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Purpose: To assess and describe chemotherapy-induced peripheral neuropathy (CIPN), a well-known complication to cancer treatment, using different methodologies in hematological patients. Methods: Patients scheduled for treatment with vincristine, bortezomib, or lenalidomide were included in this longitudinal observational study. The patients were examined for CIPN before treatment (baseline), before each chemotherapy cycle, one month after end of treatment, and one year after baseline using patient-reported outcomes (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Ntx-13 (FACT/GOG-Ntx-13)) and clinician-assessed outcomes (the Common Terminology Criteria for Adverse Events (CTCAE) and the Total Neuropathy Score-clinical version (TNSc©)). Results: A total of 23 patients with 171 examination visits were included between 2020 and 2022. Four patients were treated with vincristine, five with bortezomib, and fourteen with bortezomib and lenalidomide combined. Defining CIPN as a ≥ 10% decrease in the FACT/GOG-Ntx-13, 11 patients (47.8%) developed CIPN during treatment and follow-up. CTCAE score for paresthesia increased from baseline throughout treatment until 1 month after the last treatment (p ≤ 0.045). Overall, the highest proportion of CIPN was present at cycle 3–4 and 1 month after last treatment. Conclusion: This study describes the course of CIPN in patients treated with vincristine, bortezomib, or lenalidomide using both patient-reported and clinician-assessed outcomes. The highest proportion of CIPN was present at cycle 3–4 and 1 month after treatment, at which timepoints clinicians must be especially aware of CIPN. Trial registration: Registered at Clinicaltrials.gov (Trial Registration Number: NCT04393363) on March 19, 2020. [ABSTRACT FROM AUTHOR]

How people in long-term recovery (clinical and personal) in first-episode psychosis (schizophrenia and bipolar spectrum disorders) experience the mental health and welfare services they interact with is not frequently studied but has significant implications. We therefore aimed to explore which aspects of these services people with FEP evaluate as important for their long-term recovery. Twenty participants in clinical and/or personal recovery from two Norwegian long-term follow-up studies after FEP (TOP 10-year and TIPS 20-year) were sampled for this interview-based qualitative study. The research-team included service user experience. A deductive analysis based on personal accounts of recovery generated five service aspects. Few specific types of interventions were reported to promote recovery although medications, psychotherapy and employment support were mentioned. Participants valued services based in collaboration and that focused on their resources rather than limitations. The importance of long-term follow-up with a consistent aim was highlighted, as was the inclusion of caregivers and peers. Welfare services contributed to recovery by supporting basic needs and safety, but some experienced social exclusion when not participating in the labor market. This study is unique in exploring the role of services, including welfare, in long-term FEP recovery from service user perspectives. Participants evaluated that services played a more indirect role in long-term recovery by supporting their personal resources, although what they needed from services had frequently not been offered. Their expertise by experience contributes valuable knowledge. Better service coordination and consistent implementation of this knowledge are crucial to support recovery in FEP. [ABSTRACT FROM AUTHOR]

The International Prognostic Index (IPI) is the most frequently used tool for prognostication in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of all ages. This study validated and compared six models developed for patients above 60 with International Prognostic Indices (IPI, R-IPI, NCCN-IPI). Moreover, we created a clinical nomogram with an online tool for individualized predictions. A total of 2,835 patients aged over 60 with newly diagnosed DLBCL treated with potentially curative immunochemotherapy were identified in the Danish Lymphoma Registry. A nomogram was developed by combining NCCN-IPI variables (excluding extranodal localization), albumin, and platelet levels in 1,970 patients and verified the results in the remaining 956 patients. Compared to other models, the elderly IPI (E-IPI) and age-adjusted IPI (aaIPI) showed better accuracy and discriminatory ability. However, the models failed to identify a high-risk group with a 3-year overall survival rate below 40%. Our nomogram-based model demonstrated superior discriminatory ability and provided more precise individual predictions than all other models based on a risk stratification system. Most clinical prognostic models fail to accurately predict patient outcomes in patients over 60 years old. Therefore, nomogram-based models should be considered in this population to prevent information loss due to variable dichotomization. [ABSTRACT FROM AUTHOR]

Purpose: Group B streptococcus (GBS) colonizes the gastrointestinal and vaginal mucosa in healthy adults, but has also become an increasing cause of invasive infection. The aims of this study were to describe the incidence and factors associated with the occurrence of invasive GBS disease in adults in Norway. Methods: We performed a nationwide retrospective case–control study of invasive GBS infections during 1996–2019, with two control groups; invasive Group A streptococcal disease (GAS) to control for changes in surveillance and diagnostics, and a second representing the general population. Results: A total of 3710 GBS episodes were identified. The age-standardized incidence rate increased steadily from 1.10 (95% CI 0.80–1.50) in 1996 to 6.70 (95% CI 5.90–7.50) per 100,000 person-years in 2019. The incidence rate had an average annual increase of 6.44% (95% CI 5.12–7.78). Incidence rates of GAS varied considerably, and there was no evidence of a consistent change over the study period. GBS incidence was highest among adults > 60 years of age. Cardiovascular disease, cancer, and diabetes were the most common comorbid conditions. There was a shift in the distribution of capsular serotypes from three dominant types to more equal distribution among the six most common serotypes. Conclusions: The incidence of invasive GBS disease in adults increased significantly from 1996 to 2019. The increasing age of the population with accompanying underlying comorbid conditions might contribute to the increasing burden of invasive GBS disease. Interestingly, type 1 diabetes was also associated with the occurrence of invasive GBS disease. [ABSTRACT FROM AUTHOR]

Background: It can be challenging for children to cooperate for a magnetic resonance imaging (MRI) exam. General anesthesia is often used to ensure a high-quality image. When determining the need for general anesthesia, many institutions use a simple age cutoff. Decisions on the necessity for anesthesia are often left to schedulers who lack training on determination of patient compliance. Objective: The study aimed to evaluate whether screening questions administered by certified child life specialists (CCLS) could successfully predict which children could complete an MRI without sedation. Materials and methods: This is a retrospective, institutional review board approved study. Data was collected as part of a quality improvement program, where a CCLS screened 4- to 12-year-old children scheduled for MRI scanning using a questionnaire. Parent responses to the screening questions, CCLS's recommendation for scheduling the MRI awake, start and end time for the MRI scan, and scan success were recorded. A predictive model for the CCLS's recommendation was developed using the child's age, estimated scan length, scan difficulty, and the parent's responses to the screening questions. The primary outcome measure was a successfully completed MRI not requiring additional imaging under anesthesia. Results: Of the 403 screened children, 317 (79%) were recommended to attempt the MRI without anesthesia. The median age of participants was 7 (IQR 4–17) years. Overall, 309 of 317 (97.5%) participants, recommended by the CCLS for the program, met the primary outcome of successful MRI completion on their first attempt. The multivariable regression model which included clinical information about the child's age, estimated scan length, scan difficulty, and four of the six parent screening questions had excellent performance (area under the curve = 0.89). Conclusion: Information collected by the CCLS via screening along with the child's age, the estimated scan length, and difficulty can help predict which children are likely to successfully complete a non-sedate MRI. [ABSTRACT FROM AUTHOR]

