored, video-recorded examination using the Unified Batten Disease Rating Scale (UBDRS) and Abnormal Involuntary Movement Scale. Noncanonical movement disorders are common: while ataxia (89%) and myoclonus (83%) were near-universal, spasticity and dystonia were experienced by over half (61% each), with children having a median of 4 distinct movement disorder phenotypes. This progression was stereotyped with initial ataxia/myoclonus, then hyperkinesia/spasticity, and later hypokinesia. ERT slows progression of movement disorders, as measured by the UBDRS physical subscale, with 1.45 points-per-month progression before diagnosis and 0.44 points-per-month while on treatment (p = 0.019). Movement disorders are a core feature of CLN2-disease and follow a typical pattern of progression which is slowed by ERT. Identifying and treating movement disorders should become standard, especially given increased patient survival.

MRI-Derived Modeling of Disease Progression Patterns in Patients With Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is assumed to follow a steady course that is similar across patients. To date, phenotypic and temporal diversities of TLE evolution remain unknown. In this study, we aimed at simultaneously characterizing these sources of variability based on cross-sectional data. We studied consecutive patients with TLE referred for evaluation by neurologists to the Montreal Neurological Institute epilepsy clinic, who underwent in-patient video EEG monitoring and multimodal imaging at 3 Tesla, comprising 3D T1 and fluid-attenuated inversion recovery and 2D diffusion-weighted MRI. The cohort included patients with drug-resistant epilepsy and patients with drug-responsive epilepsy. The neuropsychological evaluation included Wechsler Adult Intelligence Scale-III and Leonard tapping task. The control group consisted of participants without TLE recruited through advertisement and who underwent the same MRI acquisition as patients. Based on surface-based analysis of key MRI markers of pathology (gray matter morphology and white matter microstructure), the Subtype and Stage Inference algorithm estimated subtypes and stages of brain pathology to which individual patients were assigned. The number of subtypes was determined by running the algorithm 100 times and estimating mean and SD of disease trajectories and the consistency of patients' assignments based on 1,000 bootstrap samples. Effect of normal aging was subtracted from patients. We examined associations with clinical and cognitive parameters and utility for individualized predictions. We studied 82 patients with TLE (52 female, mean age 35 ± 10 years; 11 drug-responsive) and 41 control participants (23 male, mean age 32 ± 8 years). Among 57 operated, 43/37/20 had Engel-I outcome/hippocampal sclerosis/hippocampal isolated gliosis, respectively. We identified 3 trajectory subtypes: S1 (n = 35), led by ipsilateral hippocampal atrophy and gliosis, followed by white-matter damage; S2 (n = 27), characterized by bilateral neocortical atrophy, followed by ipsilateral hippocampal atrophy and gliosis; and S3 (n = 20), typified by bilateral limbic white-matter damage, followed by bilateral hippocampal gliosis. Patients showed high assignability to their subtypes and stages (>90% bootstrap agreement). S1 had the highest proportions of patients with early disease onset (effect size d = 0.27 vs S2, d = 0.73 vs S3), febrile convulsions (χ2 = 3.70), drug resistance (χ2 = 2.94), a positive MRI (χ2 = 8.42), hippocampal sclerosis (χ2 = 7.57), and Engel-I outcome (χ2 = 1.51), pFDR < 0.05 across all comparisons. S2 and S3 exhibited the intermediate and lowest proportions, respectively. Verbal IQ and digit span were lower in S1 (d = 0.65 and d = 0.50, pFDR < 0.05) and S2 (d = 0.76 and d = 1.09, pFDR < 0.05), compared with S3. We observed progressive decline in sequential motor tapping in S1 and S3 (T = -3.38 and T = -4.94, pFDR = 0.027), compared with S2 (T = 2.14, pFDR = 0.035). S3 showed progressive decline in digit span (T = -5.83, p = 0.021). Supervised classifiers trained on subtype and stage outperformed subtype-only and stage-only models predicting drug response in 73% ± 1.0% (vs 70% ± 1.4% and 63% ± 1.3%) and 76% ± 1.6% for Engel-I outcome (vs 71% ± 0.8% and 72% ± 1.1%), pFDR < 0.05 across all comparisons. Cross-sectional MRI-derived models provide reliable prognostic markers of TLE disease evolution, which follows distinct trajectories, each associated with divergent patterns of hippocampal and whole-brain structural alterations, as well as cognitive and clinical profiles.

