Real-world experience of second-line axitinib in metastatic renal cell carcinoma: analysis of the Swedish population.

Aim: Assess the time-to-treatment discontinuation (TTD) and overall survival (OS) in a Swedish metastatic renal cell carcinoma (mRCC) nationwide cohort who received second-line axitinib. Methods: Retrospective analysis of 110 patients with mRCC treated with second-line axitinib in Sweden (2012-2019). Patients included in the study received axitinib after mainly first-line sunitinib or pazopanib. Results: The median (95% CI) TTD of patients who received second-line axitinib was 5.2 (3.7-6.1) months with 6 (5.5%) patients still receiving treatment at the time of analysis. Median (95% CI) OS was 12.2 (7.7-14.2) months. Conclusion: The results are consistent with previous findings in mRCC and add to the evidence demonstrating efficacy of second-line axitinib, after failure of a prior anti-angiogenic therapy in a real-world setting.Clinical Trial Registration: NCT04669366 (ClinicalTrials.gov).

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Prevalence of diabetes and hospitalization due to poor glycemic control in people with bladder cancer or renal cell carcinoma in Sweden.

BACKGROUND: Bladder cancer (BC) and Renal cell carcinoma (RCC) are the most common urogenital cancers among both sexes, with a yearly global incidence of around 500 000 each. Both BC and RCC have been linked to diabetes. Poor glycemic control (malglycemia) is a serious consequence of diabetes and a possible consequence of systemic treatments used in BC and RCC. The objective of this study was to investigate the prevalence of diabetes and use of hospital-based care for malglycemia in people with BC or RCC. METHODS: This Swedish retrospective population-based register study used national health-data registers for longitudinal data on cancer incidence covering 15 years, use of hospital-based health care, and filled prescriptions of outpatient medications. Study endpoints included co-prevalence of diabetes in individuals with BC/RCC, healthcare resource utilization due to malglycemia, use of systemic corticosteroids, and changes in diabetes management for people with concomitant type 2 diabetes. RESULTS: We identified 36,620 and 15,581 individuals diagnosed with BC and RCC, respectively, between 2006 and 2019. The proportion of individuals registered with diabetes was 24% in BC and 23% in RCC. An association between BC/RCC and poor glycemic control was found, although the number of malglycemic events in hospital-based care were few (65/59 per 1000 individuals with diabetes and BC/RCC respectively with at least one event). An earlier switch to insulin-based diabetes management was observed in BC/RCC compared to matched individuals with type 2 diabetes but no cancer. The results also indicated an association between steroid treatment and poor glycemic control, and that systemic corticosteroids were more common among people with BC/RCC compared to diabetes controls. CONCLUSION: The high prevalence of diabetes and increased use of systemic corticosteroid treatment observed in this large national study highlights the need for specific clinical management, risk-assessment, and monitoring of individuals with BC/RCC and diabetes.

Wall Shear Stress Measured with 4D Flow CMR Correlates with Biomarkers of Inflammation and Collagen Synthesis in Mild-to-Moderate Ascending Aortic Dilation and Tricuspid Aortic Valves.