Myositis is associated with reduced quality of life, which is accompanied by significant impairments in muscle endurance and strength, altogether representing cardinal traits in patients with myositis. This randomised controlled trial aimed to investigate the effect of high-intensity resistance training on quality of life in patients with myositis. Thirty-two patients with established, stable myositis were randomised to 16 weeks of high-intensity resistance training (intervention group) or 16 weeks of usual care (control group). Primary outcome was quality of life assessed as the change in the physical component summary score (PCS) of the Short Form-36 health questionnaire from baseline to post-intervention. Secondary outcomes included functional capacity measures, such as functional index 3, and International Myositis Assessment and Clinical Studies Group (IMACS) disease activity and damage core set measures, including manual muscle testing 8 (MMT8). The primary outcome PCS showed an improvement in favour of high-intensity resistance training with a between-group difference of 5.33 (95% CI 0.61; 10.05) (p = 0.03). Additionally, functional index 3 showed a between-group difference indicating greater gains with high-intensity resistance training 11.49 (95% CI 3.37; 19.60) (p = 0.04), along with a between-group improvement in MMT8 1.30 (95% CI 0.09; 2.51) (p = 0.04). High-intensity resistance training for 16 weeks effectively improved quality of life in patients with myositis. Clinical measures of muscle endurance and muscle strength were also found to improve with high-intensity resistance training, while patients stayed in disease remission. Consequently, progressively adjusted high-intensity resistance training is feasible and causes no aggravation of the disease, while benefitting patients with myositis. Clinical trial registration: Clinicaltrials.gov ID: NCT04486261—https://clinicaltrials.gov/study/NCT04486261. [ABSTRACT FROM AUTHOR]

Blow flies (Diptera: Calliphoridae) are generally early colonisers of fresh cadavers, enabling the estimation of a minimum post-mortem interval (minPMI) based on an accurate aging of the oldest immature stages associated with a cadaver. In blow flies, the pupal stage and the subsequent development of the adult take place inside a protective case, the puparium, formed from the hardened and darkened cuticle of the third instar larva. Because the puparium is an opaque structure that shows virtually no external changes, qualitative analyses of the internal tissues can be very informative for determining reliable age-specific morphological markers. Those analyses can be performed using either non-invasive but expensive and not widely accessible techniques, or traditional histological methods, which are invasive as they require the serial sectioning of the sample. Histological methods are often readily available for forensic researchers and practitioners; however, the histological study of blow fly intra-puparial stages has traditionally been hampered by the poor paraffin infiltration of tissues due to the abundance of fat bodies, resulting in usually fragmented sections and the subsequent loss of relevant information. We present here an effective method for the preparation of histological sections of blow fly intra-puparial stages, maximising the paraffin infiltration while enabling the production of clean and entire sections that allow for the use of reliable age-specific morphological markers, thus improving the accuracy of minPMI estimations when access to more costly techniques is not feasible. [ABSTRACT FROM AUTHOR]

Background: Stereo-DIC is a widely used optical measurement technique that provides a dense full-field 3D measurement of the shape, displacement, and strain of a solid sample. When compared with 2D-DIC, Stereo-DIC provides greater flexibility and expands its use beyond flat, planar specimens. Furthermore, the widespread availability of commercial systems has led to the adoption of the technique throughout industry, academia, and government research labs. Objective: Even though some research has been done to understand the effects of different experimental and stereo-DIC parameters, no reference is available to benchmark and compare the performance of current stereo-DIC algorithms to each other. Methods: This paper provides the description and analysis of a carefully controlled 3D experiment and associated images used to compare the results from five subset based DIC software packages. Both the images and analysis codes used in this paper to compare the results are described here and are available for download and use for continued research. Results: We show that over a very large range of motion, the 3D errors are very small, less than 80 μ m over a travel of ±20 mm out-of-plane and ±20 mm in-plane. While all codes performed similarly, there are important differences noted in the paper. Conclusion: The image sets and results comparison software are hosted by the International DIC Society (www.iDICs.org) and are freely available for download and analysis for comparison with results in this paper. Furthermore, it is hoped that this set of images can be used for future research in improving stereo-DIC by future authors. [ABSTRACT FROM AUTHOR]

Overall survival (OS) for patients with a hematological cancer may differ between immigrant and Danish-born patients due to disparities in socioeconomic status, health literacy, and language proficiency. This cohort study aimed to investigate survival and hospitalization according to immigrant status while controlling for confounders. Patients with newly diagnosed hematological cancer in 2000–2020 were identified in the Danish nationwide hematological registers and stratified into Danish-born, Western, and non-Western patients. Patients were followed from diagnosis until death, 31st December 2021, or emigration, whichever came first. Crude OS, standardized OS, and 5-years OS differences were computed using flexible parametric models and hazard ratios using Cox regression. Number of hospitalization days in the year before and after diagnosis, respectively, were calculated using Poisson regression. A total of 2,241 immigrants and 41,519 Danish-born patients with a hematological cancer were included. Standardized 5-years OS was similar between groups with 58% (95% confidence interval 57–58%) for Danish-born patients, 57% (55–60%) for Western, and 56% (53–58%) for non-Western immigrant patients. Subgroup analyses identified OS differences in selected subgroups. Non-Western immigrant patients had 1.3 (0.5–2.1) more hospitalization days in the year before diagnosis and an adjusted incidence rate ratio of hospitalization days of 1.14 (1.13–1.15) in the year after diagnosis compared with Danish-born patients. In conclusion, there were no overall differences in survival when comparing immigrant patients to Danish-born patients after controlling for relevant confounders. Healthcare utilization was slightly higher among non-Western immigrant patients before and after diagnosis, but differences were small on an individual patient level. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to determine which of the ankle, knee or hip joint is the most important contributor to horizontal velocity during maximal sprint running. Furthermore, it was undertaken to quantify the fraction of propulsive power and work produced at each of the three joints. Methods: Seven athletes of national class served as subjects for the study. One running cycle of each subject was recorded by four video cameras (240 f/s) and a recessed force platform. Inverse dynamics in 3D was calculated as well as an angle between joint moment and angular velocity to express propulsive power and propulsive joint work. Results: Previous studies indicating the hip joint being the most important joint could not be confirmed by the present results due to large inter-individual differences for the hip joint. Averaged across all subjects, 64% of the normalized positive ankle joint work and 71% of the knee joint work were propulsive, while for the hip joint, four athletes showed 0%, one athlete 8%, and two athletes 96% and 97% propulsive work, respectively. For the whole leg, the propulsive fraction was 70% of the total positive work (range 40–87%). Normalized propulsive work was significantly correlated with maximal running velocity. Conclusion: The whole leg should be considered as one functional unit in which one or more of the joints may dominate generation of propulsive joint work. [ABSTRACT FROM AUTHOR]