Генетически-фенотипический профиль детей с атипичным гемолитико-уремическим синдромом

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease caused by dysregulation of the alternative complement pathway as a result of mutations in complement genes or the formation of antibodies (AB) to some of the complement factors. Identification of the gene mutations incidence and the corresponding phenotypic features in pediatric patients with aHUS in Russia is aimed at improving the diagnosis and prognosis of the disease as well as treatment tactics planning for patient management. The purpose of this research was to determine the patterns of progression, prognosis and outcomes of aHUS in children depending on their genetic profile. Materials and methods used: the Article represents data from a retro- and prospective analyses of the characteristics of the course of aHUS in 172 children depending on their genetic profile performed in Jan. 2012-Feb. 2022. The sporadic form of aHUS was diagnosed after exclusion of the other forms of thrombotic microangiopathy (TMA), the familial form (in cases with the familial records), the acquired (CFH-Ab HUS) in cases with AB increase to factor H. AutoAb against factor H was determined by enzyme-linked immunosorbent assay (ELISA-VIDITEST anti-complement factor H). The search for mutations (n=167) was carried out using Next-generation Sequencing (NGS) and Sanger sequencing methods. Results: the sporadic form of aHUS was diagnosed in 96.9% of cases, familial in 3.1% and CFH-Ab HUS in 23.8%. The genetic nature of aHUS was confirmed in 53.4% of cases. Pathogenic mutations were detected in 8.6% of cases, probably pathogenic in 42.8% and those with unclear clinical significance in 46.8%. The complement genes mutations were detected in 88.5% of cases and mutations of genes not related to the complement system (ADAMTS13, DGKE, INF2) in 11.5%. The most frequently identified mutations were in the CFH (17.1%), C3 (12.9%) and CD46 (12.9%) genes and less frequently in CFI (7.1%), THBD (5.7%), CFHR5 (5.7%) and CFB (1.4%). In children with CFH-Ab HUS, the CFHR1/CFHR3 deletion was detected in 87.8% of cases, including in 19.4% in combination with mutations of unknown clinical significance. Multiple organ failure syndrome had developed in 77.8% of cases in children with pathogenic/probably pathogenic mutations, in 85.3% in patients with mutations of unknown clinical significance, in 91.8% in patients without mutations and in 83.3% in patients with CFHR1/CFHR3 deletion. Chronic kidney disease (CKD) stages 3 to 5 in sporadic/familial aHUS, regardless of genetic profile, had counted for 14.5% and 16.7% in CFH-Ab HUS. Lethal outcome occurred in 4.3% of cases in the presence of mutations, in 4.9% in the absence of mutations and in 2.8% in cases of CFHR1/CFHR3 deletion. Relapses of aHUS prior to the Eculizumab treatment had developed more often in the presence of CFHR1/CFHR3 mutations and deletion in comparison with children without mutations (31.4% v. 13.1%, p=0.0313 and 44.4% v. 13.1%, p= 0.004). Relapse of aHUS after discontinuation of the Eculizumab therapy had developed in 16.4% of cases. Risk factors for the relapse of aHUS were as follows: patient’s age above 12 months old at the time of the development of aHUS, severe arterial hypertension in the acute period, the use of Eculizumab at the fourth week after the onset of the disease and/or later, recurrent course of aHUS and the presence of CKD prior to the start of the Eculizumab therapy. Conclusion: The genetic profile of patients does not determine the severity and outcome of aHUS though it does affect the relapse rate. The prognosis and survival of patients with aHUS are determined by the severity of the acute period and the timeliness of the complement blocking therapy management.

