Approach to Estimate the Phase Formation and the Mechanical Properties of Alloys Processed by Laser Powder Bed Fusion via Casting

A high-performance tool steel with the nominal composition Fe85Cr4Mo8V2C1 (wt%) was processed by three different manufacturing techniques with rising cooling rates: conventional gravity casting, centrifugal casting and an additive manufacturing process, using laser powder bed fusion (LPBF). The resulting material of all processing routes reveals a microstructure, which is composed of martensite, austenite and carbides. However, comparing the size, the morphology and the weight fraction of the present phases, a significant difference of the gravity cast samples is evident, whereas the centrifugal cast material and the LPBF samples show certain commonalities leading finally to similar mechanical properties. This provides the opportunity to roughly estimate the mechanical properties of the material fabricated by LPBF. The major benefit arises from the required small material quantity and the low resources for the preparation of samples by centrifugal casting in comparison to the additive manufacturing process. Concluding, the present findings demonstrate the high attractiveness of centrifugal casting for the effective material screening and hence development of novel alloys adapted to LPBF-processing

Targeted Lipidomics of Mitochondria in a Cellular Alzheimer’s Disease Model

Alzheimer’s disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and lipid-homeostasis exists, little is known about potential alterations in the lipid composition of mitochondria. Here, we investigate potential changes in the main mitochondrial phospholipid classes phosphatidylcholine, phosphatidylethanolamine and the corresponding plasmalogens and lyso-phospholipids of a cellular AD-model (SH-SY5Y APPswedish transfected cells), comparing these results with changes in cell-homogenates. Targeted shotgun-lipidomics revealed lipid alterations to be specific for mitochondria and cannot be predicted from total cell analysis. In particular, lipids containing three and four times unsaturated fatty acids (FA X:4), such as arachidonic-acid, are increased, whereas FA X:6 or X:5, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), are decreased. Additionally, PE plasmalogens are increased in contrast to homogenates. Results were confirmed in another cellular AD model, having a lower affinity to amyloidogenic APP processing. Besides several similarities, differences in particular in PE species exist, demonstrating that differences in APP processing might lead to specific changes in lipid homeostasis in mitochondria. Importantly, the observed lipid alterations are accompanied by changes in the carnitine carrier system, also suggesting an altered mitochondrial functionalit

Conditional Stat1 Ablation Reveals the Importance of Interferon Signaling for Immunity to Listeria monocytogenes Infection

Signal transducer and activator of transcription 1 (Stat1) is a key player in responses to interferons (IFN). Mutations of Stat1 cause severe immune deficiencies in humans and mice. Here we investigate the importance of Stat1 signaling for the innate and secondary immune response to the intracellular bacterial pathogen Listeria monocytogenes (Lm). Cell type-restricted ablation of the Stat1 gene in naïve animals revealed unique roles in three cell types: macrophage Stat1 signaling protected against lethal Lm infection, whereas Stat1 ablation in dendritic cells (DC) did not affect survival. T lymphocyte Stat1 reduced survival. Type I IFN (IFN-I) signaling in T lymphocytes reportedly weakens innate resistance to Lm. Surprisingly, the effect of Stat1 signaling was much more pronounced, indicating a contribution of Stat1 to pathways other than the IFN-I pathway. In stark contrast, Stat1 activity in both DC and T cells contributed positively to secondary immune responses against Lm in immunized animals, while macrophage Stat1 was dispensable. Our findings provide the first genetic evidence that Stat1 signaling in different cell types produces antagonistic effects on innate protection against Lm that are obscured in mice with complete Stat1 deficiency. They further demonstrate a drastic change in the cell type-dependent Stat1 requirement for memory responses to Lm infection

