Background: Guidelines suggest pharmacological thromboprophylaxis for patients with multiple myeloma (MM) treated with immunomodulatory drugs due to a high risk of venous thromboembolisms (VTE). Objectives: To analyze rates of VTE and bleeding, risk profiles, and patterns of thromboprophylaxis in MM patients. Methods: For this cohort study, all consecutive patients with newly diagnosed MM between January 2012 and January 2022 who received induction treatment at our center were included. Characteristics at time of diagnosis, antimyeloma treatment, thromboprophylaxis, and thrombotic and bleeding events during 2-year follow-up were recorded. Results: Of 293 patients screened, 208 were included. During follow-up, VTE occurred in 19 (9.1%) patients, any bleeding in 35 (16.8%), and major bleeding in 14 (6.7%). IMPEDE-VTE score predicted VTE, but SAVED score did not. Two-year cumulative incidences of VTE by type of thromboprophylaxis prescribed after diagnosis (1) and at landmark 3 months (2) for aspirin versus standard anticoagulation (low molecular weight heparin or vitamin K antagonist) versus direct oral anticoagulants versus no antithrombotic therapy were (1) 18.73% (95% CI: 7.43-33.97) versus 2.78% (95% CI: 0.21-12.6) versus 4.00% (95% CI: 0.27-17.36) versus 9.88% (95% CI: 5.03-16.67) and (2) 12.46% (95% CI: 4.48-24.74) versus 5.56% (95% CI: 0.34-23.06) versus 0.00% versus 10.51% (95% CI: 4.88-18.64), respectively. Major bleeding rates did not significantly differ between antithrombotic strategies. Conclusion: We observed a high rate of VTE and bleeding in patients with newly diagnosed MM. Use of anticoagulant therapy including direct oral anticoagulants was associated with a trend toward reduced risk of VTE compared with aspirin or no antithrombotic therapy. Bleeding risk was high irrespective of antithrombotic strategy.

Due to its high printing resolution and ability to print multiple materials simultaneously, inkjet technology has found wide application in medicine. However, the biological safety of 3D-printed objects is not always guaranteed due to residues of uncured resins or support materials and must therefore be verified. The aim of this study was to evaluate the quality of standard assessment methods for determining the quality and properties of polyjet-printed scaffolds in terms of their dimensional accuracy, surface topography, and cytotoxic potential.Standardized 3D-printed samples were produced in two printing orientations (horizontal or vertical). Printing accuracy and surface roughness was assessed by size measurements, VR-5200 3D optical profilometer dimensional analysis, and scanning electron microscopy. Cytotoxicity tests were performed with a representative cell line (L929) in a comparative laboratory study. Individual experiments were performed with primary cells from clinically relevant tissues and with a Toxdent cytotoxicity assay.Dimensional measurements of printed discs indicated high print accuracy and reproducibility. Print accuracy was highest when specimens were printed in horizontal direction. In all cytotoxicity tests, the estimated mean cell viability was well above 70% (p < 0.0001) regardless of material and printing direction, confirming the low cytotoxicity of the final 3D-printed objects.