A few epidemiological studies have examined personality disorders (PDs) among children and adolescents in secondary mental health services. This study aims to describe the prevalence and incidence of PDs among children and adolescents who have attended Danish child and adolescent psychiatric services (CAPS). Using register-based data, we studied all patients under the age of 18 years who were admitted to in- and outpatient CAPS (N = 115,121) in Denmark from 2007 to 2017. A total of 4952 patients were diagnosed with a PD during the study period. The mean prevalence was 859 patients per year, and the mean incidence was 274 patients per year, including an increased incidence and prevalence of borderline, anxious, and unspecified PDs over the decade. The number of patients diagnosed with PDs increased from 700 to 851 per year, but the proportion of patients with PDs compared to all psychiatric diagnoses decreased from 4.2% to 2.8% over the study period. The PD population had an older age (14.8 years vs. 11.3 years; p < 0.001), a higher likelihood of being female (74% vs. 44%; p < 0.001), and four times more contacts with the psychiatric emergency departments than other patients with a psychiatric diagnosis. Future studies should focus on (a) implementing further epidemiological studies in different countries; (b) tracking diagnostic practices to facilitate comparisons and provide feedback for training clinicians and raising awareness; and (c) estimating trajectories of PDs, including costs within the CAPS, to facilitate informed decision-making regarding the future organization and provision of services to these children, adolescents, and their families. [ABSTRACT FROM AUTHOR]

The article discusses the technical challenges of studying the impact of plasma components on the efficacy of lipid nanoparticles (LNPs) for vaccine and therapeutic applications. The authors question a method proposed by Liu et al. to isolate LNPs from plasma, expressing concerns about the potential co-isolation of lipoproteins and extracellular vesicles (EVs). They highlight the importance of understanding how LNPs interact with the biochemical environment they are intended to function in and suggest control experiments to verify the isolation method. The article emphasizes the need for further research to ensure accurate characterization of LNPs and their interactions with plasma constituents. [Extracted from the article]

Background: The reproductive years provide a window into future risk for Type 2 Diabetes (T2DM); women's risk is seven to 10 times higher after gestational diabetes (GDM) and two to four times higher after a hypertensive disorder of pregnancy (HDP). Targeting reproductive-aged women at high risk for T2DM could reduce future incidence. However, little is known about such women's diabetes risk perceptions, barriers to/motivators of lifestyle change or their knowledge about lifestyle change—information essential to understanding how to engage these at-risk women in tailored prevention programs promoting long-term health. This study's aims were to describe: among reproductive-aged women at high risk for T2DM, what is/are (1) personal health-risk awareness, (2) lifestyle-change interest, and (3) barriers to/motivators of participation in lifestyle-change programs? Methods: Women aged 18 and older were eligible if they had one of the following health risks: (1) GDM or HDP during pregnancy, (2) prediabetes diagnosis, or (3) BMI classified as obese. Three Zoom focus groups, organized by risk group, were conducted with a total of 20 participants. Qualitative content and thematic analysis were used for the focus-group transcriptions. Results: Women's personal health-risk awareness was limited and generalized (e.g., being overweight might lead to other risks) and rarely reflected awareness connected to their personal health history (e.g., GDM increases their lifetime risk of T2DM). Participants had at least one of the outlined eligibility health risks (e.g., GDM, prediabetes); they did not believe their healthcare providers sufficiently followed or addressed those risks. All women expressed interest in making healthy-lifestyle changes, including engagement in formal programs, but they identified multiple barriers to healthy-behavior change related to being "busy moms." Women emphasized the need for social support and realistic solutions that accounted for the dynamics of motherhood and family life. Common motivators included the desire to maintain health for their families and to set a good example for their children. Conclusions: Participants lacked knowledge and were eager for information. Healthcare improvement opportunities include better coordination of care between primary and specialty-care providers, and more frequent communication and education on diabetes-related health risks and long-term health. Formal lifestyle programs should tailor content by providing multiple formats and flexibility of scheduling while leveraging peer support for sustained engagement. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) is a metabolically diverse biofluid and a key specimen for exploring biochemical changes in neurodegenerative diseases. Detecting lipid species in CSF using mass spectrometry (MS)-based techniques remains challenging because lipids are highly complex in structure, and their concentrations span over a broad dynamic range. This work aimed to develop a robust lipidomics and metabolomics method based on commonly used two-phase extraction systems from human CSF samples. Prioritizing lipid detection, biphasic extraction methods, Folch, Bligh and Dyer (B&D), Matyash, and acidified Folch and B&D (aFolch and aB&D) were compared using 150 μL of human CSF samples for the simultaneous extraction of lipids and metabolites with a wide range of polarity. Multiple chromatographical separation approaches, including reversed-phase liquid chromatography (RPLC), hydrophilic interaction liquid chromatography (HILIC), and gas chromatography (GC), were utilized to characterize human CSF metabolome. The aB&D method was found as the most reproducible technique (RSD < 15%) for lipid extraction. The aB&D and B&D yielded the highest peak intensities for targeted lipid internal standards and displayed superior extracting power for major endogenous lipid classes. A total of 674 unique metabolites with a wide polarity range were annotated in CSF using, combining RPLC-MS/MS lipidomics (n = 219), HILIC-MS/MS (n = 304), and GC-quadrupole time of flight (QTOF) MS (n = 151). Overall, our findings show that the aB&D extraction method provided suitable lipid coverage, reproducibility, and extraction efficiency for global lipidomics profiling of human CSF samples. In combination with RPLC-MS/MS lipidomics, complementary screening approaches enabled a comprehensive metabolite signature that can be employed in an array of clinical studies. [ABSTRACT FROM AUTHOR]

