Polymerase Chain Reaction on Respiratory Tract Specimens of Immunocompromised Patients to Diagnose Pneumocystis Pneumonia: A Systematic Review and Meta-analysis.

BACKGROUND: This meta-analysis examines the comparative diagnostic performance of polymerase chain reaction (PCR) for the diagnosis of Pneumocystis pneumonia (PCP) on different respiratory tract samples, in both human immunodeficiency virus (HIV) and non-HIV populations. METHODS: A total of 55 articles met inclusion criteria, including 11 434 PCR assays on respiratory specimens from 7835 patients at risk of PCP. QUADAS-2 tool indicated low risk of bias across all studies. Using a bivariate and random-effects meta-regression analysis, the diagnostic performance of PCR against the European Organisation for Research and Treatment of Cancer-Mycoses Study Group definition of proven PCP was examined. RESULTS: Quantitative PCR (qPCR) on bronchoalveolar lavage fluid provided the highest pooled sensitivity of 98.7% (95% confidence interval [CI], 96.8%-99.5%), adequate specificity of 89.3% (95% CI, 84.4%-92.7%), negative likelihood ratio (LR-) of 0.014, and positive likelihood ratio (LR+) of 9.19. qPCR on induced sputum provided similarly high sensitivity of 99.0% (95% CI, 94.4%-99.3%) but a reduced specificity of 81.5% (95% CI, 72.1%-88.3%), LR- of 0.024, and LR+ of 5.30. qPCR on upper respiratory tract samples provided lower sensitivity of 89.2% (95% CI, 71.0%-96.5%), high specificity of 90.5% (95% CI, 80.9%-95.5%), LR- of 0.120, and LR+ of 9.34. There was no significant difference in sensitivity and specificity of PCR according to HIV status of patients. CONCLUSIONS: On deeper respiratory tract specimens, PCR negativity can be used to confidently exclude PCP, but PCR positivity will likely require clinical interpretation to distinguish between colonization and active infection, partially dependent on the strength of the PCR signal (indicative of fungal burden), the specimen type, and patient population tested.

An Overview of Systematic Reviews of Polymerase Chain Reaction (PCR) for the Diagnosis of Invasive Aspergillosis in Immunocompromised People: A Report of the Fungal PCR Initiative (FPCRI)-An ISHAM Working Group.

This overview of reviews (i.e., an umbrella review) is designed to reappraise the validity of systematic reviews (SRs) and meta-analyses related to the performance of Aspergillus PCR tests for the diagnosis of invasive aspergillosis in immunocompromised patients. The methodological quality of the SRs was assessed using the AMSTAR-2 checklist; the quality of the evidence (QOE) within each SR was appraised following the GRADE approach. Eight out of 12 SRs were evaluated for qualitative and quantitative assessment. Five SRs evaluated Aspergillus PCR on bronchoalveolar lavage fluid (BAL) and three on blood specimens. The eight SRs included 167 overlapping reports (59 evaluating PCR in blood specimens, and 108 in BAL), based on 107 individual primary studies (98 trials with a cohort design, and 19 with a case-control design). In BAL specimens, the mean sensitivity and specificity ranged from 0.57 to 0.91, and from 0.92 to 0.97, respectively (QOE: very low to low). In blood specimens (whole blood or serum), the mean sensitivity ranged from 0.57 to 0.84, and the mean specificity from 0.58 to 0.95 (QOE: low to moderate). Across studies, only a low proportion of AMSTAR-2 critical domains were unmet (1.8%), demonstrating a high quality of methodological assessment. Conclusions. Based on the overall methodological assessment of the reviews included, on average we can have high confidence in the quality of results generated by the SRs.

Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendation to administer antifungal prophylaxis in patients with HM with long-lasting neutropenia, i.e. <500 cells/µL for >7 days remains unchanged. Posaconazole remains the drug of choice for mould-active prophylaxis in these patients. Novel treatment options in HM, such as CAR-T-cell treatment or novel targeted therapies for acute myeloid leukaemia (AML) were considered, however, data are insufficient to give general recommendations for routine antifungal prophylaxis in these patients. Major changes regarding specific recommendations compared to the 2017 edition are the now moderate instead of mild support for the recommendations of isavuconazole and voriconazole. Furthermore, published evidence on micafungin allows recommending it at moderate strength for its use in HM. For the first time we included recommendations for non-pharmaceutical measures regarding IFD, comprising the use of high-efficiency particulate air (HEPA) filters, smoking, measures during construction work and neutropenic diets. We reviewed the impact of antifungal prophylaxis with triazoles on drug-drug interactions with novel targeted therapies that are metabolized via cytochrome p450 where triazoles inhibit CYP3A4/5. The working group recommends reducing the dose of venetoclax when used concomitantly with strong CYP3A4 inhibiting antifungals. Furthermore, we reviewed data on the prophylactic use of novel antifungal agents. Currently there is no evidence to support their use in a prophylactic setting in clinical practice.

Safety and performance assessment of hyaluronic acid-based vitreous substitutes in patients with phthisis bulbi.

PURPOSE: To assess the safety and performance of hyaluronic acid-based vitreous substitutes in phthitic eyes. METHODS: In this retrospective interventional study a total of 21 eyes from 21 patients with phthisis bulbi were treated at the Eye Clinic Sulzbach between August 2011 and June 2021. Patients who underwent a 23G pars plana vitrectomy received a vitreous substitute composed of (I) a non-crosslinked hyaluronic acid (Healon GV), (II) a crosslinked hyaluronic acid-based hydrogel (UVHA), or (III) silicone oil (SO-5000). Main outcome measures were the intraocular pressure (IOP), the visual acuity and the structural integrity of the retina and choroid assessed by optical coherence tomography. RESULTS: An increase in IOP ≥ 5 mmHg was achieved with SO-5000 in 5/8 eyes (6/10 interventions, 60.0%) for 36.4 ± 39.5 days, with Healon GV in 4/8 eyes (7/11 interventions, 63.6%) for 82.6 ± 92.5 days and with UVHA in 4/5 eyes (5/6 interventions, 83.3%) for 93.6 ± 92.5 days. Visual acuity increased in 5/21 eyes (23.8%), remained constant in 12/21 eyes (57.1%) and decreased in 4/21 eyes (19.0%). No enucleations were required during the mean follow-up time of 192 ± 182 days. The OCT images indicated the preservation of retinal structures, while choroidal folds were only diminished in UVHA eyes. CONCLUSIONS: Hyaluronic acid-based hydrogels are biocompatible vitreous substitutes in humans and can increase and stabilize IOP in patients with phthisis bulbi for about 3 months.

Microstructure and Mechanical Properties of Hypereutectic Al-High Si Alloys up to 70 wt.% Si-Content Produced from Pre-Alloyed and Blended Powder via Laser Powder Bed Fusion.

Hypereutectic Al-high Si alloys are of immense interest for applications in the automotive, space or electronic industries, due their low weight, low thermal expansion, and excellent mechanical and tribological properties. Additionally, their production by laser powder bed fusion (LPBF) technology provides high flexibility in geometrical design and alloy composition. Since, most of the alloy properties could be improved by increasing the Si content, there is much interest in discovering the maximum that could be realized in LBPF Al-high Si alloys, without the appearance of any material failure. For this reason, in this work the production of Al-high Si alloys with extremely high silicon content of up to 70 wt.% was fundamentally investigated with respect to microstructure and mechanical properties. Highly dense (99.3%) and crack-free AlSi50 samples (5 × 5 × 5 mm3), with excellent hardness (225 HV5) and compressive strength (742 MPa), were successfully produced. Further, for the first time, AlSi70 LBPF samples of high density (98.8%) without cracks were demonstrated, using moderate scanning velocities. Simultaneously, the hardness and the compressive strength in the AlSi70 alloys were significantly improved to 350 HV5 and 935 MPa, as a result of the formation of a continuous Si network in the microstructure of the alloy. With respect to the powder source, it was found that the application of powder blends resulted in similar alloy properties as if pre-alloyed powders were used, enabling higher flexibility in prospective application-oriented alloy development.

