Clinical Relevance of Immunoresistance to Botulinum Therapy

Because botulinum toxin is a bacterial antigen, the therapy with this biological bears the risk that the formation of antibodies is elicited which can neutralize the neurotoxin. Several factors have an impact on this immune response. There are (unknown) patient-related factors but also the dose, the injection interval and the purity of the product play a role in the formation of antibodies. Several assays to detect antibodies are available; immunological assays such as FIA (fluorescence immunoassay) and ELISA, function assays such as MPA (mouse protection assay) and HDA (hemidiaphragm assay), clinical assays such as the EDB assay (extensor digitorum brevis assay), and SCM assay (sternocleidomastoid) which have different sensitivities. Clinical studies with different BoNT/A products demonstrate that the rate of antibody formation is low. Important for the physician is whether the antibody formation has an impact on the responsiveness of the patient. Not all patients with positive sera are nonresponders. The antibody titer is certainly important which might not be high enough to neutralize the injected dose completely but the titer might increase during further treatment with the neurotoxin leading to complete nonresponse. To avoid the formation of antibodies, the lowest dose necessary for the patient should be injected keeping the longest acceptable injection interval

The Effect of Accelerator Dosage on Fresh Concrete Properties and on Interlayer Strength in Shotcrete 3D Printing

Recently, the progress in 3D concrete printing has developed enormously. However, for the techniques available, there is still a severe lack of knowledge of the functional interaction of processing technology, concrete rheology and admixture usage. For shotcrete 3D printing technology, we present the eect of accelerator dosages (0%, 2%, 4% and 6%) on fresh concrete properties and on interlayer strength. Therefore, early yield stress development up to 90 min is measured with penetration resistance measurements. Deformation of layers under loading is investigated with digital image correlation and a mechanical testing machine. One point in time (10 min after deposition) is examined to quantify vertical buildability of elements depending on the accelerator dosage. Four dierent interlayer times (0, 2, 5 and 30 min), which occur for the production of small and large elements as well as due to delay during production, are investigated mechanically as well as quantitatively with computed tomography regarding the formation of cold joints. With increased accelerator dosage, an instantaneous increase in early age yield stress and yield stress evolution was observed. An increase in interlayer time leads to a reduced strength. This is mainly attributed to the observed reduced mechanical interlocking eect of the strands. Finally, a model to describe interlayer quality is presented. In the end, advantages as well as limitations of the findings are discussed

Effect of Pre-Shear on Agglomeration and Rheological Parameters of Cement Paste

Cementitious pastes are multiphase suspensions that are rheologically characterized by viscosity and yield stress. They tend to flocculate during rest due to attractive interparticle forces, and desagglomerate when shear is induced. The shear history, e.g., mixing energy and time, determines the apparent state of flocculation and accordingly the particle size distribution of the cement in the suspension, which itself affects suspension's plastic viscosity and yield stress. Thus, it is crucial to understand the effect of the mixing procedure of cementitious suspensions before starting rheological measurements. However, the measurement of the in-situ particle agglomeration status is difficult, due to rapidly changing particle network structuration. The focused beam reflectance measurement (FBRM) technique offers an opportunity for the in-situ investigation of the chord length distribution. This enables to detect the state of flocculation of the particles during shear. Cementitious pastes differing in their solid fraction and superplasticizer content were analyzed after various pre-shear histories, i.e., mixing times. Yield stress and viscosity were measured in a parallel-plate-rheometer and related to in-situ measurements of the chord length distribution with the FBRM-probe to characterize the agglomeration status. With increasing mixing time agglomerates were increasingly broken up in dependence of pre-shear: After 300 s of pre-shear the agglomerate sizes decreased by 10 µm to 15 µm compared to a 30 s pre-shear. At the same time dynamic yield stress and viscosity decreased up to 30% until a state of equilibrium was almost reached. The investigations show a correlation between mean chord length and the corresponding rheological parameters affected by the duration of pre-shear

Injection 3D Concrete Printing (I3DCP): Basic Principles and Case Studies

Today, the majority of research in 3D concrete printing focuses on one of the three methods: firstly, material extrusion; secondly, particle-bed binding; and thirdly, material jetting. Common to all these technologies is that the material is applied in horizontal layers. In this paper, a novel 3D concrete printing technology is presented which challenges this principle: the so-called Injection 3D Concrete Printing (I3DCP) technology is based on the concept that a fluid material (M1) is robotically injected into a material (M2) with specific rheological properties, causing material M1 to maintain a stable position within material M2. Different to the layered deposition of horizontal strands, intricate concrete structures can be created through printing spatially free trajectories, that are unconstrained by gravitational forces during printing. In this paper, three versions of this method were investigated, described, and evaluated for their potential in construction: A) injecting a fine grain concrete into a non-hardening suspension; B) injecting a non-hardening suspension into a fine grain concrete; and C) injecting a fine grain concrete with specific properties into a fine grain concrete with different properties. In an interdisciplinary research approach, various material combinations were developed and validated through physical experiments. For each of the three versions, first architectural applications were developed and functional prototypes were fabricated. These initial results confirmed both the technological and economic feasibility of the I3DCP process, and demonstrate the potential to further expand the scope of this novel technology

Botulinum toxin antibody titres: measurement, interpretation, and practical recommendations

