PARI (Germany)

The effect of stress relieving and substrate preheating on the grain refinement of additively manufactured Ti‐6Al‐4V at room and elevated temperatures is investigated. Specimens are produced using wire‐based directed energy deposition under vacuum conditions. The microstructure is characterized by scanning electron microscopy (SEM), electron backscatter diffraction (EBSD), and X‐ray diffraction (XRD). Tensile tests are conducted at room temperature and at 700 °C. The as‐deposited specimens exhibit a heterogeneous microstructure consisting of fine acicular α′‐martensite and fine Widmanstätten structures. Substrate preheating at 600 °C enables a complete transition from a columnar grain structure in the as‐deposited condition to a refined prior‐β grain structure. The as‐substrate‐heated specimens show the highest tensile strength of 1010 MPa with 3% elongation at room temperature and 600 MPa with 15% elongation at 700 °C.

Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity.

Topical drug delivery to poorly ventilated paranasal sinuses is challenging. Pulsating aerosols can improve the deposition of drugs like cortisol in paranasal sinuses. The current study compares the effect of Budesonid administered as pulsating aerosol in comparison to conventional nasal spray

High values of lipoprotein(a), related to atherosclerosis progression, are often considered a marker of thrombosis. Weassessed the lipoprotein(a) profile in a group of patients with high vascular risk and no cardiovascular events, established its correlationwith other cardiovascular risk factors and inferred the results for patients with metabolic disorders and, at least, two risk factors. This longitudinal observational study included 516 patients, who had at least two cardiovascular risk factors andregularly attended, for at least two years, the outpatient consultations at a clinic of metabolism and vascular risk for primary prevention.Sociodemographic, clinical and anthropometric parameters were obtained at the baseline visit. Hepatic morphology was assessedin 509 patients (98.6%) by ultrasonography. The 10-year vascular risk was estimated using Framingham risk score, atheroscleroticcardiovascular disease and systematic coronary risk evaluation tables. Significant correlations were found between lipoprotein(a) levels and the addressed vascular risk factors, as well as between lipoprotein(a), and Framingham risk score, atherosclerotic cardiovascular disease and systematic coronary risk evaluation charts.Lipoprotein(a) values were also considerably higher in patients with steatosis. Increased lipoprotein(a) values were directly associated with all markers of cardiovascular risk and with non-alcoholichepatic steatosis. Due to its high availability and low cost, lipoprotein(a) should become part of the routine evaluation of patients at vascularrisk.

Akute Atemwegsinfekte gehören zu den häufigsten Auslösern von Arbeitsunfähigkeit, wirken sich aber auch außerhalb der Arbeitswelt aus. Freizeitsportlern wird z.B. geraten, bei Erkältung zur Regeneration zu pausieren. Im internationalen Hochleistungssport ist dies aber meist nicht möglich. Wirksame Maßnahmen gegen akute Atemwegserkrankungen sind daher gefragt. Der Inhalation von isotonischer Salzlösung werden therapeutische und präventive Effekte zugeschrieben. Die vorliegende Arbeit untersucht den Einfluss dieser Therapieoption während einer Wintersport-Wettkampf-Saison.

Patient adherence to the protocol in clinical trials is a critical factor in determining the outcome of the trial. An investigational eFlow nebulizer was used with an eTrack controller featuring adherence-monitoring capability (PARI Pharma, Germany) to deliver drug to the lungs via inhalation and to objectively monitor adherence. The inhalation data were available via the PARItrack web portal and allowed evaluation and graphical visualization of each patient's adherence. The clinical trial involved 10 patients who self-administered drug in their homes twice a day for 6 weeks. The eTrack controller automatically transferred data of each nebulization via a Bluetooth connection to a 2netHub (Qualcomm) and via GSM to a server. The data could be accessed through the PARItrack web portal. The clinical trial nurses, investigators and CRO could remotely monitor adherence and an alert system was established for information on missed inhalations. This allowed individual adherence issues to be addressed immediately and corrective actions to be implemented to ensure ongoing adherence. This setup resulted in a high adherence rate over the duration of the clinical trial. The overall mean adherence rate was 96 %. Seven out of ten patients had an adherence rate of 100 %, two had 95 %, and one had 64 %. This compares with a reported adherence rate of 78 % in the first 4 weeks of another clinical trial using a monitoring nebulizer without remote data access and intervention [Fuchs et al. ECFC 2011]. The high adherence rates achieved in this study demonstrate the utility of remote monitoring and immediate intervention to achieve good adherence in a clinical trial.

Inhalation of aerosolized drugs is a promising route for noninvasive targeted drug delivery to the lung. Nanocarrier systems such as liposomes have been explored for inhalation therapy opening new avenues, including stabilization of nonsoluble drugs (e.g., Ciclosporin A [CsA]) and controlled release. The biokinetic behavior of the immunosuppressive drug CsA encapsulated in liposomes (L-CsA) at the lung epithelial barrier was studied in vitro. Human lung epithelial cells (alveolar A549 and bronchial 16HBE14o- epithelial cells) were exposed to aerosolized L-CsA at the air-liquid interface (ALI) using a dose-controlled air-liquid interface cell exposure (ALICE) system and the temporal profile of the L-CsA dose in the apical, basal, and cell compartment was monitored up to 24 hours. Aerosolization of different volumes of L-CsA solution with the ALICE resulted in dose-controlled, spatially uniform, and reproducible L-CsA delivery. Cell viability at 24 hours postexposure was not impaired and immunofluorescence staining revealed the typical epithelial cell morphology in control as well as in L-CsA-exposed cells. The (pro-)inflammatory interleukin-8 levels were not elevated under any condition. The biokinetic analysis revealed that both cell types formed a tight, but imperfect, barrier for L-CsA resulting in initially high transbarrier L-CsA transport rates, which ceased after about 4 hours. Although substantial transbarrier L-CsA transport was observed for both cell types, respectively, a 150-fold higher L-CsA concentration was established in the apical and cell compared to the basal compartment. Most importantly, for pulmonary drug targeting, a high cellular L-CsA dose level (20%-25% of the delivered dose) was obtained rapidly (<1 hour) and maintained for at least 24 hours. The ALICE system combined with lung epithelial cells cultured at the ALI offers a reliable and relevant in vitro platform technology to study the effects of inhalable substances such as L-CsA under biomimetic conditions.