The compound artemisinin is attributed to several biological activities including antimalaria for which it is popularly known. However, its commercial production is hindered by a low accumulation in Artemisia annua. Chemical synthesis of artemisinin is difficult and expensive, while exploration of microbial hosts resulted in partial synthesis requiring other chemical steps making the production system not cost effective. Metabolic engineering of artemisinin biosynthetic pathway in A. annua has been the point of focus, however, attention is now shifting towards more viable plant heterologous hosts. This review aims at discussing the latest advancements in enhancing artemisinin production with emphasis on the metabolic engineering of artemisinin biosynthetic pathway in A. annua and heterologous plant hosts, genes and transcription factors regulating artemisinin biosynthesis, and the roles of biotic and abiotic factors. The challenges and perspectives towards its commercial production were also discussed. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is increasing in prevalence and has a severe impact on patients' lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.72, 95%CI (0.71–0.73)). Higher age, BMI and prescription of non-steroidal anti-inflammatory drugs contributed most to increased OA risk prediction ahead of diagnosis. We identified 14 subgroups of OA risk profiles. These subgroups were validated in an independent set of patients evaluating the 11-year OA risk, with 88% of patients being uniquely assigned to one of the 14 subgroups. Individual OA risk profiles were characterised by personalised biomarkers. Omics integration demonstrated the predictive importance of key OA genes and pathways (e.g., GDF5 and TGF-β signalling) and OA-specific biomarkers (e.g., CRTAC1 and COL9A1). In summary, this work identifies opportunities for personalised OA prevention and insights into its underlying pathogenesis. Osteoarthritis can be caused by multiple biological mechanisms but the drivers of disease risk are not well understood. Here, the authors use data from UK Biobank in machine learning models to identify clinical and biological markers associated with development of osteoarthritis and identify sub-groups with different risk profiles. [ABSTRACT FROM AUTHOR]

We investigated the feasibility of using a dopamine transporter (DaT) tracer ligand ([123I]FP-CIT) along with novel multi-pinhole brain collimators for dynamic brain single photon emission computed tomography (SPECT) in suspected Parkinson's disease patients. Thirteen patients underwent dynamic tracer acquisitions before standard imaging. Uptake values were corrected for partial volume effects. Specific binding ratio (SBRcalc) was calculated, reflecting binding potential relative to non-displaceable binding (BPND) in the cortex. Additional pharmacokinetic parameters (BPND, R1, k2) were estimated using the simplified reference tissue model, revealing differences between Kahraman low-score (LS) and high-score (HS) groups. Results showed increasing striatal tracer uptake until 100 min post-injection, with consistent values afterward. Uptake and SBRcalc ratios matched visual assessment. LS patients had lower putamen than caudate nucleus tracer uptake, decreased BPND values, while R1 and k2 values were comparable to HS patients. In conclusion, dynamic multi-pinhole SPECT using DaT tracer with the extraction of pharmacokinetic parameters is feasible and could help enable early differentiation of reduced and normal DaT values. [ABSTRACT FROM AUTHOR]

Background: Abnormalities in cerebrospinal fluid (CSF)-amyloid-beta (Aβ)42, CSF-Aβ40, CSF-Aβ38, CSF-soluble amyloid precursor proteins α and β, CSF-total-tau, CSF-phosphorylated-tau, CSF-neurofilament light protein (NF-L), CSF-neurogranin, plasma-Aβ42, plasma-Aβ40, plasma-total-tau, plasma-NF-L and, serum-S100B during affective episodes may reflect brain changes that could impact cognitive function in patients with bipolar disorder (BD). The study aimed to investigate the association between these biomarkers indicative of Alzheimer's disease and those reflecting neurodegeneration alongside their impact on cognitive function in patients with BD and healthy control individuals (HC). The primary hypothesis was that GL and VL would increase with increasing levels of CSF-Aβ42 based on data from T0 and T3 in BD and HC jointly. Methods: In a prospective, longitudinal case–control study euthymic patients with BD (N = 85) and HC (N = 44) were evaluated with clinical assessment and neuropsychological testing at baseline (T0) and during euthymia after a year (T3). Patients' affective states were recorded weekly as euthymic, subthreshold level, major depression, or (hypo)mania. If an episode occurred during follow-up, the patient was also assessed in post-episode euthymia. Cognitive performance was measured as a global cognitive score (GL) for four cognitive domains including verbal learning and memory (VL). Results: Estimated in a linear mixed model GL increased with 0.001 for each increase of 1 pg/ml of CSF-Aβ42 (97.5%, CI 0.00043–0.0018, adjusted-p = 0.0005) while VL increased by 0.00089 (97.5%, CI 0.00015–0.0018, adjusted-p = 0.045) in BD and HC jointly. The association was weak, however stronger in patients with BD compared to HC. Associations between other biomarkers including CSF-neurogranin, and cognitive domains were overall weak, and none remained significant after adjustment for multiple testing. Limitations: Modest sample size. A complete data set regarding both CSF-AB-42 and cognitive test scores was obtained from merely 61 patients with BD and 38 HC individuals. Conclusion: CSF-Aβ42 may be associated with cognitive dysfunction in patients with BD and HC individuals. The association appeared to be stronger in BD but with overlapping confidence intervals. Hence it remains uncertain whether the association is a general phenomenon or driven by BD. [ABSTRACT FROM AUTHOR]