Translation of hyaluronic acid-based vitreous substitutes towards current regulations for medical devices.

PURPOSE: Hydrogel-based vitreous substitutes have the potential to overcome the limitations of current clinically used endotamponades. With the goal of entering clinical trials, the present study aimed to (I) transfer the material synthesis of hyaluronic acid-based hydrogels into a routine, pharmaceutical-appropriate production and (II) evaluate the properties of the vitreous substitutes in terms of the current regulations for medical devices (MDR/ISO standards). METHODS: The multistep manufacturing process of the vitreous substitutes, including the modification of hyaluronic acid with glycidyl methacrylate, photocopolymerization with N-vinylpyrrolidone, and successive hydrogel purification, was developed under laboratory conditions, characterized using 1 H-NMR, FT-IR and UV/Vis spectroscopies and HPLC, and transferred towards a pharmaceutical production environment considering GMP standards. The optical and viscoelastic characteristics of the hyaluronic acid-based hydrogels were compared with those of extracted human vitreous and silicone oil. The effect of the hydrogels on the metabolic activity, proliferation and apoptosis of fibroblast (MRC-5, BJ, L929), retinal pigment epithelial (ARPE-19, hiPSC-derived RPE) and photoreceptor cells (661W) was studied as well as their mucosal tolerance via a HET-CAM assay. RESULTS: Hyaluronic acid-based hydrogels having a suitable purity, sterility, high transparency (>90%), appropriate refractive index (1.3365) and viscoelasticity (G' > G″) were prepared in a standardized manner under controlled process conditions. The metabolic activity, proliferation and apoptosis of various cell types as well as egg choroid were unaffected by the hyaluronic acid-based vitreous substitutes, demonstrating their biocompatibility. CONCLUSIONS: The present study demonstrates the successful transferability of the crucial synthesis steps of hyaluronic acid-based hydrogels into a routine, GMP-compliant production process while achieving the optical and viscoelastic properties, biocompatibility and purity required for their clinical use as vitreous substitutes.

Empiric vs Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown. METHODS: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization. RESULTS: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001). CONCLUSIONS: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27.

Biohybrid elastin-like venous valve with potential for in situ tissue engineering.

Chronic venous insufficiency (CVI) is a leading vascular disease whose clinical manifestations include varicose veins, edemas, venous ulcers, and venous hypertension, among others. Therapies targeting this medical issue are scarce, and so far, no single venous valve prosthesis is clinically available. Herein, we have designed a bi-leaflet transcatheter venous valve that consists of (i) elastin-like recombinamers, (ii) a textile mesh reinforcement, and (iii) a bioabsorbable magnesium stent structure. Mechanical characterization of the resulting biohybrid elastin-like venous valves (EVV) showed an anisotropic behavior equivalent to the native bovine saphenous vein valves and mechanical strength suitable for vascular implantation. The EVV also featured minimal hemolysis and platelet adhesion, besides actively supporting endothelialization in vitro, thus setting the basis for its application as an in situ tissue engineering implant. In addition, the hydrodynamic testing in a pulsatile bioreactor demonstrated excellent hemodynamic valve performance, with minimal regurgitation (<10%) and pressure drop (<5 mmHg). No stagnation points were detected and an in vitro simulated transcatheter delivery showed the ability of the venous valve to withstand the implantation procedure. These results present a promising concept of a biohybrid transcatheter venous valve as an off-the-shelf implant, with great potential to provide clinical solutions for CVI treatment.

Associations of early childhood medication exposure and molar incisor hypomineralization (MIH): A routine data analysis.