AIMS: Understanding the mechanisms underlying ascending aortic dilation is imperative for refined risk stratification of these patients, particularly among incidentally identified patients, most commonly presenting with tricuspid valves. The aim of this study was to explore associations between ascending aortic hemodynamics, assessed using four-dimensional flow cardiovascular magnetic resonance imaging (4D Flow CMR), and circulating biomarkers in aortic dilation. METHODS AND RESULTS: Forty-seven cases with aortic dilation (diameter ≥40 mm) and 50 sex-and age-matched controls (diameter <40 mm), all with tricuspid aortic valves, underwent 4D flow CMR and venous blood sampling. Associations between flow displacement, wall shear stress (WSS), and oscillatory shear index in the ascending aorta derived from 4D Flow CMR, and biomarkers including interleukin-6, collagen type I α1 chain, metalloproteinases (MMPs), and inhibitors of MMPs derived from blood plasma, were investigated. Cases with dilation exhibited lower peak systolic WSS, higher flow displacement, and higher mean oscillatory shear index compared to controls without dilation. No significant differences in biomarkers were observed between the groups. Correlations between hemodynamics and biomarkers were observed, particularly between maximum time-averaged WSS and interleukin-6 (r = 0.539, p < 0.001), and maximum oscillatory shear index and collagen type I α1 chain (r = -0.575, p < 0.001 in cases). CONCLUSION: Significant associations were discovered between 4D flow CMR derived whole-cardiac cycle WSS and circulating biomarkers representing inflammation and collagen synthesis, suggesting an intricate interplay between hemodynamics and the processes of inflammation and collagen synthesis in patients with early aortic dilation and tricuspid aortic valves.

GPAW: An open Python package for electronic structure calculations.

We review the GPAW open-source Python package for electronic structure calculations. GPAW is based on the projector-augmented wave method and can solve the self-consistent density functional theory (DFT) equations using three different wave-function representations, namely real-space grids, plane waves, and numerical atomic orbitals. The three representations are complementary and mutually independent and can be connected by transformations via the real-space grid. This multi-basis feature renders GPAW highly versatile and unique among similar codes. By virtue of its modular structure, the GPAW code constitutes an ideal platform for the implementation of new features and methodologies. Moreover, it is well integrated with the Atomic Simulation Environment (ASE), providing a flexible and dynamic user interface. In addition to ground-state DFT calculations, GPAW supports many-body GW band structures, optical excitations from the Bethe-Salpeter Equation, variational calculations of excited states in molecules and solids via direct optimization, and real-time propagation of the Kohn-Sham equations within time-dependent DFT. A range of more advanced methods to describe magnetic excitations and non-collinear magnetism in solids are also now available. In addition, GPAW can calculate non-linear optical tensors of solids, charged crystal point defects, and much more. Recently, support for graphics processing unit (GPU) acceleration has been achieved with minor modifications to the GPAW code thanks to the CuPy library. We end the review with an outlook, describing some future plans for GPAW.

Modular 3D printed platform for fluidically connected human brain organoid culture.

Brain organoid technology has transformed both basic and applied biomedical research and paved the way for novel insights into developmental processes and disease states of the human brain. While the use of brain organoids has been rapidly growing in the past decade, the accompanying bioengineering and biofabrication solutions have remained scarce. As a result, most brain organoid protocols still rely on commercially available tools and culturing platforms that had previously been established for different purposes, thus entailing suboptimal culturing conditions and excessive use of plasticware. To address these issues, we developed a 3D printing pipeline for the fabrication of tailor-made culturing platforms for fluidically connected but spatially separated brain organoid array culture. This all-in-one platform allows all culturing steps-from cellular aggregation, spheroid growth, hydrogel embedding, and organoid maturation-to be performed in a single well plate without the need for organoid manipulation or transfer. Importantly, the approach relies on accessible materials and widely available 3D printing equipment. Furthermore, the developed design principles are modular and highly customizable. As such, we believe that the presented technology can be easily adapted by other research groups and fuel further development of culturing tools and platforms for brain organoids and other 3D cellular systems.

High-Throughput Search for Triplet Point Defects with Narrow Emission Lines in 2D Materials.

We employ a first-principles computational workflow to screen for optically accessible, high-spin point defects in wide band gap, two-dimensional (2D) crystals. Starting from an initial set of 5388 point defects, comprising both native and extrinsic, single and double defects in ten previously synthesized 2D host materials, we identify 596 defects with a triplet ground state. For these defects, we calculate the defect formation energy, hyperfine (HF) coupling, and zero-field splitting (ZFS) tensors. For 39 triplet transitions exhibiting particularly low Huang-Rhys factors, we calculate the full photoluminescence (PL) spectrum. Our approach reveals many spin defects with narrow PL line shapes and emission frequencies covering a broad spectral range. Most of the defects are hosted in hexagonal BN (hBN), which we ascribe to its high stiffness, but some are also found in MgI2, MoS2, MgBr2 and CaI2. As specific examples, we propose the defects vSMoS0 and NiSMoS0 in MoS2 as interesting candidates with potential applications to magnetic field sensors and quantum information technology.