Purpose: To describe katG and inhA mutations, clinical characteristics, treatment outcomes and clustering of drug-resistant tuberculosis (TB) in the State of São Paulo, southeast Brazil. Methods: Mycobacterium tuberculosis isolates from patients diagnosed with drug-resistant TB were screened for mutations in katG and inhA genes by line probe assay and Sanger sequencing, and typed by IS6110-restriction fragment-length polymorphism for clustering assessment. Clinical, epidemiological and demographic data were obtained from surveillance information systems for TB. Results: Among the 298 isolates studied, 127 (42.6%) were isoniazid-monoresistant, 36 (12.1%) polydrug-resistant, 93 (31.2%) MDR, 16 (5.4%) pre-extensively drug-resistant (pre-XDR), 9 (3%) extensively drug-resistant (XDR) and 17 (5.7%) susceptible after isoniazid retesting. The frequency of katG 315 mutations alone was higher in MDR isolates, while inhA promoter mutations alone were more common in isoniazid-monoresistant isolates. Twenty-six isolates phenotypically resistant to isoniazid had no mutations either in katG or inhA genes. The isolates with inhA mutations were found more frequently in clusters (75%) when compared to the isolates with katG 315 mutations (59.8%, p = 0.04). In our population, being 35–64 years old, presenting MDR-, pre-XDR- or XDR-TB and being a retreatment case were associated with unfavourable TB treatment outcomes. Conclusion: We found that katG and inhA mutations were not equally distributed between isoniazid-monoresistant and MDR isolates. In our population, clustering was higher for isolates with inhA mutations. Finally, unfavourable TB outcomes were associated with specific factors. [ABSTRACT FROM AUTHOR]

Changes in pharmacokinetics and endogenous metabolites may underlie additive biological effects of concomitant use of antipsychotics and opioids. In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine + methadone (QTP + MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC–MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225–296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP + MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered. [ABSTRACT FROM AUTHOR]

Background: The LIMB-Q is a newly developed patient-reported outcome measure (PROM), applicable for lower extremity trauma patients requiring fracture treatment, soft tissue debridement, reconstruction, and/or amputation. The aim of this study was to translate and linguistically validate the LIMB-Q from English to Danish. Method: The translation and linguistic validation were performed by combining guidelines from the World Health Organization (WHO) and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). This approach involved 2 forward translations, a backward translation, an expert panel meeting, and 2 rounds of cognitive patient interviews. The main goal of these steps was to achieve a conceptual translation with simple and clear items. Feedback from the Danish translation was used in combination with psychometric analyses for item reduction of the final international version of LIMB-Q. Results: In the forward translation, 6 items were found difficult to translate into Danish. The two translations were harmonized to form the backward translation. From the backward translation, 1 item was identified with a conceptually different meaning and was re-translated. The revised version was presented at the expert panel meeting leading to revision of 10 items. The cognitive patient interviews led to revision of 11 items. The translation process led to a linguistically validated and conceptually equivalent Danish version of the LIMB-Q. Conclusion: The final Danish LIMB-Q version consisting of 16 scales is conceptually equivalent to the original and ready for field-testing in Denmark. Level of evidence: Not gradable. [ABSTRACT FROM AUTHOR]

We consider implicit representation of an arbitrary family of relations on finite sets. We derive upper and lower bounds for the general cases and for a number of restricted subfamilies, in particular for sparse and symmetric relations, and for relations first-order definable from families for which labeling schemes are already known. Our work extends existing work on implicit representation of graphs in two ways: (i) the known upper and lower bounds for many standard families of graphs are special cases of the results we derive; (ii) we allow families of relations to relate elements on both distinct sets and on multiple copies of the same set, and for different relations in the same family to have different arities, and to be defined on distinct or overlapping sets. The present paper is the first to study bounds on the size of labeling schemes for relations (including graphs) defined from existing relations using basic operations such as first-order logic. The techniques used to prove new results in this setting may be of independent interest. [ABSTRACT FROM AUTHOR]

Angelica sinensis roots (Angelica roots) are rich in many bioactive compounds, including phthalides, coumarins, lignans, and terpenoids. However, the molecular bases for their biosynthesis are still poorly understood. Here, an improved chromosome-scale genome for A. sinensis var. Qinggui1 is reported, with a size of 2.16 Gb, contig N50 of 4.96 Mb and scaffold N50 of 198.27 Mb, covering 99.8% of the estimated genome. Additionally, by integrating genome sequencing, metabolomic profiling, and transcriptome analysis of normally growing and early-flowering Angelica roots that exhibit dramatically different metabolite profiles, the pathways and critical metabolic genes for the biosynthesis of these major bioactive components in Angelica roots have been deciphered. Multiomic analyses have also revealed the evolution and regulation of key metabolic genes for the biosynthesis of pharmaceutically bioactive components; in particular, TPSs for terpenoid volatiles, ACCs for malonyl CoA, PKSs for phthalide, and PTs for coumarin biosynthesis were expanded in the A. sinensis genome. These findings provide new insights into the biosynthesis of pharmaceutically important compounds in Angelica roots for exploration of synthetic biology and genetic improvement of herbal quality.A chromosome-level genome assembly for Angelica sinensis var. Qinggui1 combined with metabolomic and transcriptomic analyses provides insight into the pathways involved in the biosynthesis of pharmaceutically important compounds in roots of this plant. [ABSTRACT FROM AUTHOR]

It is unclear whether children with autism spectrum disorders have atypical semantic fluency and lower memory for the semantics of words. Therefore, we examined semantic typicality, fluency and recall for the categories of fruits and animals in 60 children with autism aged 7–15 years (boys: 48/girls: 12) compared to 60 typically developing controls. Relative to controls, the autism group had reduced animal fluency, fruit typicality and recall for fruits. Notably, these measures were associated with more autistic-like symptoms and/or lower adaptive functioning across the autism and control groups. In conclusion, atypical semantics of fruits in the autism group may reflect development of idiosyncratic semantic networks while their lower semantic fluency and recall suggest impaired executive language functions. [ABSTRACT FROM AUTHOR]

Cells use noncanonical autophagy, also called conjugation of ATG8 to single membranes (CASM), to label damaged intracellular compartments with ubiquitin‐like ATG8 family proteins in order to signal danger caused by pathogens or toxic compounds. CASM relies on E3 complexes to sense membrane damage, but so far, only the mechanism to activate ATG16L1‐containing E3 complexes, associated with proton gradient loss, has been described. Here, we show that TECPR1‐containing E3 complexes are key mediators of CASM in cells treated with a variety of pharmacological drugs, including clinically relevant nanoparticles, transfection reagents, antihistamines, lysosomotropic compounds, and detergents. Interestingly, TECPR1 retains E3 activity when ATG16L1 CASM activity is obstructed by the Salmonella Typhimurium pathogenicity factor SopF. Mechanistically, TECPR1 is recruited by damage‐induced sphingomyelin (SM) exposure using two DysF domains, resulting in its activation and ATG8 lipidation. In vitro assays using purified human TECPR1‐ATG5‐ATG12 complex show direct activation of its E3 activity by SM, whereas SM has no effect on ATG16L1‐ATG5‐ATG12. We conclude that TECPR1 is a key activator of CASM downstream of SM exposure. Synopsis: TECPR1 utilizes its Dysferlin domains to detect cytosol‐exposed sphingomyelin at sites of membrane damage, which also triggers its E3 activity in CASM. Unlike ATG16L1, TECPR1 activity remains unaffected by the Salmonella Typhimurium factor SopF. TECPR1‐ATG5‐ATG12 is a key E3 complex in CASM response to membrane damage.TECPR1 is recruited by damage‐induced cytosolic sphingomyelin exposure.DysF domains of TECPR1 bind to sphingomyelin and activate its E3 activity.Inhibition of ATG16L1‐mediated CASM by the Salmonella Typhimurium factor SopF does not affect the E3 activity of TECPR1. [ABSTRACT FROM AUTHOR]