Projections of primary hip arthroplasty in Germany until 2040

Background and purpose — The number of hip replacements in Germany has increased considerably during the last 2 decades but lately levelled off with no significant increase in operation rates. We analyzed the future trend of hip arthroplasty and projected the number of primary hip replacements that will be performed in Germany until 2040. Patients and methods — We used prevalence data of hip arthroplasty patients from 2010 to 2016 from the nationwide inpatient statistics and population forecasts from the German Federal Bureau of Statistics up to the year 2040. We used Poisson regression to estimate the expected annual number of arthroplasty surgeries with calendar year and patient age as covariates to account for differences among age groups and changes over time. Results — The number of primary hip replacements performed in Germany in 2040 was estimated to grow by 27% to 288 x 103 (95% CI 250 x 103–332 x 103) from 2010. Projected counts were highest for patients aged 60 to 70 years. The estimated incidence rate was projected to 360 (95% CI 312–414) per 100,000 residents. However, incidence rates for individual age classes were found to be constant with a slight decrease over time for individual age classes. Interpretation — Our findings suggest a growth in the total hip arthroplasty count whereas incidence rate remained constant over age classes. We consider the future demographic change to an older population as well as the increasing life expectancy to be the main reasons for the increasing patient numbers rather than a general increase in the operation frequency

Projections of primary hip arthroplasty in Germany until 2040

<p>Background and purpose — The number of hip replacements in Germany has increased considerably during the last 2 decades but lately levelled off with no significant increase in operation rates. We analyzed the future trend of hip arthroplasty and projected the number of primary hip replacements that will be performed in Germany until 2040.</p> <p>Patients and methods — We used prevalence data of hip arthroplasty patients from 2010 to 2016 from the nationwide inpatient statistics and population forecasts from the German Federal Bureau of Statistics up to the year 2040. We used Poisson regression to estimate the expected annual number of arthroplasty surgeries with calendar year and patient age as covariates to account for differences among age groups and changes over time.</p> <p>Results — The number of primary hip replacements performed in Germany in 2040 was estimated to grow by 27% to 288 x 10³ (95% CI 250 x 10³–332 x 10³) from 2010. Projected counts were highest for patients aged 60 to 70 years. The estimated incidence rate was projected to 360 (95% CI 312–414) per 100,000 residents. However, incidence rates for individual age classes were found to be constant with a slight decrease over time for individual age classes.</p> <p>Interpretation — Our findings suggest a growth in the total hip arthroplasty count whereas incidence rate remained constant over age classes. We consider the future demographic change to an older population as well as the increasing life expectancy to be the main reasons for the increasing patient numbers rather than a general increase in the operation frequency.</p

Contracting retail pharmacies as a source of essential medicines for public sector clients in low- and middle-income countries: a scoping review of key considerations, challenges, and opportunities

Abstract Background Insurances in high-income countries (HIC) often contract with private community pharmacies to dispense medicines to outpatients. In contrast, dispensing of medicines in low- and middle-income countries (LMICs) often lacks such contractual arrangements. Furthermore, many LMICs lack sufficient investment in supply chains and financial and human resources to guarantee stock levels and services at public medicine-dispensing institutions. Countries striving to achieve universal health coverage (UHC) can, in principle, incorporate retail pharmacies into their supply chains to expand access to essential medicines (EMs). The objectives of this paper are (a) to identify and analyze key considerations, opportunities and challenges for public payers when contracting out the supply and dispensing of medicines to retail pharmacies and (b) to provide examples of strategies and policies to address these challenges. Methods A targeted literature strategy was used to conduct this scoping review. We created an analytical framework of key dimensions: (1) governance (including medicine and pharmacy regulation); (2) contracting (3) reimbursement; (4) medicine affordability (5) equitable access; and (6) quality of care (including ‘patient-centered’ pharmaceutical care). Using this framework, we selected a mix of three HIC and four LMIC case studies and analyzed the opportunities and challenges encountered when contracting retail pharmacies. Results From this analysis, we identified a set of opportunities and challenges that should be considered by public payers considering public–private contracting: (1) balancing business viability with medicine affordability; (2) incentivizing equitable access to medicines; (3) ensuring quality of care and delivery of services; (4) ensuring product quality; (5) task-sharing from primary care providers to pharmacies and (6) securing human resources and related capacity constraints to ensure sustainability of the contract. Conclusion Public–private partnerships offer opportunities to improve access to EMs. Nonetheless, managing these agreements is complex and is influenced by a variety of factors. For effective contractual partnerships, a systems approach is needed in which business, industry and regulatory contexts are considered in tandem with the health system. Special attention should be devoted to rapidly changing health contexts and systems, such as changes in patient preferences and market developments brought about by the COVID-19 pandemic