OBJECTIVES: Molar incisor hypomineralization (MIH) has become a major oral health problem of widely unknown origin. Besides genetic predisposition, exposure to certain drugs in early childhood are suspected to be associated with MIH. Aim of this routine data analysis was to examine associations of MIH and exposure to medication as well as perinatal factors. METHODS: Individuals with MIH were identified in claims data using a validated predefined specific treatment pattern. The database was a comprehensive routine data set of a major national health insurance company (BARMER, Germany). Based on this treatment pattern a MIH group and an unaffected control group were formed for analysis. Various medical data including medical diagnoses and prescriptions were available. Associations were examined comparing results for a set of variables in both groups. Differences between the groups were tested for significance using T-tests (P<0.01). RESULTS: Between 2010 to 2019, a total of 298,502 children between 6 and 9 years of age were included in this analysis. 22,947 were assigned to the MIH group. For individuals in this group, significantly larger prescription quantities in the main ATC (Anatomical, Therapeutic, Chemical) groups J (antiinfectives for systemic use), R (respiratory system) and S (sensory organs) were found in the first 4 years of life compared to MIH unaffected individuals. With antibiotics, there were both significantly larger prescription quantities and significantly higher numbers of respective prescriptions in the first 4 years of life. The differences amounted up to about 10.62% in frequently used antibiotics to be found in ATC J01D (other beta-lactam antibacterials) for the number of prescriptions in the 4th year of life. No association was found for premature birth, mode of delivery or the use of antipyretic or anti-inflammatory medication. CONCLUSIONS: While perinatal factors do not seem to be associated with MIH development, early life exposure to antibiotics might play a role. CLINICAL SIGNIFICANCE STATEMENT: Although causal relations can still not be proven, a responsible use of the unquestionably beneficial antibiotics is encouraged from a clinical point of view.

Tooth loss in periodontally treated patients: A registry- and observation-based analysis.

AIM: According to retrospective clinical studies, periodontal treatment retains teeth. However, evidence on the effectivity of periodontal treatment stemming from the general population is lacking. MATERIALS AND METHODS: We analysed data of periodontally treated patients from routine data of a major German national health insurance (BARMER-MV; sub-sample of the Federal State of Mecklenburg-Vorpommern) and from a clinical cohort (Greifswald Approach to Individualized Medicine, GANI_MED), as well as periodontally untreated and treated participants of the Study of Health in Pomerania (SHIP-TREND) with either ≥2 or ≥4 teeth with pocket depths ≥4 mm. Yearly tooth loss (YTL) estimates and incidence rates were evaluated. RESULTS: For moderately to severely affected groups, YTL and incidence rates were higher in BARMER-MV patients (0.35 and 0.18, respectively) than in untreated SHIP-TREND controls (0.19 and 0.08, respectively). In line, treated SHIP-TREND participants exhibited higher YTL rates than untreated SHIP-TREND controls (0.26 vs. 0.19). For severely affected groups, results with respect to tooth loss were inconclusive regarding the beneficial effects of periodontal treatment conducted either in the university (GANI_MED data) or in the general practice. CONCLUSION: Until 2021, periodontal treatment performed in German general dental practices within the national health insurance system was probably not efficient in retaining more teeth in the short- to mid-term. Since reimbursement schemes were changed in 2021 and now cover periodontal treatment to a much larger extent, the future will show whether these new reimbursement codes will improve the quality of periodontal treatment and whether they will lead to more long-term tooth retainment.

Management of herpesvirus reactivations in patients with solid tumours and hematologic malignancies: update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) on herpes simplex virus type 1, herpes simplex virus type 2, and varicella zoster virus.

Clinical reactivations of herpes simplex virus or varicella zoster virus occur frequently among patients with malignancies and manifest particularly as herpes simplex stomatitis in patients with acute leukaemia treated with intensive chemotherapy and as herpes zoster in patients with lymphoma or multiple myeloma. In recent years, knowledge on reactivation rates and clinical manifestations has increased for conventional chemotherapeutics as well as for many new antineoplastic agents. This guideline summarizes current evidence on herpesvirus reactivation in patients with solid tumours and hematological malignancies not undergoing allogeneic or autologous hematopoietic stem cell transplantation or other cellular therapy including diagnostic, prophylactic, and therapeutic aspects. Particularly, strategies of risk adapted pharmacological prophylaxis and vaccination are outlined for different patient groups. This guideline updates the guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) from 2015 "Antiviral prophylaxis in patients with solid tumours and haematological malignancies" focusing on herpes simplex virus and varicella zoster virus.