Human WIPI β-propellers function as PI3P effectors in autophagy, with WIPI4 and WIPI3 being able to link autophagy control by AMPK and TORC1 to the formation of autophagosomes. WIPI1, instead, assists WIPI2 in efficiently recruiting the ATG16L1 complex at the nascent autophagosome, which in turn promotes lipidation of LC3/GABARAP and autophagosome maturation. However, the specific role of WIPI1 and its regulation are unknown. Here, we discovered the ABL-ERK-MYC signalling axis controlling WIPI1. As a result of this signalling, MYC binds to the WIPI1 promoter and represses WIPI1 gene expression. When ABL-ERK-MYC signalling is counteracted, increased WIPI1 gene expression enhances the formation of autophagic membranes capable of migrating through tunnelling nanotubes to neighbouring cells with low autophagic activity. ABL-regulated WIPI1 function is relevant to lifespan control, as ABL deficiency in C. elegans increased gene expression of the WIPI1 orthologue ATG-18 and prolonged lifespan in a manner dependent on ATG-18. We propose that WIPI1 acts as an enhancer of autophagy that is physiologically relevant for regulating the level of autophagic activity over the lifespan. The ABL-ERK-MYC signaling axis inhibits WIPI1 gene expression, thereby controlling the autophagy-enhancing effect of WIPI1 in the context of C. elegans lifespan control. [ABSTRACT FROM AUTHOR]

Theory of mind (ToM) is considered crucial for understanding social-cognitive abilities and impairments. However, verbal theories of the mechanisms underlying ToM are often criticized as under-specified and mutually incompatible. This leads to measures of ToM being unreliable, to the extent that even canonical experimental tasks do not require representation of others' mental states. There have been attempts at making computational models of ToM, but these are not easily available for broad research application. In order to help meet these challenges, we here introduce the Python package tomsup: Theory of mind simulations using Python. The package provides a computational eco-system for investigating and comparing computational models of hypothesized ToM mechanisms and for using them as experimental stimuli. The package notably includes an easy-to-use implementation of the variational recursive Bayesian k-ToM model developed by (Devaine, Hollard, & Daunizeau, 2014b) and of simpler non-recursive decision models, for comparison. We provide a series of tutorials on how to: (i) simulate agents relying on the k-ToM model and on a range of simpler types of mechanisms; (ii) employ those agents to generate online experimental stimuli; (iii) analyze the data generated in such experimental setup, and (iv) specify new custom ToM and heuristic cognitive models. [ABSTRACT FROM AUTHOR]

Cognitive behavioural therapy (CBT) is recommended as the frontline treatment for depression and anxiety disorders and has been implemented in a wide range of mental health care contexts. In Danish mental health services, group CBT is the most common psychotherapeutic treatment format. Recently, a standardized, time-restricted treatment format has been implemented. No studies have investigated the patients' experiences of group CBT in such a format. Furthermore, few studies have investigated patients' experiences of group CBT for anxiety and depression. The current study set out to explore patients' experiences of group CBT for anxiety and depression and the role of a standardized, time-restricted treatment format, using a qualitative framework.We explored the experiences of 23 patients with a primary diagnosis of social anxiety, panic disorder/agoraphobia, or depression. Data were collected through semi-structured interviews. Data were analyzed using phenomenological narrative analysis. The results revealed a common narrative across the 23 interviews. The narrative was made up of six distinct themes, namely: How did I get here?; Being seen, heard and recognized; Shared responsibility of problems and solutions; Education and tools; Limitations of this group format; and Launchpad. The results indicated that the patients found group CBT helpful due to a range of factors, both common factors and treatment-specific factors. Patients expressed skepticism towards group CBT prior to beginning, because of a lack of information and previous failed treatment attempts. The patients highlighted the importance of the context of the mental health system by explaining how systemic factors impacted negatively on their psychotherapy experience. Many described feeling abandoned due to the sudden ending of a treatment course that was generally considered insufficient. [ABSTRACT FROM AUTHOR]

Lytic polysaccharide monooxygenases (LPMOs) are oxidative enzymes that help break down lignocellulose, making them highly attractive for improving biomass utilization in industrial biotechnology. The catalytically essential N-terminal histidine (His1) of LPMOs is post-translationally modified by methylation in filamentous fungi to protect them from auto-oxidative inactivation, however, the responsible methyltransferase enzyme is unknown. Using mass-spectrometry-based quantitative proteomics in combination with systematic CRISPR/Cas9 knockout screening in Aspergillus nidulans, we identify the N-terminal histidine methyltransferase (NHMT) encoded by the gene AN4663. Targeted proteomics confirm that NHMT was solely responsible for His1 methylation of LPMOs. NHMT is predicted to encode a unique seven-transmembrane segment anchoring a soluble methyltransferase domain. Co-localization studies show endoplasmic reticulum residence of NHMT and co-expression in the industrial production yeast Komagataella phaffii with LPMOs results in His1 methylation of the LPMOs. This demonstrates the biotechnological potential of recombinant production of proteins and peptides harbouring this specific post-translational modification. N-terminal histidine methylation modification has only been observed on certain fungal proteins. Here, the authors identify and validate the methyltransferase responsible for this modification through the combination of mass spectrometry-based proteomics and CRISPR/Cas9. [ABSTRACT FROM AUTHOR]