Feasibility and Implementation of Ex Vivo Fluorescence Confocal Microscopy for Diagnosis of Oral Leukoplakia: Preliminary Study

Background: Oral leukoplakia is a potentially malignant lesion with a clinical impression similar to different benign and malignant lesions. Ex vivo fluorescence confocal microscopy is a developing approach for a rapid “chairside” detection of oral lesions with a cellular-level resolution. A possible application of interest is a quick differentiation of benign oral pathology from normal or cancerous tissue. The aim of this study was to analyze the sensitivity and specificity of ex vivo fluorescence confocal microscopy (FCM) for detecting oral leukoplakia and to compare confocal images with gold-standard histopathology. Methods: Imaging of 106 submosaics of 27 oral lesions was performed using an ex vivo fluorescence confocal microscope immediately after excision. Every confocal image was qualitatively assessed for presence or absence of leukoplakia by an expert reader of confocal images. The results were compared to conventional histopathology with H&amp;E staining. Results: Leukoplakia was detected with an overall sensitivity of 96.3%, specificity of 92.3%, positive predictive value of 93%, and negative predictive value of 96%. Conclusion: The results demonstrate the potential of ex vivo confocal microscopy in fresh tissue for rapid real-time assessment of oral pathologies

Approach to Estimate the Phase Formation and the Mechanical Properties of Alloys Processed by Laser Powder Bed Fusion via Casting

A high-performance tool steel with the nominal composition Fe85Cr4Mo8V2C1 (wt%) was processed by three different manufacturing techniques with rising cooling rates: conventional gravity casting, centrifugal casting and an additive manufacturing process, using laser powder bed fusion (LPBF). The resulting material of all processing routes reveals a microstructure, which is composed of martensite, austenite and carbides. However, comparing the size, the morphology and the weight fraction of the present phases, a significant difference of the gravity cast samples is evident, whereas the centrifugal cast material and the LPBF samples show certain commonalities leading finally to similar mechanical properties. This provides the opportunity to roughly estimate the mechanical properties of the material fabricated by LPBF. The major benefit arises from the required small material quantity and the low resources for the preparation of samples by centrifugal casting in comparison to the additive manufacturing process. Concluding, the present findings demonstrate the high attractiveness of centrifugal casting for the effective material screening and hence development of novel alloys adapted to LPBF-processing

Clinical outcomes of relapsed and refractory Hodgkin lymphoma patients after contemporary first-line treatment: a German Hodgkin Study Group analysis

To evaluate patterns of rrHL after contemporary first-line treatment we studied 409 patients with first rrHL (HD13: n = 87, HD14: n = 118, HD15: n = 188, HDR3i: n = 51) at a median age of 37.4 years (18.4-76.8) from the GHSG database. Time to first relapse was <= 12 months in 49% and stage III/IV rrHL present in 52% of patients. In total, 291 patients received high-dose chemotherapy and autologous stem-cell transplantation (ASCT) and intended ASCT failed in 38 patients. ASCT was primarily not intended in 80 patients largely due to low risk disease or age/comorbidities. Overall, 10-year progression-free (PFS) and overall survival (OS) rates after first relapse were 48.2% (95% CI 41.9-54.2%) and 59.4% (95% CI 53.0-65.2%), respectively, with significant differences between subgroups. Inferior survival was observed with no ASCT due to advanced age/comorbidities (five-year PFS 36.2%, 95% CI 17.7-55.0%) or failure of salvage therapy (five-year PFS 36.3%, 95% CI 19.7-53.2%). Similarly, presence of primary refractory disease or stage IV at rrHL conferred inferior survival. In patients with low-risk disease, however, survival appeared favorable even without ASCT (10 y PFS 72.6%, 95% CI 53.7-84.8%). We herein confirm the curative potential of current rrHL treatments providing a robust benchmark to evaluate novel therapeutic strategies in rrHL. Approximately 50% of rrHL patients experienced a consecutive relapse