The psychology and policy of overcoming economic inequality.

Recent arguments claim that behavioral science has focused - to its detriment - on the individual over the system when construing behavioral interventions. In this commentary, we argue that tackling economic inequality using both framings in tandem is invaluable. By studying individuals who have overcome inequality, "positive deviants," and the system limitations they navigate, we offer potentially greater policy solutions.

The persistence of cognitive biases in financial decisions across economic groups.

While economic inequality continues to rise within countries, efforts to address it have been largely ineffective, particularly those involving behavioral approaches. It is often implied but not tested that choice patterns among low-income individuals may be a factor impeding behavioral interventions aimed at improving upward economic mobility. To test this, we assessed rates of ten cognitive biases across nearly 5000 participants from 27 countries. Our analyses were primarily focused on 1458 individuals that were either low-income adults or individuals who grew up in disadvantaged households but had above-average financial well-being as adults, known as positive deviants. Using discrete and complex models, we find evidence of no differences within or between groups or countries. We therefore conclude that choices impeded by cognitive biases alone cannot explain why some individuals do not experience upward economic mobility. Policies must combine both behavioral and structural interventions to improve financial well-being across populations.

Cost­Effectiveness of Lorlatinib in First-Line Treatment of Adult Patients with Anaplastic Lymphoma Kinase (ALK)­Positive Non­Small­Cell Lung Cancer in Sweden.

BACKGROUND: We aimed to investigate the cost effectiveness of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), used first-line in Sweden to treat patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). In January 2022, the European Medicines Agency (EMA) extended its approval of lorlatinib to include adult patients with ALK+ NSCLC not previously treated with an ALK inhibitor. Extended first-line approval was based on results from CROWN, a phase III randomized trial that enlisted 296 patients randomized 1:1 to receive lorlatinib or crizotinib. Our analysis compared lorlatinib against the first-generation ALK-TKI crizotinib, and second-generation ALK TKIs alectinib and brigatinib. METHODS: A partitioned survival model with four health states [pre-progression, non-intracranial (non-central nervous system [CNS]) progression, CNS progression, and death] was constructed. The progressed disease state (which is typically modelled in cost-effectiveness analyses of oncology treatments) was explicitly separated into non-CNS and CNS progression as brain metastases, which are common in NSCLC, and can have a large impact on patient prognosis and health-related quality of life. Treatment effectiveness estimates in the lorlatinib and crizotinib arms of the model were derived from CROWN data, while indirect relative effectiveness estimates for alectinib and brigatinib were informed using network meta-analysis (NMA). Utility data were derived from the CROWN study in the base case, and cost-effectiveness results were compared when applying UK and Swedish value sets. Costs were obtained from Swedish national data. Deterministic and probabilistic sensitivity analyses were conducted to test model robustness. RESULTS: Fully incremental analysis identified crizotinib as the least costly and least effective treatment. Brigatinib was extendedly dominated by alectinib and, subsequently, alectinib was extendedly dominated by lorlatinib. Lorlatinib was associated with an incremental cost-effectiveness ratio (ICER) of Swedish Krona (SEK) 613,032 per quality-adjusted life-year (QALY) gained compared with crizotinib. Probabilistic results were generally consistent with deterministic results, and one-way sensitivity identified NMA HRs, alectinib and brigatinib treatment duration, and the CNS-progressed utility multiplier as key model drivers. CONCLUSIONS: The ICER of SEK613,032 for lorlatinib versus crizotinib falls below the typical willingness-to-pay threshold per QALY gained for high-severity diseases in Sweden (approximately SEK1,000,000). Furthermore, as brigatinib and alectinib were extendedly dominated in the incremental analysis, the results of our study indicate that lorlatinib may be considered a cost-effective treatment option for first-line patients with ALK+ NSCLC in Sweden when compared with crizotinib, alectinib, and brigatinib. Longer-term follow-up data for endpoints informing treatment effectiveness for all first-line treatments would help to reduce uncertainty in the findings.