We consider the cons-free programming language of Neil Jones, a simple pure functional language, which decides exactly the polynomial-time relations and whose tail recursive fragment decides exactly the logarithmic-space relations. We exhibit a close relationship between the running time of cons-free programs and the running time of logspace-bounded auxiliary pushdown automata. As a consequence, we characterize intermediate classes like NC in terms of resource-bounded cons-free computation. In so doing, we provide the first "machine-free" characterizations of certain complexity classes, like P-uniform NC. Furthermore, we show strong polynomial lower bounds on cons-free running time. Namely, for every polynomial p, we exhibit a relation R ∈Ptime such that any cons-free program deciding R must take time at least p almost everywhere. Our methods use a "subrecursive version" of Blum complexity theory, and raise the possibility of further applications of this technology to the study of the fine structure of Ptime. [ABSTRACT FROM AUTHOR]

Regulation of cell division is crucial for the development of multicellular organisms, and in plants, this is in part regulated by the D-type cyclins (CYCD) and cyclin-dependent kinase A (CDKA) complex. Cell division regulation in Physcomitrium differs from other plants, by having cell division checks at both the G1 to S and G2 to M transition, controlled by the CYCD1/CDKA2 and CYCD2/CDKA1 complexes, respectively. This led us to hypothesize that upregulation of cell division could be archived in Bryophytes, without the devastating phenotypes observed in Arabidopsis. Overexpressing lines of PpCYCD1, PpCYCD2, PpCDKA1, or PpCDKA2 under Ubiquitin promotor control provided transcriptomic and phenotypical data that confirmed their involvement in the G1 to S or G2 to M transition control. Interestingly, combinatorial overexpression of all four genes produced plants with dominant PpCDKA2 and PpCYCD1 phenotypes and led to plants with twice as large gametophores. No detrimental phenotypes were observed in this line and two of the major carbon sinks in plants, the cell wall and starch, were unaffected by the increased growth rate. These results show that the cell cycle characteristics of P. patens can be manipulated by the ectopic expression of cell cycle regulators. [ABSTRACT FROM AUTHOR]

Background: This paper presents the baseline characteristics and their moderators in the Healthy Learning Mind (HLM)– school-based cluster-randomized controlled trial. Objectives: The paper evaluates the state of various measures of well-being, their moderators and how these results compare to national and global norms/population studies. Methods: Data were collected from all participants prior to the intervention and further analyzed by gender, grade and perceived socioeconomic status, including standardized measures for resilience, depressive symptoms and socioemotional functioning; health-related quality of life, dispositional mindfulness, satisfaction with life, compassion/self-kindness, self-rated health and morning tiredness. Results: Participating 2793 students (1425 girls, 1368 boys), ages 12 to 15 years, filled in the questionnaires. The outcomes were in line with previous research, demonstrating gender differentiation and lower wellbeing among older children and adolescents. Conclusions: All outcomes were associated with perceived socioeconomic status, suggesting that perceived low socioeconomic status should be addressed as a serious risk factor and included as a moderator in similar trials. [ABSTRACT FROM AUTHOR]

There exists a marked circadian variation for several bone markers (BM), which is influenced by endogenous as well as exogenous factors including hormones, physical activity, and fasting. Consequently, was the aim of this review to provide an overview of the knowledge of the circadian variation of BM and which factors influence this rhythmicity. A systematic search of PubMed was performed for studies evaluating the circadian variation of BM and which factors influence this rhythmicity. The studies were screened for eligibility by a set of predetermined criteria including a list of relevant BM and a minimum study duration of 24 h with at least 3 blood samples of which two should be at least 6 h apart. In total were 29 papers included. There exists a marked circadian variation for most BM including Carboxy-terminal Cross-Linked Telopeptide of Type I Collagen (CTX) and osteocalcin (OC) with nighttime or early morning peak. Pro-collagen Type I N-terminal Propeptide (PINP) and PTH also showed circadian rhythm but with less amplitude. The inter-osteoblast-osteoclast regulatory markers such as OPG, RANKL, FGF23, and sclerostin showed no circadian rhythm. The markers were differently affected by exogenous factors like fasting, which greatly reduced the circadian variation of CTX but did not affect PINP or OC. The marked circadian variation and the factors which influence the rhythmicity, e.g., fasting are of great consequence when measuring BM. To reduce variation and heighten validity should circadian variation and fasting be kept in mind when measuring BM. [ABSTRACT FROM AUTHOR]

In this work principal component analysis (PCA) was used to study the effect of batch, reduction temperature, TiO2 content and UV-C irradiation on the surface energy, -polarity and interlayer spacing of photoactive TiO2/GO composite membranes. Two PCA models were successfully developed. The first PCA model shows a negative correlation between reduction temperature and d-spacing. Less hydrophilic TiO2/GO membranes were obtained at 160 °C compared to membranes reduced at 140 °C. Also, the surface polarity and surface energy were significantly enhanced by the addition of higher TiO2 content. The second model explain the effect of UV-C activation on the surface energy of the TiO2/GO composite membranes. For the GO membranes containing TiO2 a significant increase in surface energy and -polarity was observed after UV-C activation. Moreover, a positive correlation between the TiO2 content and surface energy after UV-C activation was observed. Higher TiO2 content results in higher surface energy. GO batches prepared by different groups was not found to significantly affect the properties of the TiO2/GO composite membranes suggesting that the preparation method is relative robust. [ABSTRACT FROM AUTHOR]

Efficient plasma membrane repair (PMR) is required to repair damage sustained in the cellular life cycle. The annexin family of proteins, involved in PMR, are activated by Ca2+ influx from extracellular media at the site of injury. Mechanistic studies of the annexins have been overwhelmingly performed using a single annexin, despite the recruitment of multiple annexins to membrane damage sites in living cells. Hence, we investigate the effect of the presence of the crosslinking annexins, annexin A1, A2 and A6 (ANXA1, ANXA2 and ANXA6) on the membrane curvature induction of annexin A4 (ANXA4) in model membrane systems. Our data support a mechanistic model of PMR where ANXA4 induced membrane curvature and ANXA6 crosslinking promotes wound closure. The model now can be expanded to include ANXA1 and ANXA2 as specialist free edge membrane crosslinkers that act in concert with ANXA4 induced curvature and ANXA6 crosslinking. [ABSTRACT FROM AUTHOR]