Histopathological Patterns of Otosclerosis Progression: Exploring Otic Capsule and Round Window Involvement.

Obliteration of the round window (RW) in cases of otosclerosis presents a significant clinical challenge due to its association with more severe hearing loss and a poorer prognosis for functional recovery after stapes surgery. The objective is to assess and characterize the occurrence of RW involvement in otosclerosis cases and to identify patterns of disease progression that may indicate a potential for RW obliteration. We selected archival temporal bones from donors with otosclerosis. We evaluated the degree of RW obliteration using a semi-quantitative scale and the location of the foci within the temporal bone, and whether the foci were continuous or isolated. Most of the foci were located anteriorly to the oval window (89.2%), while RW area involvement was seen in 26.9% of the ears. In cases with fenestral foci, 68.1% directly involved and/or fixed the footplate. Among donors with bilateral otosclerosis, foci affected both ears in a similar pattern in 64.2%. Among donors with RW involvement, ones with continuous, large lesions that extended from the oval window associated with complete RW obliteration, while ones with smaller degrees of obliteration had solitary foci scattered within the otic capsule. Our results demonstrate a high rate of RW involvement in cases of otosclerosis. Ears with continuous lesions extending from the oval window region to the RW area were more likely to present with complete RW obliteration. These results provide insights that could lead to better prognostic assessment of patients with otosclerosis in the future. N/A Laryngoscope, 2024.

Micronutrient Dynamics in Soil under Integrated Thermochemical Organic Fertilizer Pellet Application

A soil incubation study was carried out in the Department of Soil Science and Agricultural Chemistry, to assess dynamics of micronutrient release. Soil pots were filled with 5 kg air-dried, 2 mm sieved soil. The study was laid in Completely Randomized Design with 5 treatments and 4 replications. Treatments were, T1: Pellet formulation 1; T2: Pellet formulation 2; T3: Pellet formulation 3; T4: FYM+NPK (RDF as per POP) and T5: Control (Soil alone). The Fe, Mn, Zn, Cu and B content of soil were 10.14 mg kg-1, 8.59 mg kg-1, 1.90 mg kg-1, 2.50 mg kg-1 and 0.30 mg kg-1, respectively. Three distinct pellet formulations P1, P2 &amp; P3 were used in study based on thermochemical organic fertilizer (TOF). Fe, Mn and Zn exhibited a gradual and progressive release pattern throughout the incubation period. Whereas Cu and B availability showed a decreasing trend from the 15th day onwards. Highest Fe, Mn and Zn availability were observed towards the end of the incubation study. While the Cu and B recorded highest on the initial 15th day of incubation. Hence it can conclude that TOF based pellets significantly impact the micronutrient availability in soil compared to the FYM based and control treatment.

Disease progression in chronic heart failure is linear: Insights from multistate modelling.

Understanding the pattern of disease progression in chronic heart failure (HF) may inform patient care and healthcare system design. We used a four-state Markov model to describe the disease trajectory of patients with HF. Consecutive patients (n = 4918) were enrolled (median age 75 [67-81] years, 61.3% men, 44% with HF and reduced ejection fraction). We generated a model by observing events during the first 2 years of follow-up. The model yielded surprisingly accurate predictions of how a population with HF will behave during subsequent years. As examples, the predicted transition probability from hospitalization to death was 0.11; the observed probabilities were 0.13, 0.14, and 0.16 at 3, 4, and 5 years, respectively. Similarly, the predicted transition intensity for rehospitalization was 0.35; the observed probabilities were 0.38, 0.34, and 0.35 at 3, 4, and 5 years, respectively. A multivariable model including covariates thought to influence outcome did not improve accuracy. Predicted average life expectancy was approximately 10 years for the unadjusted model and 13 years for the multivariable model, consistent with the observed mortality of 41% at 5 years. A multistate Markov chain model for patients with chronic HF suggests that the proportion of patients transitioning each year from a given state to another remains constant. This finding suggests that the course of HF at a population level is more linear than is commonly supposed and predictable based on current patient status.