Background: Systemic light chain (AL) amyloidosis is a rare plasma cell disease characterized by the accumulation of amyloid fibrils in various tissues and organs throughout the body, leading to multiorgan dysfunction. Beyond anti-clonal therapy, this disease treatment requires multidisciplinary teams and resources to manage its multiorgan complications, however, the burden of the disease for health care system and health care resource use (HCRU) remain underexplored. Aims: To assess the HCRU in patients (pts) with AL amyloidosis across several European countries. Methods: EMN23, a retrospective, multicenter study, investigated the demographic and clinical characteristics, the treatment pathways, and the HCRU of adult pts with AL amyloidosis who initiated treatment in 2004–2018 from 13 sites across 10 European countries. The HCRU analysis on the 2011-2018 period included patient data from 7 countries (Greece, France, the Netherlands, Portugal, the Czech Republic, Austria, and Spain [only dialysis information available]). Patients who participated in clinical trials at any line were excluded. HCRU measures included hospitalizations, imaging examinations, adverse events of special interest (AESIs; Intensive Care Unit admission, Heart Failure, Need for pacemaker, Infections requiring hospitalization, Peripheral neuropathy), and dialysis information. Results: In 2011-2018, HCRU data and safety information were available for 462 pts (531 pts. with dialysis data). Most (63.4%) pts were males ≥65 years old (52.4%). At baseline, 41.6% (192/462) pts had 1 organ involved, 36.1% (167/462), had 2 and 20.8% (96/462) pts had ≥3 organs involved. The proportions of pts per the Eastern Cooperative Oncology Group (ECOG) status of 0, 1, 2, and 3 were 20.8% (96/462), 24.9% (115/462), 19.0% (88/462), and 7.8% (36/472), respectively; (not reported for 26.4% (122/462) pts). At diagnosis, Mayo 2004/European cardiac stages I, II, IIIa, and IIIb distribution was 75 (16.2%), 126 (27.3%), 127 (27.5%), and 59 (12.8%), respectively (Table 1) and was unknown for 75 (16.2%) pts. In 2011-2018, the number of pts with ≥1 hospitalization was 280 (60.6%). Duration of hospitalization is longer for patients stage IIIa and IIIb compared to lower cardiac stages (Table). Ultrasound and X-rays were the most common imaging exams across most cardiac stages (Stage I: 45.3%; Stage II: 42.1%, Stage IIIa: 47.2%; Stage IIIb: 39.0%), but MRIs and scintigraphy were also used commonly (see Table). At first-line, the proportions of pts treated with immunomodulatory (IMiD)-based regimens, bortezomib-based regimens, chemotherapy, and autologous stem cell transplantation were 2.2% (10/462), 62.3% (288/462), 12.6% (58/426) and 11.5% (53/462), respectively. The proportions of pts with ≥1 SAE and ≥1 AESI were 49.4% (228/462) and 28.8% (133/462), respectively. Infectious complication and heart failure were common reasons for hospitalization, with, half of the AESI records for cardiac stage IIIb patients being cardiac failure and ~1/10 AESI records being ICU admissions. A median number of 70.5-139.6 dialyses per pt per year were received by 70 (13.2%) pts, across cardiac stages. Image:Summary/Conclusion: The current analysis shows that in the recent years (post-2010), the burden of HCRU for pts with AL Amyloidosis was considerable, across all Mayo2004/European cardiac stages. The main burdensome components were hospitalizations and dialysis. A cost-of-illness study from the healthcare perspective will be conducted, to reveal the cost burden on the healthcare system of pts with AL amyloidosis in Europe.