Performance of fixed dental prostheses up to 6 years-A massive data analysis.

STATEMENT OF PROBLEM: Metal and metal-ceramic fixed dental prostheses (FDPs) have been clinically determined to provide long-term durable restorations. However, data on their performance under practice conditions are sparse. PURPOSE: The purpose of this clinical study was to evaluate the longevity of FDPs under practice conditions by analyzing a large insurance claims database. MATERIAL AND METHODS: Data were extracted from the data warehouse of a major German national health insurance company (BARMER). The analysis focused on the FDP types with the lowest deductibles in the insurance system. All metal-based FDPs replacing up to 3 adjacent teeth were included. Ceramic veneering was optional and only approved on the labial surfaces of maxillary teeth mesial to the first molar and mandibular teeth mesial to the second premolar. Fee codes allowed clinical courses to be traced on a day count basis. Three groups with FDPs replacing 1 tooth, 2 teeth, and 3 teeth were formed. Kaplan-Meier survival analyses were conducted for the target events removal or extraction, indicating FDP failure and extraction of an abutment tooth. RESULTS: The sample comprised 124 660 FDPs that replaced 1 tooth (76.5%), 2 teeth (19.8%), or 3 teeth (3.7%). The cumulative survival rates for removal or extraction at 6 years differed significantly, with 83.0% for 1-pontic FDPs, 78.1% for 2-pontic FDPs, and 74.0% for 3-pontic FDPs. Thus, approximately 1 of 6 one-pontic FDPs, 1 of 5 two-pontic FDPs, and 1 of 4 three-pontic FDPs failed. The cumulative survival rates for extraction of an abutment tooth at 6 years showed no significant difference, with 96.0% for 1-pontic FDPs, 95.6% for 2-pontic FDPs, and 95.1% for 3-pontic FDPs. CONCLUSIONS: The survival rates of FDPs according to insurance data were lower than those reported by clinical studies, indicating a gap between efficacy and effectiveness.

Chatbots as a Tool to Scale Mentoring Processes: Individually Supporting Self-Study in Higher Education.

Like most curricula in the humanities and social sciences, the curriculum of pre-service teacher training in educational sciences often includes time-consuming reading and writing tasks, which require high quality support and feedback in a timely manner. A well-known way to provide this support to students is one-to-one mentoring. However, limited time and resources in the German university context require to effectively scale the benefits of individual feedback. The use of scalable technologies to support learning processes seems to be promising, but its development usually requires a deep technical understanding. With an interdisciplinary approach, this contribution investigates how personal mentoring can be made available to as many students as possible, taking into account the didactic, organizational and technical frameworks at universities. We describe the development and implementation process of two chatbots that both aim to support students of educational sciences in their self-study of the seminar topics and literature. The chatbots were used by over 700 students during the course of 1 year and our evaluations show promising results that bear the potential to improve the availability of digital mentoring support for all students.

Routine Data Analyses for Estimating the Caries Treatment Experience of Children.

Oral health surveys are considered the gold standard for assessing the caries experience of children. Analyses of routine data offer additional opportunities not yet fully explored. This study aimed at estimating the caries treatment experience by mining an insurance claims database. Comprehensive claims data sets were extracted from the data warehouse of a major health insurance company (BARMER, Germany). A surrogate variable for caries experience was formed that reflected the proportion of children without any former potentially caries-related treatment (filling, root canal treatment, and extraction) at ages from 1 to 14 years. The statistical calculations were based on Kaplan-Meier survival analyses. The evaluation for the permanent dentition comprised N = 593,330 children at 6 years and N = 114,568 at 12 years. At 12 years of age, 66.8% had not yet experienced potentially caries-related treatments. This value hints at a significantly higher caries experience at 12 years compared to available epidemiological data. For the deciduous dentition, the respective rates were 74.0% at 6 years and 45.8% at 10 years. Although various sources of bias have to be taken into account, the potential of routine data mining is evident. The approach is supplemental to oral health surveys. It can be useful in coming closer to reality when estimating the caries experience of children. From our results, we conclude that the oral health of up to 14-year-olds in Germany remains in urgent need of improvement.