Grapevine Pinot gris virus spreads in infected vineyards: latent infections have no direct impact on grape production

BackgroundGrapevine Pinot gris virus (GPGV) infects grapevines worldwide and causes symptoms such as chlorotic mottling and deformations on leaves, stunted shoots and short panicles, or none of these symptoms if it appears as latent infection. So far, the consequences of GPGV infections for winegrowers are difficult to assess since important information such as plant performance at different GPGV infection levels and symptom expression are not fully clarified.MethodsIn order to investigate the course of GPGV spread, annual visual evaluations and ELISA tests were conducted over 3–4 consecutive years in four GPGV-infected vineyards in southern Germany: GEM, HEC, NIM, and REI. The program PATCHY was used to analyze spatial disease patterns. Sanger sequencing was used to determine virus isolates in vines at different GPGV infection levels, to test their respective influence on symptom expression. Yield and GrapeScan (FTIR) analyses were conducted to test the impact of different GPGV infection levels and isolates on fruit quantity and quality.ResultsGPGV infections significantly increased in all four vineyards (GEM 22–32%, HEC 50–99%, NIM 83–90%, REI 56–76%) with significant spreading patterns across and along rows. Specific symptom progression patterns were not observed. According to our results, the virus isolate has an influence on whether symptoms develop during a GPGV infection. While yield analyses revealed that yield losses only occur in symptomatic vines and range from 13 to 96% depending on the severity of symptoms, latent infections have no impact on grape production. No relevant effects of GPGV infections on must quality were observed.ConclusionsSecondary spread of GPGV was observed in all vineyards monitored, indicating vector-borne transmission that is likely to be accelerated by human viticultural management. GPGV should be further monitored to prevent the accumulation of detrimental symptomatic isolates. The results of this study can be used to assess the risk of GPGV to viticulture and should be considered when developing management strategies against the virus.

Oral Leishmaniasis in HIV-Positive and HIV-Negative Patients: A Comparative Analysis with Two New Case Reports.

This case report examines the clinical presentation, diagnosis, treatment, and outcomes of mucocutaneous leishmaniasis with primary oral involvement in HIV-positive and HIV-negative patients diagnosed in Brazil. We discuss the clinical manifestations, diagnostic methods, and therapeutic strategies, highlighting the clinical and histopathologic diagnostic features and distinct progression patterns based on HIV status. Our findings are compared with patterns observed in other countries, emphasizing the differences between the Americas and Europe, Asia, and Africa. In the Americas, particularly in Brazil, mucocutaneous leishmaniasis often presents with localized oral lesions, even in the presence of systemic immunosuppression, whereas in the Europe, Asia, and Africa, oral involvement is typically associated with visceral leishmaniasis in immunocompromised patients. These differences were due to variations in the parasite species involved. This comparison underscores the importance of regional and immunological factors in diagnosing and managing this neglected infectious disease.

Shaking table test on progressive collapse of the double-layer cylindrical reticulated shell with infilled wall

Double-layer cylindrical reticulated shell has made rapid development in recent decades in China, which is widely used in the large-scale public buildings such as gymnasiums, airplane terminal, Shopping mall, etc. Stability and progressive collapse mechanism have been attracting a lot of attention because the large span space structure is largely affected by the geometry nonlinear, which makes it sensitive to the local damages. The infilled wall has a greater impact on the stiffness of the lower supporting structure due to sparse column grid. However, the influence of infilled walls on the collapse mechanism of large-span spatial structures is very complex due to the coupling of upper and lower structures. Therefore, the effects of infilled walls on double-layer cylindrical reticulated shell was investigated by a series of progressive collapse tests with shaking table. In order to evaluate the seismic performance and the capacity of resisting progressive collapse, the structural dynamic characteristics and response laws were obtained under different ground motions and input principal directions. The results indicated that the existence of infilled wall made the coupling between the lower supporting structure and the upper roof structure more complicated. The infilled walls influenced the structural damage evolution and development, mitigated the damage from the earthquake and changed the progressive collapse pattern, which made the catenary collapse mechanism occur when the structure collapsed. Although the further quantitative study is still needed, this paper provides lots of useful test data and conclusions, which gives references to the infilled wall design and seismic performance evaluation for double-layer cylindrical reticulated shell.

