Safety and efficacy of therapeutic early onset granulocyte transfusions in pediatric patients with neutropenia and severe infections

BACKGROUND: Bacterial and fungal infections in profound neutropenia after chemotherapy are associated with high mortality despite appropriate antibacterial and antifungal treatment. Granulocyte transfusions are used as a therapeutic addendum, but concern regarding pulmonary reactions often results in delayed use in clinical practice. Accordingly, many patients are already at advanced stages of their infectious disease once granulocytes are transfused. Thus, a prospective Phase II trial was conducted to test the safety and efficacy of therapeutic early-onset granulocyte transfusions in immunocompromised children with neutropenia and severe infections. STUDY DESIGN AND METHODS: Twenty-seven children with hematologic disorder or malignancy and severe neutropenia with clinically and/or microbiologically documented severe infection unresponsive to standard treatment were included. They received granulocyte colony-stimulating factor (G-CSF)-elicited, crossmatched granulocyte concentrates every other day until complete recovery from infection was documented. RESULTS: A median of two granulocyte transfusions with a median of 8 x 10(8) granulocytes per kilogram of body weight were administered. All transfusions were well tolerated, and no pulmonary symptoms were observed. A total of 92.6 percent of our patients were able to clear their initial infection, and 81.5 percent were alive and without signs or symptoms of their infection 1 month later. All six children with aspergillosis cleared their infection. CONCLUSIONS: G-CSF-elicited, crossmatched granulocyte concentrates are a safe and efficient therapeutic addendum in immunocompromised children with prolonged neutropenia and severe infections. Early transfusion of granulocyte concentrates can lead to an overall response rate of 92.6 percent without adverse events. Randomized clinical trials with an early-onset design are required to determine appropriate clinical applications.     

Divergent Patterns of Social Cognition Performance in Autism and 22q11.2 Deletion Syndrome (22q11DS)

Individuals with developmental disorders frequently report a range of social cognition deficits including difficulties identifying facial displays of emotion. This study examined the specificity of face emotion processing deficits in adolescents with either autism or 22q11DS compared to typically developing (TD) controls. Two tasks (face emotion recognition and weather scene recognition) were used to explore group differences in visual scanpath strategy and concurrent recognition accuracy. For faces, the autism and 22q11DS groups demonstrated lower emotion recognition accuracy and fewer fixations compared to the TD group. Individuals with autism demonstrated fewer fixations to some weather scene stimuli compared to 22q11DS and TD groups, yet achieved a level of recognition accuracy comparable to the TD group. These findings provide evidence for a divergent pattern of social cognition dysfunction in autism and 22q11DS.     

The validity of patient- and clinician-rated measures of needs and the therapeutic relationship in psychosis: A pooled analysis

Measuring outcomes of treatments for psychosis such as needs and the quality of the therapeutic relationship is important in research and routine care. However, evidence on the validity of existing outcome measures is limited. We aimed to test the convergent, discriminant, and predictive validity of two widely used patient- and clinician-rated measures of needs and the therapeutic relationship. Multitrait-multimethod (MTMM) analysis was conducted on the Camberwell Assessment of Need Short Appraisal Schedule (CANSAS) and the Helping Alliance Scale (HAS), both the clinician (CANSAS-C, HAS-C) and patient (CANSAS-P, HAS-P) versions, in a pooled sample of 605 psychotic patients and their clinicians. CANSAS-C and CANSAS-P items loaded substantially into one common unmet needs factor. By comparison, substantial factor loadings were found for HAS-C and HAS-P items on two separate clinician- and patient-rated therapeutic relationship factors. Common unmet needs and clinician-rated therapeutic relationship factors significantly predicted reduced psychiatric in-patient days. Our findings support the convergent validity of the CANSAS, discriminant validity of the HAS, and predictive validity of CANSAS and HAS-C. The findings may inform the use of CANSAS and HAS as psychosis outcome measures in research and routine care.     

Prevalence of the metabolic syndrome in patients with borderline personality disorder: results from a cross-sectional study

Metabolic syndrome (MetS) is an important risk factor for the development of type-2 diabetes and coronary artery disease. We aimed to compare the MetS prevalence in patients with borderline personality disorder (BPD) with comparison subjects followed in primary care from a similar region. One hundred and thirty-five BPD patients according to DSM-IV diagnostic criteria were compared to 1009 subjects from primary care. We used the American Heart Association/National Heart, Lung and Blood Institute criteria to determine the rate of MetS. The age-standardized prevalence of MetS was more than double in patients with BPD compared to comparison subjects (23.3 vs. 10.6 %, p < 0.05). Regarding individual MetS criteria, hyperglycemia was significantly more prevalent in both genders (p < 0.05). Abdominal obesity (p < 0.05) and hypertriglyceridemia (p < 0.05) were significantly higher only in women with BPD. Within BPD patients, an increased rate of MetS was associated with higher BMI (p = 0.004), age (p = 0.03), treatment with second-generation antipsychotics (quetiapine, olanzapine and clozapine; p = 0.032), dysthymia (p = 0.031), panic disorder (p = 0.032), benzodiazepine dependency (p = 0.015) and binge eating disorder p = 0.02). Our results demonstrate an increased MetS rate, dysregulated glucose and lipid metabolism in patients with BPD. Cardiometabolic monitoring and careful screening for physical health conditions among people with BPD is warranted.     