Promoting Social Participation and Recovery Using Virtual Reality-Based Interventions Among People With Mental Health and Substance Use Disorders: Qualitative Study.

BACKGROUND: People with mental health disorders (MHDs) and substance use disorders (SUDs) are a highly vulnerable group, particularly affected by social exclusion, marginalization, and disconnectedness. Virtual reality technology holds a potential for simulating social environments and interactions to mitigate the social barriers and marginalization faced by people recovering from MHDs and SUDs. However, it is still unclear how we can harness the greater ecological validity of virtual reality-based interventions targeting social and functional impairments in individuals with MHDs and SUDs. OBJECTIVE: The aim of this paper was to explore how service providers in community-based MHD and SUD health care services perceive the barriers to social participation among adults recovering from MHDs and SUDs to provide a broader understanding of how learning experiences can be modeled to promote social participation in virtual reality environments. METHODS: Two semistructured, open-ended, and dual-moderator focus group interviews were conducted with participants representing different community-based MHD and SUD health care services. Service providers were recruited from their MHD and SUD services in our collaborating municipality in Eastern Norway. We recruited the first participant group at a municipal MHD and SUD assisted living facility for service users with ongoing excessive substance use and severe social dysfunctionality. We recruited the second participant group at a community-based follow-up care service aimed at clients with a broad range of MHDs and SUDs and various levels of social functioning. The qualitative data extracted in the interviews were analyzed, using reflexive thematic analysis. RESULTS: The analysis of the service providers' perceptions of the barriers to social participation among clients with MHDs and SUDs revealed the following five main themes: challenging or lacking social connections, impaired cognitive functions, negative self-perception, impaired personal functioning, and insufficient social security. The barriers identified are interrelated in a cluster of cognitive, socioemotional, and functional impairments, leading to a severe and diverse complex of barriers to social participation. CONCLUSIONS: Social participation relies on people's capability to use their present social opportunities. Promoting basic human functioning is key to promoting social participation among people with MHDs and SUDs. The findings in this study indicate a need to address cognitive functioning, socioemotional learning, instrumental skills, and complex social functions to meet the complexity and diversity of the identified barriers to social functioning in our target group. Virtual reality-based interventions for promoting social participation should be sequenced into distinct scenarios dedicated to specific learning goals to build complex learning in a step-by-step process based on successively more complex levels of human and social functioning.

Hygiene may attenuate selection for antibiotic resistance by changing microbial community structure.

Good hygiene, in both health care and the community, is central to containing the rise of antibiotic resistance, as well as to infection control more generally. But despite the well-known importance, the ecological mechanisms by which hygiene (or other transmission control measures) affect the evolution of resistance remain to be elucidated. Using metacommunity ecology theory, we here propose that hygiene attenuates the effect of antibiotic selection pressure. Specifically, we predict that hygiene limits the scope for antibiotics to induce competitive release of resistant bacteria within treated hosts, and that this is due to an effect of hygiene on the distribution of resistant and sensitive strains in the host population. We show this in a mathematical model of bacterial metacommunity dynamics, and test the results against data on antibiotic resistance, antibiotic treatment, and the use of alcohol-based hand rub in long-term care facilities. The data are consistent with hand rub use attenuating the resistance promoting effect of antibiotic treatment. Our results underscore the importance of hygiene, and point to a concrete way to weaken the link between antibiotic use and increasing resistance.