State of Medical Mycology at German Academic Medical Centres: A Survey of the German-Speaking Mycological Society (DMYKG) and the Paul-Ehrlich-Society for Chemotherapy (PEG).

BACKGROUND: Little is known about the infrastructure to translate advances in the management of patients at risk to develop invasive opportunistic fungal diseases. To assess the current state of Medical Mycology support in Germany, we conducted a survey among all 36 academic medical centres. METHODS: The survey consisted of a 3-pages questionnaire sent out in the first half of 2019. Information included details of infrastructure, education and teaching; consultation services and interdisciplinary conferences; research activities and participation in network groups; radiology, microbiology and pharmacology support; publication activity; and European Confederation for Medical Mycology (ECMM) Excellence Center designation, if assigned. RESULTS: Information was returned from 24 centres (67%). Thirteen institutions (54%) reported an independent infectious disease, and two a separate Medical Mycology department (8%); a Medical Mycology working group was reported for nine institutions (38%). An infectious disease consultation service was existent in 16 institutions (67%) and a multidisciplinary conference in 13 (54%). Fifteen institutions reported a separate study office with activities in infectious disease studies (63%). Laboratory capability for fungal identification and susceptibility testing was confirmed by all 24 institutions; testing of galactomannan by 23 (96%), cryptococcal antigen by 21 (88%), ß-D-Glucan by 9 (38%), and panfungal and Pneumocystis PCR by 21 and 22 (88% and 92%), respectively. Therapeutic drug monitoring of voriconazole was reported to be available in 15 (63%) institutions with a turnaround of ≤24 h during weekdays in 10 (42%). Two of the 24 University hospitals (8%) reported ECMM Diamond Excellence Status. CONCLUSIONS: The results of this survey document the continuing need to improve the availability of specialised Medical Mycology support in German academic medical centres.

About the Role of Interfaces on the Fatigue Crack Propagation in Laminated Metallic Composites.

The influence of gradients in hardness and elastic properties at interfaces of dissimilar materials in laminated metallic composites (LMCs) on fatigue crack propagation is investigated experimentally for three different LMC systems: Al/Al-LMCs with dissimilar yield stress and Al/Steel-LMCs as well as Al/Ti/Steel-LMCs with dissimilar yield stress and Young's modulus, respectively. The damage tolerant fatigue behavior in Al/Al-LMCs with an alternating layer structure is enhanced significantly compared to constituent monolithic materials. The prevalent toughening mechanisms at the interfaces are identified by microscopical methods and synchrotron X-ray computed tomography. For the soft/hard transition, crack deflection mechanisms at the vicinity of the interface are observed, whereas crack bifurcation mechanisms can be seen for the hard/soft transition. The crack propagation in Al/Steel-LMCs was studied conducting in-situ scanning electron microscope (SEM) experiments in the respective low cycle fatigue (LCF) and high cycle fatigue (HCF) regimes of the laminate. The enhanced resistance against crack propagation in the LCF regime is attributed to the prevalent stress redistribution, crack deflection, and crack bridging mechanisms. The fatigue properties of different Al/Ti/Steel-LMC systems show the potential of LMCs in terms of an appropriate selection of constituents in combination with an optimized architecture. The results are also discussed under the aspect of tailored lightweight applications subjected to cyclic loading.

Formation of Die Soldering and the Influence of Alloying Elements on the Intermetallic Interface.

