Miracle-dz/UniFAR-FTUs huggingface dataset:
Nano-crystallization of flubendazole for enhanced dissolution rate and improved in vivo efficacy against Trichinella spiralis

Abstract The aim was to enhance the dissolution rate and in vivo efficacy of flubendazole against trichinella spiralis. Flubendazole nanocrystals were developed by controlled anti-solvent recrystallization. Saturated flubendazole solution was prepared in DMSO. This was injected into phosphate buffer (pH 7.4) containing Aerosil 200, Poloxamer 407 or sodium lauryl sulphate (SLS) while mixing using paddle mixer. The developed crystals were separated from DMSO/aqueous system by centrifugation. The crystals were characterized using DSC, X-ray diffraction and electron microscopy. The crystals were suspended in Poloxamer 407 solution and dissolution rate was monitored. Optimal formulation was administered to Trichinella spiralis infected mice. Administration protocol attacked the parasite in intestinal, migrating and encysted phases. The crystals were spherical nanosized with formulation employing 0.2% Poloxamer 407 as stabilizer being optimum with size of 743.1 nm. DSC and X-ray supported particle size reduction with partial amorphization. Optimal formulation showed fast dissolution to deliver 83.1% after 5 min. Nanocrystals provided complete eradication of intestinal Trichinella and reduced larval count by 90.27 and 85.76% in migrating and encysted phases compared with marginal effect in case of unprocessed flubendazole. The efficacy was clearer from improved histopathological features of the muscles. The study introduced nano-crystallization for enhanced dissolution and in vivo efficacy of flubendazole.
Differentiation of Self and Interpersonal Functioning with the Level of Personality Functioning Scale – Brief Form 2.0

Abstract Research on Criterion A of the alternative model for personality disorders is recently expanding and provides mixed results concerning the unidimensional operational definition of severity by the model, characterized by impaired self (identity and self-direction) and interpersonal (empathy and intimacy) functioning. Studies resulted in one, as well as two or more factor structures. The present study demonstrated the importance of the structural and relational differentiation of self and interpersonal dimensions of personality functioning. One thousand seventy-four participants (community and clinical mixed sample) completed the Level of Personality Functioning Scale – Brief Form 2.0 (LPFS-BF 2.0), the Personality Inventory for DSM-5 Short Form and the Questionnaire for the World Health Organization Disability Assessment. An LPFS-BF 2.0 two-factor structure with self and interpersonal functioning factors was corroborated by confirmatory factor analyses and bifactor modeling. Joint Exploratory Factor Analysis of the LPFS-BF 2.0 domains with maladaptive personality domains clearly differentiated the personality functioning factors. While the self-functioning factor was more closely linked to negative affect (and to disinhibition and psychoticism), the interpersonal functioning factor connected to detachment. Self-functioning predicted functional impairment along and beyond personality domains. The LPFS-BF 2.0 appears a useful tool for clinical routine monitoring of both self and interpersonal functioning.
Neoadjuvant Pyrotinib plus Trastuzumab, Docetaxel, and Carboplatin in Early or Locally Advanced Human Epidermal Receptor 2-Positive Breast Cancer in China: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