Long-Term Follow-Up of Right Ventricle to Pulmonary Artery Biologic Valved Conduits Used in Pediatric Congenital Heart Surgery.

Valved conduit reconstruction between the right ventricle (RV) and the pulmonary circulation is often necessary in the surgical treatment of complex congenital heart defects. The aim of this study is to evaluate the long-term performance of the three types of conduits we have used and assess risk factors for conduit failure. Retrospective, single-center review of 455 consecutive pediatric patients with 625 conduits from 1990 to 2019 undergoing RV-to-pulmonary artery (PA) reconstruction with a valved conduit. The three conduit types investigated were pulmonary homograft, aorta homograft, and bovine jugular vein (BJV) graft. Overall patient survival was 91.4%, freedom from conduit replacement (FCR) was 47.4%, and freedom from reintervention (FFR) was 37.8% with a median follow-up of 8.7 years (interquartile range 4.3-13.3 years). For pulmonary homografts, 10-, 20-, and 28-year FCR was 79.6%, 68.6%, and 66.0%, respectively. For aortic homografts, 10-, 20-, and 30-year FCR was 49.8%, 31.5%, and 23.0%, respectively. For BJV grafts, 10- and 19-year FCR was 68.1% and 46.0%, respectively. When controlling for baseline variables, FCR was similar for pulmonary homografts and BJV grafts. Overall patient survival was excellent. Risk factors for conduit failure in patients operated with reconstruction of the RV-PA outflow tract included low age, low weight, small conduit size, and certain cardiac diagnoses. There was no evidence for a shorter life span of the second graft. Pulmonary homografts and BJV grafts performed similarly but the risk of endocarditis was greater in the BJV group.

Use of ALK-tyrosine kinase inhibitors (ALK TKI) in clinical practice, overall survival, and treatment duration - a Swedish nationwide retrospective study.

BACKGROUND: The real-world treatment and outcomes of patients with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer treated with ALK Tyrosine Kinase Inhibitor (TKI) drugs in Sweden is not well described. MATERIAL AND METHODS: A retrospective population-based cohort study was conducted using Swedish national registers. All patients with a filled prescription for an ALK TKI between January 2012 and October 2020 were included. The sequencing of ALK TKI and duration of treatment (DOT) were described, and overall survival (OS) was estimated using the Kaplan-Meier method. Patients were stratified based on treatment with frontline chemotherapy, presence of CNS metastases prior to the first ALK TKI, and generation of ALK TKI agent. RESULTS: Among the total of 579 patients, 549 (95%) underwent a therapy sequence in line with current clinical practice with 204 (37%) patients receiving frontline chemotherapy. Single-line ALK TKI was given to 366 patients (crizotinib: 211; alectinib: 146; ceritinib: 9), whereas 128 patients received two different ALK TKI (frontline crizotinib: 100, alectinib: 24, ceritinib: 4); 40 patients received three lines and 15 patients four ALK TKI lines or more. With frontline chemotherapy, the mean (standard deviation) DOT was 1.07 (1.25) years for the entire TKI therapy sequence compared to 1.23 (1.28) years with frontline ALK TKI. The median (95% confidence interval) OS was 1.83 (1.48-2.13) years for the entire cohort, 1.44 (0.89-1.98) years for patients given frontline chemotherapy, and 2.02 (1.60-2.58) years for patients given frontline ALK TKI. CONCLUSION: This study provides a unique overview of the patient population treated with ALK TKI in Sweden and reveals the treatment patterns applied in real clinical practice. More research is needed when longer follow-up data are available for later-generation ALK TKI, to fully understand ALK TKI sequencing and its effect on patient survival in a real-world setting.

A Combined α-Synuclein/Fibril (SynFib) Model of Parkinson-Like Synucleinopathy Targeting the Nigrostriatal Dopamine System.