Background: Carfilzomib (K)-based combinations have been established as effective frontline and relapse regimens in pts with multiple myeloma (MM). Aims: In this randomized phase II trial we evaluated the impact of either Revlimid (R) or Thalidomide (T) as combination partner for K and dexamethasone (KRd or KTd) on outcome in pts with newly diagnosed MM (NDMM) not eligible for autologous transplantation (TNE). Further, we evaluated the role of one year K maintenance therapy compared to observation. Methods: One hundred twenty two pts have been enrolled (ITT population). Median age was 75 yrs, ISS stage I/II/III: 29 (23.8%)/48 (39.3%)/45 (36.9%), ECOG stage 0/1: 64 (52.5%) / 58 (47.5%). t(4;14) ± del17p was noted in 15 (16.3%) of 92 pts with results available. Pts were randomized to 9 cycles of KRd or KTd, and 107 pts received at least one full cycle. Carfilzomib (K) was started with 20mg/m2 at d 1 of cycle 1, and was continued with 27mg/m2 for the first 2 cycles (d 1 + 2, 8 + 9, 15 + 16 schedule); followed by K administration at 57mg/m2 once weekly for a 28 d cycle. Thalidomide 100mg/d (50mg in pts >75 yrs of age), d 1-28, or Revlimid 25mg/d (15mg in pts 375 yrs of age) d 1-21. Dexamethasone 40mg (20mg in pts 375 yrs of age) once/week. After induction, pts with 3SD were randomized to K maintenance (d 1 and 15) for 12 cycles or observation. MRD was assessed by NGF with a sensitivity of 10-6 in pts with ≥VGPR. Survival estimates were calculated according to Kaplan-Meier and survival curves were compared with the log-rank test. PFS and OS results presented are given for the ITT population. This trial is registered on clinicaltrials.gov (NCT02891811). Results: Median follow-up was 25.3 mos, 15 pts discontinued therapy within the first cycle due to patient (3) or investigator (1) decision, AE/toxicity (8), death or progressive disease (2) or other reason (1). Overall response rate was 91.3% in the entire group with available data (n=115). Results for sCR, CR, VGPR, PR, and ORR for KRd and KTd were similar between both groups (7.3%/10.0%, 27.3%/33.3%, 38.2%/35.0%, 14.5/16.7%, 87.3%/95.0%, respectively). Minor response was noted in 4 (3.5%), stable disease in 5 (4.3%) and progressive disease in 1 (0.8%) pts. PFS (median 26.9 and 23.5 mos, p=0.832) and OS (not reached vs 52.2 mos, p=0.398) were similar between the KRd and KTd group, respectively. The OS rate at 36 mos was 82% in both groups. MRD testing was performed in 57 pts at time of CR/VGPR. Of those, 43.9%, (20.5% of the ITT group) pts were found to be MRDneg. PFS was significantly longer in MRDneg vs. MRDpos pts (p=0.003). Seventy six pts were randomized to K maintenance therapy or observation. Median PFS was numerically higher in the pts with K maintenance treatment (median 33.0 vs 24.0, p=0.714), but the difference was not statistically significant. Data on OS are not mature yet (only 9 events). Grade 3/4 hematologic AEs were anemia (4.1%), leukopenia (0.8%), thrombocytopenia (7.4%), while non-hematologic grade 3/4 AEs were infection (20.5%), GI-disorders (7.4%), hypertension (7.4%), renal and cardiac impairment/failure (6.6% and 8.2% respectively). Image:Summary/Conclusion: Our data show similar high efficacy of KRd and KTd in elderly NTE NDMM pts, including no difference in ORR (KRd and KTd, 87.3% and 95%, respectively), PFS and OS. Overall survival rate at 3 yrs was 82%. Median PFS was significantly longer in MRDneg pts. PFS was numerically, but not statistically longer in pts on K maintenance vs observation. Treatment was associated with an acceptable tolerance profile.

Background Barrier membranes and bone substitute are major tools of guided tissue regeneration (GTR) after periodontal disease. Integrity of the periodontal ligament plays a key role in periodontal health, but its functionality fails to be fully re-established by GTR after disease or trauma. Microtissue models suggest an in vivo-like model to develop novel GTR approaches due to its three-dimensionality. This study aims to assess the effects of collagen membranes and bone substitute on cell viability, adhesion and gene expression of regenerative and inflammatory biomarkers by periodontal ligament cell (PDLC) microtissues. Methods Human PDLC microtissues and monolayers were cultured on collagen membranes or bone substitute. After 24 hours incubation, metabolic activity, focal adhesion, mRNA and protein production of collagen-type-I (COL1A1), periostin (POSTN), vascular endothelial growth factor (VEGF), angiogenin (ANG), interleukin (IL)6 and IL8 were measured by resazurin-based toxicity assay, focal adhesion staining, quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Results PDLC microtissues and monolayers were viable on collagen membranes and bone substitute, but microtissues were less metabolically active. Dominant staining of actin filaments was found in PDLC microtissues on collagen membranes. COL1A1, POSTN, VEGF, ANG and IL6 were modulated in PDLC microtissues on bone substitute, while there were no significant changes on collagen membranes. PDLC monolayers showed a different character of gene expression changes. Conclusions PDLC microtissues and monolayers react diversely to collagen membranes and bone substitute. Further descriptive and mechanistic tests will be required to clarify the potential of PDLC microtissues as in vivo-like model for GTR.