Comparison of the Long-term Survival Outcome of Surgery versus Stereotactic Body Radiation Therapy as Initial Local Treatment for Pulmonary Oligometastases from Colorectal Cancer: A Propensity Score Analysis

PurposeOptimal local treatment for pulmonary oligometastases from colorectal cancer (CRC) remains unclear. We aimed to compare the long-term survival outcomes between surgery and stereotactic body radiotherapy (SBRT) as the initial local treatment for CRC pulmonary oligometastases. Materials and MethodsWe retrospectively reviewed 335 consecutive patients who initially underwent surgery or SBRT for CRC pulmonary metastases from 2011 to 2022, and 251 patients (173 surgery and 78 SBRT) were ultimately included. Freedom from intrathoracic progression (FFIP), progression-free survival (PFS), and overall survival (OS) were compared using stabilized inverse probability of treatment weighting (sIPTW) analysis. In addition, patterns of intrathoracic progression and subsequent treatment were analyzed. ResultsMedian follow-up was 61.6 months for surgery and 54.4 months for SBRT. After sIPTW adjustment, significant differences emerged in both FFIP and PFS between surgery and SBRT (FFIP: hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.31–0.79; PFS: HR = 0.56, 95% CI, 0.36–0.87). The 3- and 5-year FFIP rates were 58.6% and 54.8%, respectively, after surgery, and 34.6% and 31.3%, respectively, after SBRT (P = 0.006). The 3- and 5-year PFS rates were 49.4% and 45.2%, respectively, after surgery, and 28.8% and 26.1%, respectively, after SBRT (P = 0.010). However, OS was not significantly affected by treatment approach (HR = 0.93, 95% CI, 0.49–1.76). The 3- and 5-year OS rates were 85.9% and 73.1%, respectively, after surgery, and 78.9% and 68.7%, respectively, after SBRT (P = 0.849). Recurrence at the treated site was more prevalent after SBRT than after surgery (33.3% vs. 16.9%), whereas new intrathoracic tumors occurred more frequently after surgery than after SBRT (71.8% vs. 43.1%). Both groups chose radiotherapy as the primary local salvage treatment. ConclusionsNotwithstanding the significant differences in FFIP and PFS between surgery and SBRT, the long-term survival of patients with CRC pulmonary oligometastases did not depend on the initial choice of the local treatment approach.

Patterns of lymph node involvement for oral cavity squamous cell carcinoma

AimWhereas the prevalence of lymph node level (LNL) involvement in oral cavity squamous cell carcinomas (OCSCC) has been reported, the details of lymphatic progression patterns are insufficiently quantified. We investigate how the risk of metastases in each LNL depends on the involvement of adjacent LNLs, T-category, subsite, primary tumor lateralization, and other risk factors. MethodsWe retrospectively analyzed patients with newly diagnosed OCSCC from two institutions, totaling 348 patients. Involvement of LNLs I-V was recorded individually based on pathology after neck dissection with clinicopathological factors. The dataset is publicly available in a previously developed web-app, which allows querying patients with specific combinations of co-involved LNLs and tumor characteristics. ResultsIpsilateral involvement prevalence of levels I-III was higher for advanced T-category (T3/T4) patients (32 %, 38 %, 14 %) compared to early (T1/T2) patients (14 %, 23 %, 11 %). Involvement of level I increased the involvement probability in levels II and III. Similarly, involvement of level II increased the involvement probability in levels I and III. However, there was significant isolated involvement of level I or II. Advanced nodal involvement (>1 LNL involved) was more frequent for patients with extracapsular extension. Overall contralateral involvement in levels I-III was 7 %, 4 %, 3 % and more frequent for more advanced ipsilateral involvement and for midline-crossing tumors. Involvement of levels IV and V was rare: 3 % ipsilateral and 1 % contralateral in both levels. ConclusionsDetailed quantification of LNL involvement in OCSCC depending on involvement of adjacent LNLs and clinicopathological factors may allow further personalizing guidelines on elective nodal treatment.

