julilili42/papers huggingface dataset:
Cognitive composites for genetic frontotemporal dementia: GENFI-Cog
2022-01-19

Abstract Background Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. Methods A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72 , 41 GRN , and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be). Results The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72 , GRN , and MAPT ). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period. Discussion We created gene-specific cognitive composite scores for C9orf72 , GRN , and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
Hyperglycemia, Risk of Subsequent Stroke, and Efficacy of Dual Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial
2022-01-19

Background One‐quarter of all strokes are subsequent events. It is not known whether higher levels of blood glucose are associated with an increased risk of subsequent stroke after high‐risk transient ischemic attack or minor ischemic stroke. Methods and Results We performed a secondary analysis of the POINT (Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial to evaluate the relationship between serum glucose hyperglycemia (≥180 mg/dL) versus normoglycemia (&lt;180 mg/dL) before enrollment in the trial and outcomes at 90 days. The primary end point was subsequent ischemic stroke modeled by a multivariable Cox model with adjustment for age, sex, race, ethnicity, study treatment assignment, index event, and key comorbidities. Of 4878 patients included in this study, 267 had a recurrent stroke. There was a higher hazard of subsequent stroke in patients with hyperglycemia compared with normoglycemia (adjusted hazard ratio [HR], 1.50 [95% CI, 1.05–2.14]). Treatment with dual antiplatelet therapy was not associated with a reduced hazard of subsequent stroke in patients with hyperglycemia (HR, 1.18 [95% CI, 0.69–2.03]), though the wide confidence interval does not exclude a treatment effect. When modeled as a continuous variable, there was evidence of a nonlinear association between serum glucose and the hazard of subsequent stroke ( P &lt;0.001). Conclusions Hyperglycemia on presentation is associated with an increased risk of subsequent ischemic stroke after high‐risk transient ischemic attack or minor stroke. A rapid, simple assay of serum glucose may be a useful biomarker to identify patients at particularly high risk of subsequent ischemic stroke. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT0099102.
Systematic Assessment of the Accuracy of Subunit Counting in Biomolecular Complexes Using Automated Single-Molecule Brightness Analysis
2022-01-19

Analysis of single-molecule brightness allows subunit counting of high-order oligomeric biomolecular complexes. Although the theory behind the method has been extensively assessed, systematic analysis of the experimental conditions required to accurately quantify the stoichiometry of biological complexes remains challenging. In this work, we develop a high-throughput, automated computational pipeline for single-molecule brightness analysis that requires minimal human input. We use this strategy to systematically quantify the accuracy of counting under a wide range of experimental conditions in simulated ground-truth data and then validate its use on experimentally obtained data. Our approach defines a set of conditions under which subunit counting by brightness analysis is designed to work optimally and helps in establishing the experimental limits in quantifying the number of subunits in a complex of interest. Finally, we combine these features into a powerful, yet simple, software that can be easily used for the analysis of the stoichiometry of such complexes.
Rational Design of Pore Parameters in Monodisperse Porous Poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) Particles Based on Response Surface Methodology
2022-01-19

Monodisperse porous poly(glycidyl methacrylate-co–ethylene glycol dimethacrylate) particles are widely applied in different fields, as their pore properties can be influenced and functionalization of the epoxy group is versatile. However, the adjustment of parameters which control morphology and pore properties such as pore volume, pore size and specific surface area is scarcely available. In this work, the effects of the process factors monomer:porogen ratio, GMA:EDMA ratio and composition of the porogen mixture on the response variables pore volume, pore size and specific surface area are investigated using a face centered central composite design. Non-linear effects of the process factors and second order interaction effects between them were identified. Despite the complex interplay of the process factors, targeted control of the pore properties was possible. For each response a response surface model was derived with high predictive power (all R2predicted &gt; 0.85). All models were tested by four external validation experiments and their validity and predictive power was demonstrated.
Effect of fire on the palatability of plants in an African woodland savanna: varying impacts depending on plant functional groups
2022-01-19

Fire and herbivores are two important drivers of changes in vegetation composition, quality and dynamics and both are highly related to each other. Herbivores are known to respond to fire both in terms of foraging decisions and distribution. However, little is known about the actual changes in plant chemistry following a fire event and how long these changes will last. We investigated the effect of fire on two different plant functional groups (grasses and woody species) in a woodland savanna of southern Africa. We studied chemical compounds known to be important for palatability of five perennial grass and seven woody species (trees and shrubs) common in the woodland savanna and known to be utilized by herbivores. We wanted to know if plant chemistry differs between a recently burned site (burned 2 years ago) and a control site, burned 16 years ago, and if grasses and woody species show similar relative differences between sites ( i.e. , the plants’ response to fire). We found a clear difference in chemical composition patterns between the plant functional groups, with an almost homogenous response to fire among woody species, but higher variability in response among grass species. Furthermore, we found that woody species maintained a higher nutritional value even 2 years after burning, whereas grasses did not show clear differences among the two investigated sites. Hence, few years after burning, woody plants might still serve as an attraction for herbivores, especially browsers, in contrast to grasses. The knowledge about these differences between the two functional groups in response to fire is beneficial for the development of management strategies for large herbivores whether domestic or wild.
Intranasal orexin A modulates sympathetic vascular tone: a pilot study in healthy male humans
2022-01-19