BACKGROUND:Daratumumab was the first monoclonal CD38 antibody with single-agent activity approved for the treatment of multiple myeloma. Moreover, daratumumab demonstrated high response rates in relapsed immunoglobulin light-chain (AL) amyloidosis.PATIENTS AND METHODS:In our single-center retrospective real-life case series, we analyzed the efficacy and safety of daratumumab as first-line treatment. Daratumumab was administered with low-dose dexamethasone alone or in combination with other multiple myeloma therapeutics RESULTS: Fourteen patients were eligible, including nine patients with cardiac stage IIIa or IIIb. Overall hematologic response rate was 100%, with 64.3% achieving complete response after a median of 16 cycles of treatment. Median time to hematologic response was 1.4 months. Organ response rates were 45.5% after a median of 4.0 months and 66.7% after a median of 10.0 months, for heart and kidney involvement, respectively. After a median follow-up of 20.5 months, two patients underwent successful autologous stem cell transplantation (ASCT), while another three patients were in preparation for ASCT. Three patients remained on daratumumab at the last follow-up. There were no unexpected toxicities and no grade III or IV adverse events, although more than half of our patients were in stage IIIa or IIIb.CONCLUSION:Daratumumab proved to be highly effective in newly diagnosed AL amyloidosis with excellent hematologic and organ response rates, a remarkable safety profile, and good tolerability even in patients with advanced stage of disease.

Teeth are the hardest substance of the body and the gatekeeper of the digestive tract. They can survive extreme environmental conditions and they are the last part of the body that is decomposed after death. With these unique features, teeth are often the only remaining body part of a deceased person in a criminal case. Teeth can help investigators to find out who a dead person is, how old the person was, if the person was male or female, what kind of daily habits and lifestyle a person had and how the person died. Thus, the examination of teeth plays a key role in crime scene investigations and can help solve crimes.

The development of novel strategies in tissue engineering and regenerative medicine is inspired by the knowledge on the cell biological processes underlying regeneration. A clear key element in the early phase of healing is the cellular response to hypoxia. Novel therapeutic approaches target the cellular “oxygen sensors” by applying hypoxic pre-conditioning and pharmacologically simulated hypoxia. The cellular response to hypoxia is highly conserved, is well-orchestrated, and relies on hypoxia-inducible factors, which require labile transcription factor subunits and initiate among other pathways the cellular adaption to hypoxia and increase the production of pro-angiogenic factors. Hence, targeting cellular oxygen sensors is considered to be a promising strategy for tissue engineering and regenerative medicine. In this chapter, an overview of the current knowledge on the biology of hypoxia is given. Furthermore, we will review current research in the application of hypoxia-based strategies such as hypoxia pre-conditioning and prolyl hydroxylase (PHD) inhibitors for tissue engineering and regenerative medicine.

The factors that contribute to the morphological changes of dental pulp cell–derived microtissues are unknown. Here, we investigated the contraction dynamics of rod-shaped microtissues derived from dental pulp cells and examined the underlying cell signaling pathways. Human dental pulp cells were seeded into agarose molds to assemble into rod-shaped microtissues. Resazurin- and tetrazolium-based cytotoxicity assays, Live/Dead staining, and hematoxylin and eosin staining for histological evaluation of rods were performed. Rod contraction was evaluated and measured for a period of 10 days. The role of TGF-β, phosphoinositide 3-kinase (PI3K)/AKT, and mitogen-activated protein kinase (MAPK) signaling pathway was analyzed. Dental pulp cells readily assembled into rods, maintaining the geometric shape for 48 h. Following this period, they condensed to form stable spheroidal structures that remained vital for 10 days from seeding. Inhibition of phosphoinositide 3-kinase signaling pathway by LY294002 significantly prolonged the diminution in the length of rods formed by dental pulp cells. TGF-β and pharmacological inhibition of TGF-β signaling did not show pronounced effects. Overall, dental pulp cells readily formed rod-shaped patterns of microtissues which, over a period of time, condensed into more stable spheroidal structures. Hence, technologies like bioprinting, using direct fabrication of microtissues need to consider the contraction dynamics. The field of regenerative endodontology will benefit from our findings as it can be applied as a novel platform to test the impact of pharmacological agents, biomaterials, and regenerative approaches including bioprinting.