"If you cannot measure it, you cannot improve it". Outcome measures in Duchenne Muscular Dystrophy: current and future perspectives.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder primarily affecting males, caused by mutations in the dystrophin gene. The absence of dystrophin protein leads to progressive skeletal muscle degeneration. Recent advances in the therapeutic landscape underscore the need to identify appropriate outcome measures to assess treatment efficacy in ambulant and non-ambulant DMD patients, across clinical and research settings. This is essential for accurately evaluating new treatments and attributing therapeutic benefits.It is crucial to establish a robust correlation between outcome scores and disease progression patterns. This task is challenging since functional test performance may be influenced by different patient's characteristics, including the physiological evolution of the neurodevelopment together with the disease progression. While widely used DMD outcomes such as the North Star Ambulatory Assessment, the 6-Minute Walking Test, the 4 stairs climbed, and the Performance of the Upper Limb exhibit reliability and validity, their clinical significance is influenced by the wide phenotype and progression variability of the disease.We present and discuss the features (relevance, quantifiability, validity, objectivity, reliability, sensitivity, specificity, precision) of available DMD outcome measures, including new potential measures that may be provided by digital tools and artificial intelligence.

Earth’s metamorphic secular evolution accessed by rutile

Rutile provides crucial insights into the evolution of plate tectonics and variations in tectonomagmatic modes over Earth’s history primarily because rutile predominantly tracks higher-pressure metamorphism (>1.0–1.2 GPa). Comparison of rutile age and compositional data with diverse proxies tracks the presence of low temperature/pressure (T/P) metamorphic conditions, enabling the tracing of plate tectonics onset and evolution. We present a new compilation of rutile U-Pb ages that lag zircon ages by approximately 50 Myr, potentially indicating cooling ages of metamorphic belts. The earliest rutile age peak (ca. 1.8 Ga) aligns with the oldest evidence for low T/P metamorphic conditions. This coincides with a shift in the T/P distribution of rutile whereas the T/P of Archean rutile forms a tight normal distribution. In the Paleoproterozoic, the rutile T/P distribution is skewed to lower T/P, following the broader pattern of the full metamorphic record. The degree of lower T/P skew increases through time until the lower T/P population dominates the rutile record from the Neoproterozoic to the present. These data further highlight shifts in dominant metamorphic modes that can be tied to the evolution of the tectonic system, with early Archean metamorphism being associated with plume-driven vertical tectonics or hot, shallow subduction and post-Archean metamorphism being associated with progressive less plume-driven vertical tectonics and colder, steeper subduction. Although the frequency of rutile is lower during the Mesoproterozoic, the rutile T/P during this time follows the progressive skewing pattern from the Paleoproterozoic to the present and is likely inconsistent with a phase of interrupted tectonics characterized by stagnant lid.

Spatiotemporal Progression Patterns of Dopamine Availability and Deep Gray Matter Volume in Parkinson Disease-Related Cognitive Impairment.