Introduction: This multicenter, randomized, double-blind, placebo-controlled phase 2 trial compared the efficacy, and safety of adding pyrotinib to trastuzumab, docetaxel, and carboplatin versus placebo, trastuzumab, docetaxel, and carboplatin in Chinese patients with human epidermal receptor 2 (HER2)-positive early or locally advanced breast cancer (ClinicalTrials.gov identifier: NCT03756064). Methods: Sixty-nine women with HER2-positive early (T1-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) were recruited from October 1, 2019, to June 1, 2021. Before surgery, patients received 6 cycles of orally pyrotinib (400 mg once per day), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), docetaxel (75 mg/m2), and carboplatin (AUC = 6 mg/mL·min) or orally placebo, trastuzumab, and docetaxel, and carboplatin every 3 weeks. The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by age, hormone receptor status, tumor stage, nodal status, cTNM stage, and Ki-67 level was used to compare rates between treatment groups. Results: In total, 69 female patients were randomized (pyrotinib, 36; and placebo, 33; median age, 53 [31–69] years). In the intention-to-treat population, total pathologic complete response rates were 65.5% (19/29) in the pyrotinib group and 33.3% (10/30) in the placebo group (difference, 32.2%, p = 0.013). Diarrhea was been reported in 86.1% of patients (31/36) in the pyrotinib group as the most common adverse events (AEs) and 15.2% of patients (5/33) in the placebo group. But no grade 4 or 5 AEs were reported. Conclusion: Treatment with pyrotinib, trastuzumab, docetaxel, and carboplatin resulted in a statistically significant improvement in the total pathologic complete response rate versus placebo, trastuzumab, docetaxel, and carboplatin for the neoadjuvant treatment of HER2-positive early or locally advanced breast cancer in Chinese patients. Safety data were in line with the known pyrotinib safety profile and generally comparable between treatment groups.
The clinical phenotype of germline RUNX1 mutations in relation to the accompanying somatic variants and RUNX1 isoform expression

Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, abnormal bleeding, and an elevated risk of developing myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML) at young age. However, it is not known why or how germline carriers of RUNX1 mutations have a particular propensity to develop myeloid hematologic malignancies, but the acquisition and composition of somatic mutations are believed to initiate and determine disease progression. We present a novel family pedigree that shares a common germline RUNX1R204* variant and exhibits a spectrum of somatic mutations and related myeloid malignancies (MM). RUNX1 mutations are associated with inferior clinical outcome; however, the proband of this family developed MDS with ring sideroblasts (MDS‐RS), classified as a low‐risk MDS subgroup. His relatively indolent clinical course is likely due to a specific somatic mutation in the SF3B1 gene. While the three main RUNX1 isoforms have been ascribed various roles in normal hematopoiesis, they are now being increasingly recognized as involved in myeloid disease. We investigated the RUNX1 transcript isoform patterns in the proband and his sister, who carries the same germline RUNX1R204* variant, and has FPDMM but no MM. We demonstrate a RUNX1a increase in MDS‐RS, as previously reported in MM. Interestingly, we identify a striking unbalance of RUNX1b and ‐c in FPDMM. In conclusion, this report reinforces the relevance of somatic variants on the clinical phenotypic heterogeneity in families with germline RUNX1 deficiency and investigates a potential new role for RUNX1 isoform disequilibrium as a mechanism for development of MM.
Process-Based psychotherapy personalization: considering causality with continuous-time dynamic modeling

ABSTRACT Objective: Psychotherapy can be improved by integrating the study of mediators (how it works) and moderators (for whom it works). To demonstrate this integration, we studied the relationship between resource activation, problem-coping experiences and symptoms in cognitive-behavior therapy (CBT) for depression, to obtain preliminary insights on causal inference (which process leads to symptom improvement? ) and prediction (which one for whom? ). Method: A sample of 715 patients with depression who received CBT was analyzed. Hierarchical Bayesian continuous time dynamic modeling was used to study the temporal dynamics between the variables analyzed within the first ten sessions. Depression and self-efficacy at baseline were examined as predictors of these dynamics. Results: There were significant cross-effects between the processes studied. Under typical assumptions, resource activation had a significant effect on symptom improvement. Problem-coping experience had a significant effect on resource activation. Depression and self-efficacy moderated these effects. However, when system noise was considered, these effects may be affected by other processes. Conclusion: Resource activation was strongly associated with symptom improvement. To the extent of inferring causality, for patients with mild-moderate depression and high self-efficacy, promoting resource activation can be recommended. For patients with severe depression and low self-efficacy, promoting problem-coping experiences can be recommended.
Toxicity and effects on anuran tadpole metamorphosis of the anthranilic diamide insecticides chlorantraniliprole and cyantraniliprole