Injections of pre-formed α-synuclein fibrils (PFFs) or overexpression of α-synuclein using AAV vectors are commonly used as models of Parkinson-like synucleinopathy in rats and mice. In the modified method reviewed here, the "SynFib" model, the PFFs and the AAV vector are administered together unilaterally into the substantia nigra. This approach combines the key features of these two models, i.e., the generation of toxic α-synuclein aggregates and Lewy body-like inclusions, in combination with the increased vulnerability caused by increased cellular levels of α-synuclein. The combined AAV/PFF delivery offers several advantages over the standard PFF model due to the enhanced and accelerated α-synuclein pathology and microglial response induced by the PFF seeds in the presence of an elevated α-synuclein level. Injection of the AAV/PFF mixture into the substantia nigra makes it possible to target a larger proportion of the nigral dopamine neurons and obtain a level of dopamine cell loss (>60%) needed to induce significant impairments in drug-induced and spontaneous motor tests. The SynFib model shares attractive features of the standard 6-OHDA lesion model: a single unilateral stereotaxic intervention; pathology and cell loss developing over a short time span; and the possibility to monitor the degenerative changes using tests of motor behavior.

Silk scaffolding drives self-assembly of functional and mature human brain organoids.

Human pluripotent stem cells (hPSCs) are intrinsically able to self-organize into cerebral organoids that mimic features of developing human brain tissue. These three-dimensional structures provide a unique opportunity to generate cytoarchitecture and cell-cell interactions reminiscent of human brain complexity in a dish. However, current in vitro brain organoid methodologies often result in intra-organoid variability, limiting their use in recapitulating later developmental stages as well as in disease modeling and drug discovery. In addition, cell stress and hypoxia resulting from long-term culture lead to incomplete maturation and cell death within the inner core. Here, we used a recombinant silk microfiber network as a scaffold to drive hPSCs to self-arrange into engineered cerebral organoids. Silk scaffolding promoted neuroectoderm formation and reduced heterogeneity of cellular organization within individual organoids. Bulk and single cell transcriptomics confirmed that silk cerebral organoids display more homogeneous and functionally mature neuronal properties than organoids grown in the absence of silk scaffold. Furthermore, oxygen sensing analysis showed that silk scaffolds create more favorable growth and differentiation conditions by facilitating the delivery of oxygen and nutrients. The silk scaffolding strategy appears to reduce intra-organoid variability and enhances self-organization into functionally mature human brain organoids.

Single-cell transcriptional and functional analysis of dopaminergic neurons in organoid-like cultures derived from human fetal midbrain.

Significant efforts are ongoing to develop refined differentiation protocols to generate midbrain dopamine (DA) neurons from pluripotent stem cells for application in disease modeling, diagnostics, drug screening and cell-based therapies for Parkinson's disease. An increased understanding of the timing and molecular mechanisms that promote the generation of distinct subtypes of human midbrain DA during development will be essential for guiding future efforts to generate molecularly defined and subtype-specific DA neurons from pluripotent stem cells. Here, we use droplet-based single-cell RNA sequencing to transcriptionally profile the developing human ventral midbrain (VM) when the DA neurons are generated (6-11 weeks post-conception) and their subsequent differentiation into functional mature DA neurons in primary fetal 3D organoid-like cultures. This approach reveals that 3D cultures are superior to monolayer conditions for their ability to generate and maintain mature DA neurons; hence, they have the potential to be used for studying human VM development. These results provide a unique transcriptional profile of the developing human fetal VM and functionally mature human DA neurons that can be used to guide stem cell-based therapies and disease modeling approaches in Parkinson's disease.

Generation of Human Ventral Midbrain Organoids Derived from Pluripotent Stem Cells.