Cognitive impairment is a frequent nonmotor symptom in patients with Parkinson disease (PD), and early cognitive decline is often attributed to dopaminergic system dysfunction. We aimed to explore spatiotemporal progression patterns of striatal dopamine availability and regional brain volume based on cognitive status among patients with PD. This retrospective, cross-sectional study included patients with newly diagnosed PD who were not taking medication for this condition who visited a university-affiliated hospital in Seoul between January 2018 and December 2020. Patients were classified as having normal cognition (PD-NC), mild cognitive impairment (PD-MCI), or PD dementia (PDD) based on Seoul Neuropsychological Screening Battery-II, which includes 31 subsets covering activities of daily living and 5 cognitive domains. They all had brain imaging with MRI and PET with 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane at baseline. Subsequently, standardized uptake value ratios (SUVRs) for regional dopamine availability and regional gray matter volumes were obtained using automated segmentation. These metrics were compared across cognitive status groups, and spatiotemporal progression patterns were analyzed using the Subtype and Stage Inference machine learning technique. Among 168 patients (mean age, 73.3 ± 6.1 years; 81 [48.2%] women), 65 had PD-NC, 65 had PD-MCI, and 38 had PDD. Patients with PD-MCI exhibited lower SUVRs (3.61 ± 1.31, p < 0.001) in the caudate than patients with PD-NC (4.43 ± 1.21) but higher SUVRs than patients with PDD (2.39 ± 1.06). Patients with PD-NC had higher thalamic SUVRs (1.55 ± 0.16, p < 0.001) than patients with both PD-MCI (1.45 ± 0.16) and PDD (1.38 ± 0.19). Regional deep gray matter volumes of the caudate (p = 0.015), putamen (p = 0.012), globus pallidus (p < 0.001), thalamus (p < 0.001), hippocampus (p < 0.001), and amygdala (p < 0.001) were more reduced in patients with PD-MCI or PDD than in patients with PD-NC, and the SUVR of the caudate correlated with caudate volume (r = 0.187, p = 0.015). Hippocampal atrophy was the initial change influencing cognitive impairment. The reduced dopamine availability of the thalamus preceded reductions in volume across most deep gray matter regions. Our finding underscores the association between decreased dopamine availability and volume of the caudate and thalamus with cognitive dysfunction in PD. The dopamine availability of the caudate and thalamus was reduced before the volume of the caudate and thalamus was decreased, highlighting the spatiotemporal association between dopaminergic and structural pathology in cognitive impairment in PD.

Dissecting the Natural Patterns of Progression and Senescence in Pediatric Low-Grade Glioma: From Cellular Mechanisms to Clinical Implications.

Pediatric low-grade gliomas (PLGGs) comprise a heterogeneous set of low-grade glial and glioneuronal tumors, collectively representing the most frequent CNS tumors of childhood and adolescence. Despite excellent overall survival rates, the chronic nature of the disease bears a high risk of long-term disease- and therapy-related morbidity in affected patients. Recent in-depth molecular profiling and studies of the genetic landscape of PLGGs led to the discovery of the paramount role of frequent upregulation of RAS/MAPK and mTOR signaling in tumorigenesis and progression of these tumors. Beyond, the subsequent unveiling of RAS/MAPK-driven oncogene-induced senescence in these tumors may shape the understanding of the molecular mechanisms determining the versatile progression patterns of PLGGs, potentially providing a promising target for novel therapies. Recent in vitro and in vivo studies moreover indicate a strong dependence of PLGG formation and growth on the tumor microenvironment. In this work, we provide an overview of the current understanding of the multilayered cellular mechanisms and clinical factors determining the natural progression patterns and the characteristic biological behavior of these tumors, aiming to provide a foundation for advanced stratification for the management of these tumors within a multimodal treatment approach.

Post-Progression Analysis of EGFR-Mutant NSCLC Following Osimertinib Therapy in Real-World Settings.