First Trimester Screening – Current Status and Future Prospects After Introduction of Non-invasive Prenatal Testing (NIPT) at a Tertiary Referral Center

Objective To investigate the uptake of different components of first trimester screening (FTS) and the impact on invasive diagnostic testing (IPT) since the introduction of non-invasive prenatal testing (NIPT) at a level III center. Methods Retrospective data analysis was conducted for singleton pregnancies that presented for FTS between 01/2019–12/2019 (group 1, n = 990). Patients were categorized into three risk groups: low risk for trisomy 21 (< 1 : 1000), intermediate risk (1 : 101–1 : 1000) and high risk (≥ 1 : 100). Uptake of NIPT and IPT was analyzed for each of the risk groups. Results were compared to a previous cohort from 2012/2013 (immediately after the introduction of NIPT, group 2, n = 1178). Results Group 1 showed a significant increase in the use of NIPT as part of FTS (29.5% vs. 3.7% for group 2, p = 0.001) in all three risk groups. Overall IPT rates were lower in group 1 (8.6%) vs. group 2 (11.3%, p = 0.038), mainly due to a significant reduction of IPT in the intermediate risk group. IPT rates in the high-risk group remained stable over time. Conclusion Appropriate clinical implementation of NIPT is still currently a challenge for prenatal medicine experts. Our data suggest that widespread uptake of NIPT is becoming more common these days; however, a contingent approach might prevent redundant uptake.     

Orthotropic Behavior of Twin-Roll-Cast and Hot-Rolled Magnesium ZAX210 Sheet

Magnesium sheet metal alloys offer a deformation asymmetry, which is strongly related to grain size and texture. In order to predict deformation behavior as well as to provide methods to eliminate anisotropy and yield asymmetry, a lot of effort is invested in studying the tension–compression asymmetry of magnesium alloys. However, only a few studies deal with the characterization of the yield asymmetry of magnesium wrought alloys, especially Ca-containing alloys, related to temperature and strain. In this study, the orthotropic behavior of a twin-roll-cast, homogenized, rolled and finish-annealed Mg-2Zn-1Al-0.3Ca (ZAX210) magnesium alloy was investigated by tensile testing at room temperature, 150 °C and 250 °C. The r-values were determined and the Hill’48 yield criterion was used for the constitutive formulation of the plastic yielding and deformation. The yield loci calculated using Mises and Hill’48 as well as the determined r-values reveal an almost isotropic behavior of the ZAX210 alloy. The r-value increases with increasing logarithmic strain. At 0.16 logarithmic strain the r-values at room temperature vary between 1 (0°) and 1.5 (45° and 90°). At higher temperatures (250 °C), r-values close to 1 at all tested directions are attained. The enhanced yield asymmetry can be attributed to the weaker basal texture that arises during hot rolling and final annealing of the twin-roll-cast ZAX210 magnesium alloy. In comparison to AZ31, the ZAX210 alloy shows a yield behavior close to transversal isotropy. Finally, responsible mechanisms for this behavior are discussed.     

Determination of Water Content in Direct Resin Composites Using Coulometric Karl Fischer Titration

This study evaluated the water content and sorption of direct composites over 60 days using coulometric Karl Fischer titration (KFT). Plate-shaped specimens (10 × 10 × 1 mm³ of thickness) were built up using the composites Clearfil Majesty Posterior (CM), Grandio SO (GS), and Filtek Supreme XT (FS). Water contents were determined in non-stored specimens (control) or after storage in distilled water for up to 60 days (n = 5). The amount of water transferred from the specimens heated at 200 °C (isothermal mode) was measured in the Coulometer. The water content of non-stored specimens ranged from 0.28 to 1.69 wt% (5.6 to 31.2 μg/mm³) for GS and FS, respectively. The highest values of water sorption were observed for FS (25.3 μg/mm³ after 60 days). GS and CM showed similar water sorption after 60 days (≈9 μg/mm³), but an ultimate higher water content was observed for CM (0.9 wt%; 22.0 μg/mm³) than GS (0.7 wt%; 14.8 μg/mm³). Except for CM, no significant water sorption was observed between 21 and 60 days of storage. Since all composites presented some base water content, water sorption data alone do not account for the ultimate water content in direct resin-based composites.     

A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an Alzheimer’s disease mouse model

Tumor necrosis factor-α (TNF-α) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer’s disease (AD). Although the linkage between increased TNF-α levels and AD is widely recognized, TNF-α–neutralizing therapies have failed to treat AD. Previous research has associated this with the antithetic functions of the two TNF receptors, TNF receptor 1, associated with inflammation and apoptosis, and TNF receptor 2 (TNFR2), associated with neuroprotection. In our study, we investigated the effects of specifically stimulating TNFR2 with a TNFR2 agonist (NewStar2) in a transgenic Aβ-overexpressing mouse model of AD by administering NewStar2 in two different ways: centrally, via implantation of osmotic pumps, or systemically by intraperitoneal injections. We found that both centrally and systemically administered NewStar2 resulted in a drastic reduction in amyloid β deposition and β-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of Aβ. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates Aβ-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.