Background: Many medical schools train their faculty members to construct high cognitive level multiple choice questions (MCQs) that demand a great deal of analytical and critical thinking, application, and competence. The purpose of this study is to determine the cognitive levels of MCQs by using Moore’s Expanded Outcomes Framework and to understand whether the quality of MCQs has an effect on students’ assessment performance. Methods: Four trained faculty members analysed 100 randomly selected questions developed at the University Clinic of Dentistry (UCD) and 100 questions developed by the National Board of Dental Examinations (NBDE). Moore’s framework was applied to assist the review process. Results: The majority of questions was at the level of declarative knowledge followed by questions at the level of procedural knowledge. The cognitive level of UCD questions from 2002 to 2009 was significantly lower than that of NBDE questions but increased in questions written from 2010 to 2018. The improvement of quality of MCQs had no impact on assessment performance of students. Conclusion: The enhanced cognitive levels of UCD MCQs written 2010–2018 coincides with the implementation of a faculty training program for writing high-ordered MCQs. In addition, this study shows that the use of Moore’s expanded framework is on par with other known taxonomies in supporting educators in writing items and reviewing the process. Abbreviations: MCQs: Multiple Choice Questions; UCD: University Clinic of Dentistry; NBDE: National Board of Dental Examinations

Rabbit inhalation anesthesia by endotracheal intubation involves a higher risk among small animals owing to several anatomical and physiological features, which is pathognomonic to this species of lagomorphs. Rabbit-specific airway devices have been designed to prevent misguided intubation attempts. However, it is believed that expert anesthetic training could be a boon in limiting the aftermaths of this procedure. Our research is aimed to develop a novel biomimetic 3D printed rabbit airway model with representative biomechanical material behavior and radiodensity. Imaging data were collected for two sacrificed rabbit heads using micro-computed tomography (μCT) and micro-magnetic resonance imaging for the first head and cone beam computed tomography (CBCT) for the second head. Imaging-based life-size musculoskeletal airway models were printed using polyjet technology with a combination of hard and soft materials in replicates of three. The models were evaluated quantitatively for dimensional accuracy and radiodensity and qualitatively using digital microscopy and endoscopy for technical, tactic, and visual realism. The results displayed that simulation models printed with polyjet technology have an overall surface representation of 93% for μCT-based images and 97% for CBCT-based images within a range of 0.0–2.5 mm, with μCT showing a more detailed reproduction of the nasotracheal anatomy. Dimensional discrepancies can be caused due to inadequate support material removal and due to the limited reconstruction of microstructures from the imaging on the 3D printed model. The model showed a significant difference in radiodensities in hard and soft tissue regions. Endoscopic evaluation provided good visual and tactile feedback, comparable to the real animal. Overall, the model, being a practical low-cost simulator, comprehensively accelerates the learning curve of veterinary nasotracheal intubation and paves the way for 3D simulation-based image-guided interventional procedures.