Our pilot study adds another important part to the complex network of neuroendocrine-sympathetic interaction. Our results demonstrate that intranasal orexin A elicits an excitatory effect on sympathetic vascular tone superordinate to mere baroreflex feedback regulation. This resetting of the baroreflex set point suggests an activation of hypothalamic core centers such as the paraventricular nucleus (PVN). The role of the orexinergic system in the development of neurogenic arterial hypertension warrants further investigations.
Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: The DEMAND randomized phase II clinical trial.
2022-01-19

TPS492 Background: Atezolizumab and bevacizumab is the first approved immunotherapeutic regimen for first-line treatment of patients with advanced hepatocellular carcinoma (HCC). The efficacy and tolerability of this regimen suggests that its use could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The effect of TACE combined with atezolizumab and bevacizumab could improve response and tumor control as well as prevent disease progression in non-responders to TACE. Response to the early use of immunotherapy could also reduce the number and extent of TACE cycles needed to achieve tumor control, thereby contributing to the prevention of collateral damage to the liver parenchyma and preservation of liver function. Initiating immunotherapy first may also promote the access of circulating lymphocytes into tumor lesions. The DEMAND study investigates the efficacy and ideal sequence of TACE and immunotherapy in intermediate stage HCC. Methods: This investigator-initiated, multi-center, randomized, open-label phase 2 trial is the first study to evaluate the safety and efficacy of atezolizumab and bevacizumab prior to, or in combination with TACE in patients with unresectable HCC. 106 patients (Barcelona Clinic Liver Cancer Stage A not amenable to curative therapy or B, Child-Pugh A or B7, Eastern Cooperative Oncology Group performance status 0 or 1, no prior TACE) will be randomized in a 1:1 ratio to receive either up-front atezolizumab and bevacizumab followed by TACE selectively directed against progressive lesions (Arm A, 53 patients), or TACE and synchronous treatment with atezolizumab and bevacizumab (Arm B, 53 patients). Patients receive study treatment until loss of clinical benefit or unacceptable toxicity for up to 24 months. The use of local ablation is allowed for the treatment of lesions which cannot be targeted sufficiently selectively by TACE, or of de-novo lesions. The primary endpoint is the 24-month survival rate; secondary endpoints include objective response rate, progression-free survival, safety and quality of life. Translational analyses aim at identifying predictive biomarkers and focus on immune cell phenotyping in tumor and peripheral blood, circulating tumor DNA and changes in the diversity of the gut microbiome. Recruitment is ongoing in 15 German centers with 21 of 106 patients randomized. Clinical trial information: NCT04224636.
Reply to Komatsu et al.: From local social mindfulness to global sustainability efforts?
2022-01-19

Komatsu et al. (1) argue that Van Doesum et al. (2)\\nmay have overlooked the role of GDP in reporting a\\npositive association between social mindfulness\\n(SoMi) and the Environmental Performance Index\\n(EPI) at country level. Although the relationship\\nbetween EPI and SoMi is relatively weaker for countries with higher GDP, that does not imply that the\\noverall observed relationship is a statistical artifact.\\nRather, it implies that GDP may be a moderator of\\nthe relationship between EPI and SoMi. The\\nobserved correlation is a valid result on average\\nacross countries, and the actual effect size would, at\\nleast to some degree, depend on GDP.
Nonafluorobutanesulfonyl Fluoride
2022-01-19