Tumor necrosis factor-α (TNF-α) is a master proinflammatory cytokine involved in the regulation of innate and adaptive immunity (1). TNF-α plays a crucial role in various autoimmune and neurological disorders, including Alzheimer’s disease (AD) (2, 3). TNF-α–neutralizing therapeutics have been approved for the treatment of different inflammatory and autoimmune diseases, like rheumatoid arthritis or plaque psoriasis (4). However, the treatment of neurological disorders with TNF-α–neutralizing drugs led to inconclusive or even detrimental results (5–8). The latter could be explained, at least partly, by the different functions of the two receptors of TNF: on the one hand, stimulation of cytotoxic and strongly inflammatory pathways by TNF receptor 1 (TNFR1) in response to soluble TNF (sTNF) or membrane TNF (mTNF) or, on the other hand, activation of TNF receptor 2 (TNFR2) by mTNF eliciting pro- and antiinflammatory effects but also neuroprotective functions and tissue regeneration (9, 10).As a consequence, several studies aimed at selective targeting of TNFR1 or TNFR2, instead of completely inhibiting TNF-α. First, targeting TNFR1 by using specific TNFR1 antagonists or sTNF inhibitors resulted in amelioration of inflammation and apoptosis in various in vivo neurodegenerative disease models, such as models of multiple sclerosis (11, 12), Parkinson’s disease (13), and AD (14, 15). Second, targeting TNFR2 by specific TNFR2 agonists exerted an enhancement in neuroregeneration and tissue homeostasis in vitro (16) as well as in in vivo models (17). Therefore, specific targeting of TNFR1 and/or TNFR2 offers a promising new therapeutic avenue.However, clinical and preclinical studies on the effect of specific therapeutic targeting of TNFR2 in AD are lacking. It is acknowledged that during AD, the deposition of Aβ plaques, one of the main hallmarks of AD pathogenesis, occurs as a consequence of an imbalance between Aβ production and clearance (18). The β-secretase 1 (BACE-1) is mainly responsible for the production of toxic Aβ peptides, whereas uptake and degradation of these peptides are achieved by glial cells in the central nervous system (CNS), such as microglia and astrocytes (19, 20). Microglia are the resident macrophages of the CNS and their function is to constantly survey their environment and react to any detected insult, such as tissue damage or pathogen infection (21). Microglia are also involved in tissue repair and maintaining brain homeostasis. Moreover, microglia have been found to be essential for Aβ clearance in AD mouse models (20). It has been reported that in the context of AD, BACE-1 expression is increased, and the presence of Aβ plaques impairs the phagocytic activity of microglia (22, 23). These events could lead to an overproduction of Aβ accompanied by reduced Aβ clearance, which may partly lead to the observed pathogenesis of AD.Previous studies have proven that TNFR2 activation is neuroprotective in different disease models; however, it remains to be established whether TNFR2 stimulation has a protective effect against Aβ-mediated neuropathology and amyloid deposition and if this could improve cognitive functions. Therefore, in this study, we tested the hypothesis that selective stimulation of TNFR2 is able to abrogate Aβ-associated neuropathology and cognitive impairments.     

Effect of Paclitaxel Drug-Coated Balloon Angioplasty of Infrapopliteal Lesions on Mortality

BackgroundMeta-analyses of randomized controlled trials have suggested an increased long-term mortality risk following femoropopliteal and infrapopliteal angioplasty using paclitaxel-coated devices. This study was conducted to evaluate long-term mortality after paclitaxel drug-coated balloon (DCB) and plain old balloon angioplasty (POBA) of infrapopliteal lesions in real-world practice.MethodsA retrospective mortality analysis of patients with at least 3 years of follow-up who underwent balloon-based endovascular therapy of infrapopliteal lesions was performed.ResultsOverall, 2,424 patients with infrapopliteal lesions were treated within the study period. Five hundred seventy-six patients fulfilled the study criteria. Of those, 269 patients were treated with uncoated devices without crossover to a paclitaxel-coated device during follow-up and 307 patients with DCB angioplasty. Mean (SD) follow-up was 46.48 (32.77) months. The mortality rate was 66.9% after POBA and 46.9% after DCB (P < .001). In the matched-pair cohort, 164 patients died after uncoated treatment (66.7%), and 119 in the DCB group died (48.4%; P < .001). There was no correlation between DCB length and mortality rate (P = .357). For the entire cohort, multivariate logistic regression analysis showed type of treatment (uncoated device vs DCB; P = .002), age (P < .001), stroke (P = .005), renal insufficiency (P = .014), and critical limb ischemia (P = .001) to be independent predictors of all-cause mortality. There was no significant difference in mortality among the paclitaxel exposure groups.ConclusionIn this real-world retrospective analysis, the long-term mortality rate was lower after DCB angioplasty than after POBA of infrapopliteal lesions.