Die soldering of die castings is a serious problem in the aluminum casting industry. The precise mechanism, the influence of the alloy composition, and the options for prevention have not yet been fully elaborated. A well-established solution for alloys with low iron content is the addition of manganese. However, up to 0.8 wt.% is necessary, which increases the amount of brittle phases in the material and consequently reduces ductility. Immersion tests with 1.2343 tool steel and pure aluminum as well as a hypoeutectic AlSi-alloy with Mn, Mo, Co, and Cr additions were carried out to systematically investigate the formation of die soldering. Three different intermetallic layers and a scattered granular intermetallic phase formed at the interface between steel and Al-alloy after immersion into the melt for a duration of 6 min at 710 °C. The combined presence of the irregular, needle-shaped ß-Al5FeSi phase and the surrounding alloy was responsible for the bond between the two components. Mn and Mo inhibited the formation of the ß-phase, and instead promoted the αC-Al15(Fe,X)3Si2 phase. This led to an evenly running boundary to the AlSi-alloy and thus prevented bonding. Cr has proven to be the most efficient addition against die soldering, with 0.2 wt.% being sufficient. Contrary to the other elements investigated, Cr also reduced the thickness of the intermetallic interface.

Scrutinizing ligand exchange reactions in the formation of the precious group metal-organic framework RuII,II-HKUST-1: the impact of diruthenium tetracarboxylate precursor and modulator choice.

The precious group metal (PGM) analogues of the iconic metal-organic framework [Cu3(BTC)2] (HKUST-1; BTC = 1,3,5 benzenetricarboxylate) still represent a synthetic challenge, especially if targeting the univalent and ideally defect-free RuII,II variant. Herein we present a systematic study employing the controlled secondary building unit approach (CSA) by using a variety of diruthenium tetracarboxylate complexes [Ru2(RCO2)4] as precursors in the synthesis of univalent Ru-HKUST-1 samples. Carboxylate ligand exchange test reactions suggest the importance of a pKa match between precursor ligand and BTC linker. For example, l-mandelate substituted precursors resulted in the most "perfect" samples of the investigated series with a fourfold increase in crystalline domain sizes compared to the established acetate route (according to PXRD and HR-TEM), high compositional purity (FT-IR, Raman, TGA and elemental analysis) and feature a so far unprecedentedly high BET surface area of 1789 m2 g-1 with the expected pore size distribution and total pore volume all similar to the ideal HKUST-1 parent structure.

Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicenter, open-label phase-II trial.

The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias, anaemia, infusion-related reactions, and diarrhoea. This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with minimal residual disease negativity. However, ibrutinib should still be used as a single agent outside clinical trials. Clinicaltrials.gov number: NCT02689141.

Massive data analyses show negative impact of type 1 and 2 diabetes on the outcome of periodontal treatment.

OBJECTIVES: The aim was to evaluate the impact of diabetes on the outcome of periodontal treatment based on massive data analyses. MATERIALS AND METHODS: Data originated from the database of a major German National Health Insurance. Patients who underwent periodontal treatment were allocated to four groups according to their medical condition: type 1 diabetes (D1), type 2 diabetes with the intake of oral anti-diabetics (D2M), type 2 diabetes without the intake of oral anti-diabetics (D2), and a control group without diabetes (ND). Four-year Kaplan-Meier survival analyses on the patient level and multivariate regression analyses were conducted for tooth extraction. RESULTS: Of 415,718 patients, 4139 matched the criteria for D1, 22,430 for D2M, and 23,576 for D2. At 4 years, the cumulative survival rate (no extraction) was 51.7% in the D1 group, 54.0% in the D2M group, and 57.7% in the D2 group. The ND control group had a significantly higher survival rate of 65.9% (P < 0.0001). In the multivariate analyses, both diabetes types were significantly associated with further tooth loss after periodontal treatment. CONCLUSIONS: The diagnosis of diabetes type 1 or 2 seems to be associated with a higher risk of tooth loss after periodontal treatment. CLINICAL RELEVANCE: The long-term prognosis of teeth in diabetes patients should be judged carefully.