ABSTRACT The present study examined the acute and chronic toxicity attributed to commercial formulations of the anthranilic diamide insecticides chlorantraniliprole (CHLO) and cyantraniliprole (CYAN) on the neotropical amphibian species Rhinella arenarum, Rhinella fernandezae and Scinax granulatus. The median lethal concentrations obtained after 96 hr exposure (96 hr-LC50) were generally greater than 100 mg/L, except for stage 25 S. Granulatus, which were the most sensitive animals tested with a 96 hr-LC50 value of 46.78 mg/L. In subchronic exposures of R. arenarum, the 21day-LC50 were 151.4 mg/L for CHLO and >160 mg/L for CYAN, the weight gain of the tadpoles during this period not being markedly affected in both cases. Finally, when tadpoles of R. arenarum were exposed to CHLO throughout the metamorphic process, an inverted U-shaped non-monotonic dose-response relationship was observed between exposure concentrations and both % of individuals transiting between stage 39 and 42 and the time required to accomplish this. Data obtained raise the hypothesis of an effect of CHLO on the hypothalamic-pituitary-thyroid (HPT) axis, either directly or through an interaction with the stress-hormone system, as metamorphic progression from stage 39 to S42 occurs under the strict control of thyroid hormones. These observations are important as the anthranilic diamide insecticides are not currently known as endocrine disruptors. Further investigations are needed to clarify the pathways leading to these effects and examine whether environmentally-relevant aquatic concentrations of anthranilic diamides might be impacting amphibian populations in the wild.
Mechanical thrombectomy with intra-arterial thrombolysis versus mechanical thrombectomy alone in patients with acute ischemic stroke: A systematic review and meta-analysis

Background: There is conflicting evidence as to whether intra-arterial thrombolysis (IAT) adds benefit in patients with acute stroke who undergo mechanical thrombectomy (MT). Methods: We conducted a systematic review to identify studies that evaluate IAT in patients with acute stroke who undergo MT. Data were extracted from relevant studies found through a search of PubMed, Scopus, and Web of Science until February 2023. Statistical pooling with random effects meta-analysis was undertaken to evaluate odds of functional independence, mortality, and near-complete or complete angiographic recanalization with IAT compared to no IAT. Results: A total of 18 studies were included (3 matched, 14 unmatched, and 1 randomized). The odds ratio (OR) for functional independence (modified Rankin Scale: 0–2) at 90 days was 1.14 (95% confidence interval (CI): 0.95–1.37, p = 0.17, 16 studies involving 7572 patients) with IAT with moderate between-study heterogeneity (I2 = 38.1%). The OR for functional independence with IAT was 1.28 (95% CI: 0.92–1.78, p = 0.15) in studies that were either matched or randomized and 1.24 (95% CI: 0.97–1.58, p = 0.08) in studies with the highest quality score. IAT was associated with higher odds of near-complete or complete angiographic recanalization (OR: 1.65, 95% CI: 1.03–2.65, p = 0.04) in studies that were either matched or of randomized comparisons. Conclusion: Although the odds of functional independence appeared to be higher with IAT and MT compared with MT alone, none of the results were statistically significant. A prominent effect of the design and quality of the studies was observed on the association between IAT and functional independence at 90 days.
Insulin resistance in critical illness: consequences for nutrition therapy and glucose management

Purpose of review: Critically ill patients usually develop insulin resistance and hyperglycemia, which is aggravated by early parenteral nutrition. In observational studies, the lowest mortality risk associates with glucose concentrations close to the antecedent average glucose level. This review summarizes the most recent evidence regarding glucose control in critical illness. Recent findings: Although pioneer randomized controlled trials showed morbidity and mortality benefit by normalizing blood glucose in intensive care, the largest multicenter randomized controlled trial found increased mortality. Differences in glucose targets, the accuracy of the glucose control protocol, and differences in feeding strategy may explain these differences. Recent randomized controlled trials investigating the impact of individualized glucose control did not show benefits of targeting individualized or looser glucose values in critically ill patients with poorly controlled diabetes. Summary: It remains unclear whether tight glucose control in critical illness is beneficial or not in the absence of early parenteral nutrition, which is currently being studied in the multicenter TGC-fast randomized controlled trial. Without new evidence, it seems prudent to avoid severe hyperglycemia and hypoglycemia in all patients.
Cellular immunity in the era of modern multiple myeloma therapy

Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical importance of the immune system in the pathogenesis of MM is essential. The immune changes in MM patients after treatment are associated with prognosis. In this review, we summarize currently available MM therapies and discuss how they affect cellular immunity. We find that the modern anti‐MM treatments enhance antitumour immune responses. A deeper understanding of the therapeutic activity of individual drugs offers more effective treatment approaches that enhance the beneficial immunomodulatory effects. Furthermore, we show that the immune changes after treatment in MM patients can provide useful prognostic marker. Analysing cellular immune responses offers new perspectives for evaluating clinical data and making comprehensive predictions for applying novel therapies in MM patients.
Measurement and analysis of Zeff in EAST tokamak

Effective ion charge (Zeff) is an important parameter in fusion research and can be used to quantify impurity levels. Investigation into Zeff helps us to understand the impurity generation and transport mechanisms in order to find an effective way to control impurity levels. This key parameter Zeff is measured by the visible bremsstrahlung diagnostic in the EAST tokamak. In this report, Zeff and impurity behavior in siliconization and lithium coating experiments have been investigated. Comparisons of averaged Zeff and Zeff profiles have been made between L-mode and H-mode discharges. It is found that the dependence of Zeff on averaged electron density complies with the hyperbolic scaling. Finally, Zeff behavior in auxiliary heating experiments is analyzed in detail. The relationship between Zeff and external power injected into plasma in lower hybrid wave and ion cyclotron resonance frequency heating has been summarized and analyzed.
Proximal radiolucent lines around fully hydroxyapatite-coated tapered femoral stems: should we be concerned?

Introduction: Radiolucent lines occasionally develop around the proximal aspect of fully hydroxyapatite (HA)-coated tapered femoral stems after total hip arthroplasty (THA). It was hypothesised that distal wedging of stems may predispose to proximal radiolucent line formation, which may negatively impact clinical outcome. Methods: All primary THA performed with a collarless fully HA-coated stem that had a minimum of 1 year of radiographic follow-up were identified in a surgical database (n = 244). Radiographic measures of proximal femoral morphology and femoral canal fill at the middle and distal thirds of the stem were analysed for association with the presence of proximal radiolucent lines. Linear regression was used to explore any association between radiolucent lines and patient reported outcome measures (PROMs), available in 61% of patients. Results: Proximal radiolucent lines developed in 31 cases (12.7%) at final follow-up. Dorr A femoral morphology and increased canal-fill at the distal ⅓ of the stem correlated with the development of radiolucent lines (p < 0.001). No correlation was observed between pain or PROMs and the presence of proximal radiolucent lines. Discussion: We observed an unexpectedly high incidence of proximal femoral radiolucent lines about collarless fully HA coated stems. Distal-only implant wedging in Dorr A bone may compromise proximal fixation. Although this finding did not correlate with short-term outcomes, the long-term clinical impact requires further study.
Endocardial versus epicardial pacing in pacemaker-dependent patients after device extraction: a meta-analysis