[375-72-4] C4F10O2S (MW 302.11) InChI = 1S/C4F10O2S/c5-1(6,3(9,10)11)2(7,8)4(12,13)17(14,15)16 InChIKey = LUYQYZLEHLTPBH-UHFFFAOYSA-N (Cost effective and stable reagent for: the formation of alkyl nonaflates or alkyl fluorides from alkanols; the formation of aryl and alkenyl nonaflates (useful aryl and alkenyl triflate analogues) from the corresponding oxygen functions; the formation of nonafluorobutanesulfonamides from amines and for the diazotransfer agent nonaflyl azide from azide salts; formation of nonafluorobutanesulfones from carbon nucleophiles; powerful dehydrating agent, in the presence of phosphazene bases, to convert alkyl aldehydes and alkyl ketones to alkynes) Alternative Name: NfF. Physical Data: bp 65–66 °C/760 mmHg; d 1.682 g cm−3. Solubility: sol ether, THF; insol CH2Cl2. Form Supplied in: colorless to pale yellow liquid of 90% purity; impurities are branched nonafluorobutanesulfonyl fluorides. Analysis of Reagent Purity: 19F NMR1; MS.2 Preparative Methods: by electrochemical fluorination of alkanesulfonyl halides in anhyd HF at 4–6 V,3 or, better, by electrochemical fluorination of sulfolene.1 Purification: dried over CaCl2 and distilled. Handling, Storage, and Precautions: store in amber colored bottles protected from light; for prolonged storage, PVC bottles are recommended.
A residual marker of cognitive reserve is associated with resting-state intrinsic functional connectivity along the Alzheimer’s disease continuum
2022-01-19

Abstract Background Cognitive reserve (CR) explains interindividual differences in the impact of neurodegenerative burden on cognitive and daily functioning. A residual model was proposed to estimate CR more accurately compared to static measures, such as years of education. However, the functional brain correlates of residual CR markers (CRM) remain unexplored. Methods From the DELCODE cohort, 318 participants with resting-state functional and structural MRI data were included and stratified using cerebrospinal fluid (CSF) biomarkers according to the A(myloid-β, Aβ)/T(au)/N(eurodegeneration) classification scheme, resulting in 112 Aβ-negative healthy controls and 206 Aβ-positive patients in the Alzheimer’s disease (AD) spectrum.. CRM was calculated utilizing residuals obtained from a multilinear regression model using global cognition as dependent variable and demographic and disease burden measures as predictors. Associations between the CRM and intrinsic network connectivity (INC) in resting-state networks associated with cognition were explored, including the default mode network (DMN), frontoparietal network (FPN), salience network (SAL) and dorsal attention network (DAN). Moreover, the association between memory performance-associated regional INC and CRM was assessed. Results CRM was positively associated with INC in the DMN in the entire cohort. In a subgroup analysis, the A+T+N+ group revealed an anti-correlation between SAL and DMN. Furthermore, CRM was positively associated with the anti-correlation between the memory-related regions in the FPN and the DMN in the A+ and A+T/N+ subgroups. Conclusions CRM is associated with alterations of functional connectivity in resting-state networks of cognitive function, particularly the DMN and the FPN. Our results provide evidence on individual functional network differences associated with CRM in the AD continuum.
Safety and efficacy of pressurized intraperitoneal aerosolized chemotherapy in appendiceal and colorectal cancer patients with peritoneal carcinomatosis: A first-in-US phase I study.
2022-01-19

125 Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is being evaluated as a novel minimally invasive palliative treatment of peritoneal metastases (PM). Prior studies have established the feasibility and safety of repeated PIPAC treatments in gastrointestinal and gynecologic cancers. The goal of the present phase 1 trial was to establish the safety and feasibility of PIPAC oxaliplatin in a highly chemotherapy refractory colorectal and appendiceal cancer patient population. Methods: Patients with biopsy-proven peritoneal metastases from colorectal or appendiceal cancer underwent up to three PIPAC treatments using oxaliplatin (92 mg/m 2 ) with a six-week interval at two academic centers. Patients with bowel obstruction, extra-peritoneal metastases, or poor performance status (ECOG&gt;2) were excluded. PIPAC was nebulized over 5 min with a 30 min aerosol dwell time. Apart from the first PIPAC cycle, the patients also received a sensitizing dose of 5FU/LV (400mg/m 2 ) within 24 hours of the procedure. Primary end point was safety as assessed by dose limiting toxicities within 6 weeks of the first PIPAC. Secondary endpoints included safety with the addition of 5FU/LV, efficacy, surgical morbidity, technical failure rate, progression-free and overall survival, pharmacokinetics (PK), and quality of life assessment. Results: A total of 8 patients were included: 5 colorectal; and 3 appendiceal. Median number of prior chemotherapy cycles was 2 (Interquartile range – IQR; 1.5-3.5). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median time from diagnosis to PIPAC was 16 months (IQR; 5.6, 17.5) and Peritoneal Carcinomatosis Index was 29 (IQR; 20.5, 31.5). Five (62.5%) patients completed 3 PIPAC cycles while in 3 (37.5%) patients PIPAC was discontinued due to disease progression within the peritoneal cavity. No surgical complication or dose limiting toxicity was observed. Only one patient developed grade 3 treatment-related toxicity after first PIPAC (anemia), and another patient after second PIPAC (abdominal pain and anemia). At the completion of PIPAC treatment 5 patients had stable disease and 3 had disease progression. Pharmacokinetic, histologic response and preliminary survival data will be presented at the meeting. Conclusions: PIPAC with oxaliplatin is safe and feasible in a highly chemotherapy refractory cohort of appendiceal and colorectal carcinomatosis patients with or without sensitizing 5-FU/ LV. Clinical trial information: NCT04329494.
Medication Adherence in a Cross-Diagnostic Sample of Patients From the Affective-to-Psychotic Spectrum: Results From the PsyCourse Study
2022-01-20