Botulinum toxin (BT) therapy may be blocked by antibodies (BT-AB) resulting in BT-AB induced therapy failure (ABF). BT-AB may be detected by the mouse lethality assay (MLA), the mouse diaphragm assay (MDA) and the sternocleidomastoid test (SCMT). For the first time, we wanted to compare all three BT-AB tests and correlate them to subjective complaint of complete or partial secondary therapy failure in 37 patients with cervical dystonia (25 females, 12 males, age 51.2 ± 11.4 years, disease duration 12.4 ± 6.3 years). Complaint of therapy failure was not correlated with any of the BT-AB tests. MDA and MLA are closely correlated, indicating that the MDA might replace the MLA as the current gold standard for BT-AB measurement. The SCMT is closely correlated with MDA and MLA confirming that BT-AB titres and BT's paretic effect are in a functional balance: low BT-AB titres are reducing BT's paretic effect only marginally, whereas high BT-AB titres may completely block it. When therapy failure is classified as secondary and permanent, BT-AB evaluation is recommended and any BT-AB test may be applied. For MDA > 10 mU/ml, MLA > 3 and SCMT < 25%, ABF is highly likely. MDA < 0.6 mU/ml are therapeutically irrelevant. They are neither correlated with pathologic MLA nor with pathologic SCMT. They should not be the basis for treatment decisions, such as switching dystonia therapy to deep brain stimulation. All other results are intermediate results. Their interactions with therapy efficacy is unpredictable. In these cases, BT-AB tests should be repeated or one or two additional test methods should be applied

Overall survival and role of programmed death ligand 1 expression in patients with metastatic non-small-cell lung cancer and immunotherapy: an observational study from central Switzerland.

BACKGROUND In clinical trials, therapy with immune checkpoint inhibitors has improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). These trials were important for drug approval and for defining new treatment standards but the effect of checkpoint inhibitors in patients treated outside of clinical trials is not well known. The goal of this study was to assess the effect of immunotherapy on the overall survival of patients with metastatic NSCLC in the region of central Switzerland. MATERIALS AND METHODS The study included 274 patients with histologically confirmed metastatic (stage IV) NSCLC in central Switzerland in the years 2015 to 2018. Patients with NSCLC and actionable driver mutations were excluded. Patients with checkpoint inhibitor treatment (immuno-oncology [IO] group, n = 122) were compared with patients without checkpoint inhibitor treatment (no-IO group, n = 152). Baseline demographics, disease characteristics and therapies applied were collected retrospectively. The primary endpoint was median overall survival calculated either from diagnosis or from the start of checkpoint inhibitor therapy to death or data cut-off (21 July 2021). We used the Kaplan-Meier method and an adjusted Cox proportional-hazards regression model. The expression of programmed-death ligand 1 (PD-L1) on tumour cells was used for exploratory analysis. RESULTS Patients had a median age of 68.4 years, most were male (61.7%) and more than half were current or former smokers (65%). A test for PD-L1 expression was available for 55.8% of the tumours. Patients in the IO group were younger than patients in the no-IO group. Among the 122 patients in the IO group, the median overall survival was 15 months (95% confidence interval [CI] 12-20). In the no-IO group, the median overall survival was 4 months (95% CI 3-7) with chemotherapy and 2 months (95% CI 1-2) with best supportive care. Patients with high (≥50%) PD-L1 expression and checkpoint inhibitor therapy had a slightly longer overall survival than patients with low PD-L1 and checkpoint inhibitor therapy. CONCLUSION These results suggest that treatment with checkpoint inhibitors improves overall survival in patients with metastatic NSCLC and that PD-L1 expression could have a predictive value in patients treated outside of clinical trials. Further studies are needed to study the magnitude of the benefit of checkpoint inhibitors according to molecular NSCLC subtype

Knowledge and use of HIV pre-exposure prophylaxis among men who have sex with men in Berlin - a multicentre, cross-sectional survey

Background: HIV pre-exposure prophylaxis (PrEP) has likely contributed to large decreases in HIV incidence among men who have sex with men (MSM) in several major cities. Berlin has seen a smaller decline, and affordable PrEP has been accessible through formal channels in Germany only since autumn 2017. We aimed to investigate knowledge and use of PrEP among MSM in Berlin, and factors predictive of a desire to use PrEP and history of PrEP use. Methods: Multicentre, paper-based, self-administered survey of adult MSM whose HIV status was negative or unknown at time of participation. Data were collected from 1 October 2017 to 2 April 2018. Results: 473 of 875 questionnaires were returned (response rate 54.1%; mean age 37.4 years, range 18-79). 90.0% of participants were aware of PrEP and, of these, 48.2% felt well informed about it. Among the 17.2% of participants reporting PrEP use, 59.3% indicated obtaining some or all of it from informal sources. 23.7% of those with no history of PrEP use reported having condomless anal intercourse (CAI) with two or more partners over the past six months. Worries about side effects, cost, not having a doctor who prescribes it, and a lack of information were the most frequently reported barriers to PrEP use. A desire to use PrEP and history of PrEP use were associated in our multivariable model with having multiple CAI partners. A history of PrEP use was associated with having a university degree, one or two parents born outside Germany, or friends living with HIV. Conclusions: We found high awareness of PrEP among MSM in Berlin, but also a strong need for more education on its pros, cons and proper use. The frequency of informal PrEP use was also high, raising urgent individual and public health concerns. Policy makers need to consider recent calls to improve access to PrEP and PrEP education through regular health services