Collagen membranes and bone substitute are popular biomaterials in guided tissue regeneration for treatment of traumatized or diseased periodontal tissue. Development of these biomaterials starts in monolayer cell culture, failing to reflect in vivo tissue organization. Spheroid cultures potentially mimic in vivo tissues in structure and functionality. This study aims to compare gingiva cell (GC) monolayers and spheroids to ex vivo gingiva. Human GC monolayers, spheroids and gingiva ex vivo tissues were cultured on plastic surfaces, collagen membranes or bone substitute. Hematoxylin-eosin (HE) staining, immunohistochemistry for KI67 and caspase 3 (CASP3), resazurin-based toxicity assays, quantitative polymerase chain reaction for collagen I (COL1A1), vascular endothelial growth factor (VEGF), angiogenin (ANG), interleukin (IL)6andIL8and ELISA for COL1A1, VEGF, ANG, IL6 and IL8 were performed in all cultures. Morphology was different in all culture set-ups. Staining of KI67 was positive in monolayers and staining of CASP3 was positive in spheroids. All culture set-ups were viable. COL1A1 production was modulated in monolayers and ex vivo tissues at mRNA levels, VEGF in monolayers and ex vivo tissues at mRNA levels and in spheroids at protein levels, ANG in spheroids at mRNA levels and in monolayers and spheroids at protein levels, IL6 in monolayers and spheroids at mRNA levels and in spheroids and ex vivo tissues at protein levels and IL8 in monolayers and ex vivo tissues at mRNA levels. Modulations were surface-dependent. In conclusion, each culture model is structurally and functionally different. Neither GC monolayers nor spheroids mimicked gingiva ex vivo tissue in all measured aspects.

(1) Background: Cardiac amyloidosis (CA) is a rare and complex condition with poor prognosis. While novel therapies improve outcomes, many affected individuals remain undiagnosed due to a lack of awareness among clinicians. This study was undertaken to develop an expert-independent machine learning (ML) prediction model for CA relying on routinely determined laboratory parameters. (2) Methods: In a first step, we developed baseline linear models based on logistic regression. In a second step, we used an ML algorithm based on gradient tree boosting to improve our linear prediction model, and to perform non-linear prediction. Then, we compared the performance of all diagnostic algorithms. All prediction models were developed on a training cohort, consisting of patients with proven CA (positive cases, n = 121) and amyloidosis-unrelated heart failure (HF) patients (negative cases, n = 415). Performances of all prediction models were evaluated on a separate prognostic validation cohort with 37 CA-positive and 124 CA-negative patients. (3) Results: Our best model, based on gradient-boosted ensembles of decision trees, achieved an area under the receiver operating characteristic curve (ROC AUC) score of 0.86, with sensitivity and specificity of 89.2% and 78.2%, respectively. The best linear model had an ROC AUC score of 0.75, with sensitivity and specificity of 84.6 and 71.7, respectively. (4) Conclusions: Our work demonstrates that ML makes it possible to utilize basic laboratory parameters to generate a distinct CA-related HF profile compared with CA-unrelated HF patients. This proof-of-concept study opens a potential new avenue in the diagnostic workup of CA and may assist physicians in clinical reasoning.

The impact of kaolinite on human periodontal cells is yet unknown. The aim of the study was to assess the response of human periodontal cells to kaolinite. Human periodontal cells were treated with kaolinite at reducing concentrations from 30 to 0.0015 mg/mL and with conditioned medium, which was depleted of kaolinite. Cell viability was evaluated with a resazurin-based toxicity assay, Live-Dead staining, and MTT assay and staining. The pro-angiogenic factors vascular endothelial growth factor (VEGF) and interleukin (IL)-6 and IL-8 were quantified via ELISA in periodontal fibroblasts. L-929, a standard cell-line used for cytotoxicity studies, served as control cell line. Composition of kaolinite was verified using energy-dispersive X-ray spectroscopy. Kaolinite in suspension but not in conditioned medium impaired cell viability dose-dependently. VEGF, IL-6, and IL-8 production was not substantially modulated by kaolinite or the conditioned medium in periodontal cells. Overall, kaolinite can decrease cell viability dose-dependently while conditioned medium showed no toxic effect. No pronounced impact of kaolinite on VEGF, IL-6, and IL-8 production was observed. This study provided first insights into the impact of kaolinite on human periodontal cells thereby inferring to the basis for the evaluation of kaolinite as a carrier in regenerative dentistry. Kaolinite, a clay mineral, is successfully used in medicine due to its favorable properties. Also, applications in conservative dentistry are described. However, the response of oral cells to kaolinite is still unclear. Here, we assessed the impact of kaolinite on human periodontal cells.