Introduction According to the World Health Organization, medication adherence is defined as the extent to which a person's behavior corresponds with an agreed recommendation from a healthcare provider. Approximately 50% of patients do not take their medication as prescribed, and non-adherence can contribute to the progress of a disease. For patients suffering from mental diseases non-adherence plays an important role. Various factors have been proposed as contributing to non-adherence, however the literature remains heterogeneous dependent on the analyzed patient subgroups. This study comprehensively evaluates the association of sociodemographic, clinical, personality and quality of life related factors with medication adherence by analyzing data from the PsyCourse study. The PsyCourse study is a large and cross-diagnostic cohort of psychiatric patients from the affective-to-psychotic spectrum. Methods The study sample comprised 1,062 patients from the PsyCourse study with various psychiatric diagnoses (mean [SD] age, 42.82 [12.98] years; 47.4% female). Data were analyzed to identify specific factors associated with medication adherence, and adherence was measured by a self-rating questionnaire. Odds ratios (OR) were estimated by a logistic regression for binary outcomes. Missing data were imputed using multiple imputation. Results The following factors showed the strongest association with medication adherence: never having used illicit drugs (OR, 0.71), number of prescribed antipsychotics (OR, 1.40), the personality trait conscientiousness (OR, 1.26), and the environmental domain of quality of life (OR, 1.09). Conclusion In a large and cross-diagnostic sample, we could show that a higher level of conscientiousness, a higher number of antipsychotic medication, a better quality of life within the environmental domain, and the absence of substance abuse contribute to a better medication adherence independent of the underlying disorder.
Novel GNE Gene Variants Associated with Severe Congenital Thrombocytopenia and Platelet Sialylation Defect
2022-01-20

Abstract The GNE gene encodes an enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically associated with Nonaka myopathy and sialuria, following an autosomal recessive and autosomal dominant inheritance pattern. Reports show that single GNE variants cause severe thrombocytopenia without muscle weakness. Using panel sequencing, we identified two novel compound heterozygous variants in GNE in a young girl with life-threatening bleedings, severe congenital thrombocytopenia, and a platelet secretion defect. Both variants are located in the nucleotide-binding site of the N-acetylmannosamin kinase domain of GNE. Lectin array showed decreased α-2,3-sialylation on platelets, consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. Hematopoietic stem cell transplantation (HSCT) normalized platelet counts. This is the first report of an HSCT in a patient with an inherited GNE defect leading to normal platelet counts.
Pathological Response in the Breast and Axillary Lymph Nodes after Neoadjuvant Systemic Treatment in Patients with Initially Node-Positive Breast Cancer Correlates with Disease Free Survival: An Exploratory Analysis of the GeparOcto Trial
2022-01-20

Background: The conversion of initially histologically confirmed axillary lymph node-positive (pN+) to ypN0 after neoadjuvant systemic treatment (NAST) is an important prognostic factor in breast cancer (BC) patients and may influence surgical de-escalation strategies. We aimed to determine pCR rates in lymph nodes (pCR-LN), the breast (pCR-B), and both (tpCR) in women who present with pN+ BC, to assess predictors for response and the impact of pCR-LN, pCR-B, and tpCR on invasive disease-free survival (iDFS). Methods: Retrospective, exploratory analysis of 242 patients with pN+ at diagnosis from the multicentric, randomized GeparOcto trial. Results: Of 242 patients with initially pN+ disease, 134 (55.4%) had a pCR-LN, and 109 (45.0%) a pCR-B. Of the 109 pCR-B patients, 9 (8.3%) patients had involved LN, and 100 (41.3%) patients had tpCR. Those with involved LN still had a bad prognosis. As expected, pCR-B and intrinsic subtypes (TNBC and HER2+) were identified as independent predictors of pCR-LN. pCR-LN (ypN0; hazard ratio 0.42; 95%, CI 0.23–0.75; p = 0.0028 for iDFS) was the strongest independent prognostic factor. Conclusions: In initially pN+ patients undergoing NAST, the conversion to ypN0 is of high prognostic value. Surgical axillary staging after NAST is still essential in these patients to offer tailored treatment.