ABSTRACT Introduction Pacemaker-dependent (PM) patients with cardiac implantable electronic device (CIED) infection require implantation of a temporary-pacemaker (TP) and delayed endocardial reimplantation or implantation of an epicardial-pacing-system (EPI) before device extraction. Our aim was to compare the TP and EPI-strategy after CIED extraction through a meta-analysis. Methods We searched electronic databases up to 25 March 2022, for observational studies that reported clinical outcomes of PM-dependent patients implanted with TP or EPI-strategy after device extraction. Results 3 studies were included enrolling 339 patients (TP: 156 patients; EPI: 183 patients). TP compared to EPI showed reduction in the composite outcome of relevant complications (all-cause death, infections, need for revision or upgrading of the reimplanted CIED) (12.1% vs 28.9%; RR: 0.45; 95%CI: 0.25–0.81; p = 0.008) and a trend in reduction of all-cause death (8.9% vs 14.2%; RR: 0.58; 95%CI: 0.33–1.05; p = 0.07). Furthermore, TP-strategy proved to reduce need of upgrading (0% vs 12%; RR: 0.07; 95%CI: 0.01–0.52; p = 0.009), reintervention on reimplanted CIED (1.9% vs 14.7%; RR: 0.15; 95%CI: 0.05–0.48; p = 0.001) and significant increase in pacing threshold (0% vs 5.4%; RR: 0.17; 95%CI: 0.03–0.92; p = 0.04), with a longer discharge time (MD: 9.60 days; 95%CI: 1.98–17.22; p = 0.01). Conclusion TP-strategy led to a reduction of the composite outcome of all-cause death and complications, upgrading, reintervention on reimplanted CIED, and risk of increase in pacing threshold compared to EPI-strategy, with longer discharge time.
Novel aldo-keto reductase 1C3 inhibitor affects androgen metabolism but not ovarian function in healthy women: a phase 1 study

Abstract Objective Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors. Here, we analyzed pharmacodynamic data from a phase 1 study with a new selective AKR1C3 inhibitor, BAY1128688, to identify response biomarkers and assess effects on ovarian function. Design In a multiple-ascending-dose placebo-controlled study, 33 postmenopausal women received BAY1128688 (3, 30, or 90 mg once daily or 60 mg twice daily) or placebo for 14 days. Eighteen premenopausal women received 60 mg BAY1128688 once or twice daily for 28 days. Methods We measured 17 serum steroids by liquid chromatography–tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters. Results In both study populations, we observed substantial, dose-dependent increases in circulating concentrations of the inactive androgen metabolite androsterone and minor increases in circulating etiocholanolone and dihydrotestosterone concentrations. In premenopausal women, androsterone concentrations increased 2.95-fold on average (95% confidence interval: 0.35-3.55) during once- or twice-daily treatment. Note, no concomitant changes in serum 17β-estradiol and progesterone were observed, and menstrual cyclicity and ovarian function were not altered by the treatment. Conclusions Serum androsterone was identified as a robust response biomarker for AKR1C3 inhibitor treatment in women. Aldo-keto reductase 1C3 inhibitor administration for 4 weeks did not affect ovarian function. ClinicalTrials.gov Identifier: NCT02434640; EudraCT Number: 2014-005298-36
Psychiatric comorbidities in older adults with posttraumatic stress disorder: A systematic review

Psychiatric comorbidity is high in adults with posttraumatic stress disorder (PTSD), with up to 90% having at least one additional condition, and two‐thirds having two or more other diagnoses. With an increasing aging population in industrialized counties, knowing which psychiatric disorders frequently co‐occur in older adults with PTSD can have implications to improve diagnosis and treatment. This systematic literature review explores the current empirical literature on psychiatric comorbidity in older adults with PTSD.
Nutrition therapy during noninvasive ventilation: oral or enteral?

Purpose of review Critical care nutrition guidelines primarily focus on patients receiving invasive mechanical ventilation, yet noninvasive ventilation (NIV) is an increasingly common intervention. The optimal route of nutrition delivery in patients receiving NIV has not been established. This review aims to describe the implications of NIV on the route of feeding prescribed. Recent findings Five small, mostly observational, studies have quantified energy or protein intake in patients receiving NIV in critical care, which demonstrate intake to be poor. No study has assessed the impact of feeding route on outcomes. The predominant route of feeding observed is oral intake, yet nutrition intake via this route is lower than that from enteral or parenteral nutrition. Barriers to oral intake include fasting for intubation, the inability to remove NIV apparatus to eat, breathlessness, fatigue and poor appetite, while barriers to enteral nutrition include the impact of the naso-enteric tube on the mask seal and potential aspiration. Summary Until evidence to support the optimal route of feeding is developed, patient safety should be the key driver of route selection, followed by the ability to achieve nutrition targets, perhaps utilizing a combination of routes to overcome barriers to nutrition delivery.