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide and is caused by the degeneration and loss of dopamine (DA) neurons in the ventral midbrain (VM). The focal and progressive degeneration of DA neurons in the VM makes PD a particularly attractive target for cell-based therapies. Human pluripotent stem cells (hPSCs) offer unprecedented opportunities to model the development and functional properties of human DA neurons in a dish. The use of human in vitro models based on hPSCs has empowered studies of VM development and provided access to neurons expressing a particular disease-specific phenotype. Currently, hPSC differentiation is most routinely carried out in monolayer cultures, which do not properly recapitulate cell-cell interactions and the structural complexity of the brain. Moreover, 2D cultures are challenging to maintain long term, as the cells tend to detach from the plate and lose their functional characteristics. This precludes the possibility of mimicking later phases of DA neurogenesis and recreating the complexity of functional neural circuitries. Here, we describe protocols showing how to maintain hPSCs in an undifferentiated state and how to then drive these hPSCs into 3D regionalized VM organoids. After long-term culture, these VM organoids exhibit mature and post-mitotic molecular features, including neuromelanin pigments similar to those released in primate VMs. We also report a protocol describing how to efficiently perform immunohistochemistry and how to detect neuromelanin-containing DA neurons in VM organoids. Together, these protocols provide a 3D in vitro platform that can be used to better understand the molecular mechanisms underlying DA neuron function and disease and may serve as a powerful tool for designing more targeted disease-modifying therapies. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Human pluripotent stem cell culture Basic Protocol 2: hPS cell differentiation for the generation of human ventral midbrain organoids Basic Protocol 3: Characterization of ventral midbrain organoids.

Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease.

We have developed an efficient approach to generate functional induced dopaminergic (DA) neurons from adult human dermal fibroblasts. When performing DA neuronal conversion of patient fibroblasts with idiopathic Parkinson's disease (PD), we could specifically detect disease-relevant pathology in these cells. We show that the patient-derived neurons maintain age-related properties of the donor and exhibit lower basal chaperone-mediated autophagy compared with healthy donors. Furthermore, stress-induced autophagy resulted in an age-dependent accumulation of macroautophagic structures. Finally, we show that these impairments in patient-derived DA neurons leads to an accumulation of phosphorylated alpha-synuclein, the classical hallmark of PD pathology. This pathological phenotype is absent in neurons generated from induced pluripotent stem cells from the same patients. Taken together, our results show that direct neural reprogramming can be used for obtaining patient-derived DA neurons, which uniquely function as a cellular model to study age-related pathology relevant to idiopathic PD.

Prospective registration of symptoms and times to diagnosis in children and adolescents with central nervous system tumors: A study of the Swedish Childhood Cancer Registry.

BACKGROUND: The elapsed time taken to diagnose tumors of the central nervous system in children and adolescents varies widely. The aim of the present study was to investigate such diagnostic time intervals at a national level in Sweden as they correlate with clinical features. METHODS: Data prospectively accumulated over a 4-year period in the Swedish Childhood Cancer Registry from patients aged 0-18 years were pooled, and diagnostic time intervals were analyzed considering tumor location, tumor type, patient age and sex, initial symptoms, and clinical timelines. All six pediatric oncology centers in Sweden contributed to collection of data. Time points for calculating the total diagnostic interval (TDI) defined as the time from symptom onset to diagnosis were reported in 257 of 319 patients (81%). RESULTS: The time from symptom onset to the first healthcare consultation, median 2.6 weeks, did not vary significantly between patients categorized according to tumor type or location. The median TDI was 8.3 weeks for the 4-year study period. Patients with optic pathway glioma (TDI 26.6 weeks), those with tumors of the spinal cord (TDI 25.9 weeks), and those with midline tumors (TDI 24.6 weeks) had the longest lead times. Additionally, older age, too few initial symptoms, and seeking initial redress outside an emergency ward were factors associated with a longer time to diagnosis. CONCLUSION: This study identified several factors associated with delayed diagnosis of central nervous system tumors among Swedish children and adolescents. These novel data ought to help direct future efforts toward clinical improvement.