TRPV2 is a ligand-operated temperature sensor with poorly defined pharmacology. Here, we combine calcium imaging and patch-clamp electrophysiology with cryo-electron microscopy (cryo-EM) to explore how TRPV2 activity is modulated by the phytocannabinoid Δ9-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from rat and human mast cells. Each ligand causes distinct conformational changes in TRPV2 as revealed by cryo-EM. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine. Taken together, we discover a new cannabinoid binding site in TRPV2 that is under the influence of allosteric control by probenecid. This molecular insight into ligand modulation enhances our understanding of TRPV2 in normal and pathophysiology. TRPV2 is activated by temperature and cannabinoids. Here, the authors have used cryo-EM and electrophysiology to identify a cannabinoid binding site distinct from that of cannabidiol as a possible drug target for treatment of inflammation and immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: The objective was to examine the association between reproductive and anthropometric factors and later risk of pelvic organ prolapse (POP). Methods: We carried out a prospective cohort study including 11,114 female nurses > 44 years from the Danish Nurse Cohort. In 1993, the study population was recruited through the Danish Nurse Organization and self-reported data on age, height, weight, age at menarche, age at first birth and number of childbirths were obtained. POP diagnosis was obtained from the National Patient Registry. Risk of POP was estimated using COX regression and presented as hazard ratios (HR) with 95% confidence intervals (CI). Results: Overall, 10% of the women received a diagnosis of POP within a median follow-up of 22 years. A 4% increase in risk of POP was seen for each increasing BMI (kg/m2) unit at baseline. Compared to women of normal weight, higher risks of POP were seen in overweight (HR 1.18: 1.02–1.36) and obese women (HR 1.33: 1.02–1.74), while underweight had a lower risk (HR 0.51: 0.27–0.95). Compared to women with one childbirth, women with no childbirths had a reduced risk of 57% while increased risks of 46%, 78% and 137% were observed in women with two, three and four childbirths. Women with menarche before the age of 12 tended to have a higher risk of POP as did women who were 30–33 years at their first childbirth. Conclusions: POP is a common health problem in women, and BMI and number of childbirths are strong predictors. [ABSTRACT FROM AUTHOR]

The medial entorhinal cortex (MEC) plays a pivotal role in spatial processing together with hippocampal formation. The retrosplenial cortex (RSC) is also implicated in this process, and it is thus relevant to understand how these structures interact. This requires precise knowledge of their connectivity. Projections from neurons in RSC synapse onto principal neurons in layer V of MEC and some of these neurons send axons into superficial layers of MEC. Layer V of MEC is also the main target for hippocampal efferents from the subiculum and CA1 field. The aim of this study was to assess whether the population of cells targeted by RSC projections also receives input from the hippocampal formation and to compare the distribution of synaptic contacts on target dendrites. We labeled the cells in layer V of MEC by injecting a retrograde tracer into superficial layers. At the same time, we labeled RSC and subicular projections with different anterograde tracers. 3D-reconstruction of the labeled cells and axons revealed likely synaptic contacts between presynaptic boutons of both origins and postsynaptic MEC layer V basal dendrites. Moreover, these contacts overlapped on the same dendritic segments without targeting specific domains. Our results support the notion that MEC layer V neurons that project to the superficial layers receive convergent input from both RSC and subiculum. These data thus suggest that convergent subicular and RSC information contributes to the signal that neurons in superficial layers of EC send to the hippocampal formation. [ABSTRACT FROM AUTHOR]

During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events. We further show that the ER-localized cholesterol transport protein GRAMD1C functions as a negative regulator of starvation-induced autophagy and that both its cholesterol transport VASt domain and membrane binding GRAM domain are required for GRAMD1C-mediated suppression of autophagy initiation. Similar to its yeast orthologue, GRAMD1C associates with mitochondria through its GRAM domain. Cells lacking GRAMD1C or its VASt domain show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting that GRAMD1C may facilitate cholesterol transfer at ER-mitochondria contact sites. Finally, we demonstrate that expression of GRAMD family proteins is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins. The functions of specific lipids in autophagosome biogenesis are not entirely clear. Here, the authors show that the ER protein GRAMD1C, a cholesterol transport protein, suppresses autophagy initiation and has roles in mitochondrial cholesterol homeostasis and respiration. [ABSTRACT FROM AUTHOR]

Dementia have substantial negative impact on the affected individual, their care partners and society. Persons living with Parkinson's disease (PwP) are also to a large extent living with dementia. The aim of this study is to estimate time to dementia in PD using data from a large quality register with access to baseline clinical and patient reported data merged with Swedish national health registries. Persons with Parkinson's disease in the Swedish Neuro Registries/Parkinson's Disease Swedish PD Registry (PARKreg) in Sweden were included and linked to national health registries and matched by sex and age to controls without PD. Time to dementia was analysed with Cox regression models assuming proportional hazards, with time since diagnosis as the underlying time variable. In this large prospective cohort study, PwP had approximately four times higher risk of developing dementia as compared to age and sex-matched controls, a finding which remained after adjusting for potential confounders. The present results underline the high risk of dementia in PD and further emphasize the importance of developing symptomatic and ultimately disease modifying strategies to counteract this part of the non-motor symptomatology in PD. [ABSTRACT FROM AUTHOR]

Declarations Conflicts of interest Dr. Braemswig is a participant in the Berlin Institute of Health-Charité Clinician Scientist Program funded by the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health. Dr. Schlemm is a participant in the Berlin Institute of Health-Charité Clinician Scientist Program funded by the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health. [Extracted from the article]

Objective: Magnetic resonance imaging (MRI)-based techniques for non-invasive assessing liver iron concentration (LIC) in patients with iron overload have a limited upper measuring range around 35 mg/g dry weight, caused by signal loss from accelerated T1-, T2-, T2* shortening with increasing LIC. Expansion of this range is necessary to allow evaluation of patients with very high LIC. Aim: To assess measuring range of a gradient-echo R2* method and a T1-weighted spin-echo (SE), signal intensity ratio (SIR)-based method (TE = 25 ms, TR = 560 ms), and to extend the upper measuring range of the SIR method by optimizing echo time (TE) and repetition time (TR) in iron-loaded minipigs. Methods: Thirteen mini pigs were followed up during dextran-iron loading with repeated percutaneous liver biopsies for chemical LIC measurement and MRIs for parallel non-invasive estimation of LIC (81 examinations) using different TEs and TRs. Results: SIR and R2* method had similar upper measuring range around 34 mg/g and similar method agreement. Using TE = 12 ms and TR = 1200 ms extended the upper measuring range to 115 mg/g and yielded good method of agreement. Discussion: The wider measuring range is likely caused by lesser sensitivity of the SE sequence to iron, due to shorter TE, leading to later signal loss at high LIC, allowing evaluation of most severe hepatic iron overload. Validation in iron-loaded patients is necessary. [ABSTRACT FROM AUTHOR]