Platinum-based chemotherapy is the current standard treatment option in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who progress on osimertinib. However, outcomes with chemotherapy are dismal, and the treatment of central nervous system (CNS) disease is an unmet need in this setting. Patients with EGFR-mutant NSCLC who were candidates to receive osimertinib in the metastatic setting at our Center from 2015 to 2022 were retrospectively evaluated to identify patients who received standard platinum-based chemotherapy post-osimertinib. Data were collected on treatment outcomes, with a focus on brain metastases and progression patterns. A total of 220 patients received indication for osimertinib in the study period; n = 176 had adequate follow-up data. Overall, n = 117 patients experienced disease progression on osimertinib. The median time to osimertinib progressive disease (PD) was 15 months (95% confidence interval CI 13-18). Of them, 51 patients (45%) had no access to further treatments. Of the remaining patients, n = 8 received experimental treatments, and n = 55 received standard platinum-based chemotherapy and were considered for this study. Median duration of chemotherapy was 3 months (95% CI 2-5); the best responses among 53 evaluable patients were observed as follows: 15% partial response/complete response (PR/CR), 40% stable disease (SD), 45% PD. Median progression-free survival (PFS) and overall survival (OS) were 3 (95% CI 2-5) and 10 (95% CI 6-15) months, respectively. All patients had baseline and follow-up brain radiologic assessments, and n = 23 had brain metastases at the start of chemotherapy. With a median follow-up of 13 months, intracranial PD occurred in 47% patients, being the first site of PD in 59% of cases. The median time for intracranial (IC) PD was 2 months (95% CI 2-7). IC PD occurred as oligometastatic in 29%, whereas in 71% of cases, it was associated with systemic PD. Access to subsequent treatments and CNS progression are confirmed unmet needs in EGFR-mutant NSCLC patients. Clinical and CNS-specific outcomes in patients receiving standard chemotherapy after the failure of osimertinib are dismal. Novel upfront treatment options with demonstrated prolonged PFS and better CNS outcomes may help address this important issue.

Understanding Dementia Carer Experiences Before Admission to a Residential Aged Care Facility: Implications for Integrated Care.

In-depth understanding of dementia carer experience can assist clinicians by providing insight into dementia onset, symptoms and management, and help conceptualize and understand the pattern of dementia progress over time and what help is needed. We undertook a qualitative study to understand dementia carers experiences of providing care and reasons for admission to a residential aged care facility (RACF). Three themes were identified: (1) Challenges in the path to diagnosis and care, leading to delays accessing support; (2) Carer role impacted by living circumstances; and (3) Variation in decision support prior to admission to a RACF. Identifying dementia carer experiences, reinforces the need for more timely diagnosis, referral for support and interventions to promote better quality of life for a people living with dementia and their carer and to delay premature RACF placement.

Metal hypersensitivity in trapeziometacarpal arthroplasty: A systematic pattern of progression

Metal hypersensitivity is a rare and often underestimated complication, as shown by the small number of published studies, particularly concerning the upper limbs and the hand. However, the increase in the annual number of trapeziometacarpal arthroplasties underlines the importance of better understanding of this problem.We performed a study based on data from the revision of trapeziometacarpal prostheses to assess the incidence of this complication and to define a sequence of radiological changes to detect metal hypersensitivity.This single-center retrospective study included 37 patients operated on between January 2014 and November 2023 for revision of trapeziometacarpal prosthesis. Ten (27%) had no clearly identified cause of failure.For these 10 patients, we analyzed clinical data and postoperative X-rays. In the 11 revision arthroplasties, 2 patients had no symptoms or radiographic signs suggestive of allergy. Six patients had a-posteriori diagnosis established by allergy testing, which also identified 2 additional patients, for a total of 8 patients (21% of the initial cohort). In these cases, there was systematic metaphyseal osteolysis of the first metacarpal between 15 days and 1 month after implantation. Clinically, most patients had an asymptomatic period of 2 weeks to 1 month before onset of symptoms and osteolysis, often accompanied by local inflammation.This study found a reproducible pattern of progression, characterized by the appearance of radiographic signs of osteolysis in the first month, followed by clinical deterioration. Although this course is strongly suggestive of a metal hypersensitivity, it is crucial not to exclude the possibility of an infectious cause, which should always be considered.