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Immune-suppressive (M2-type) macrophages can contribute to the progression of cancer and fibrosis. In chronic liver diseases, M2-type macrophages promote the replacement of functional parenchyma by collagen-rich scar tissue. Here, we aim to prevent liver fibrosis progression by repolarizing liver M2-type macrophages toward a nonfibrotic phenotype by applying a pH-degradable, squaric ester–based nanogel carrier system. This nanotechnology platform enables a selective conjugation of the highly water-soluble bisphosphonate alendronate, a macrophage-repolarizing agent that intrinsically targets bone tissue. The covalent delivery system, however, promotes the drug’s safe and efficient delivery to nonparenchymal cells of fibrotic livers after intravenous administration. The bisphosphonate payload does not eliminate but instead reprograms profibrotic M2- toward antifibrotic M1-type macrophages in vitro and potently prevents liver fibrosis progression in vivo, mainly via induction of a fibrolytic phenotype, as demonstrated by transcriptomic and proteomic analyses. Therefore, the alendronate-loaded squaric ester–based nanogels represent an attractive approach for nanotherapeutic interventions in fibrosis and other diseases driven by M2-type macrophages, including cancer.

Even though AI technologies like CBR have proved their strengths for intelligent sales support in EC applications, on-line customers often encounter e-sales systems that are hard to use. Before a search process is started, they either have to answer many annoying or irrelevant questions or they are faced with technical jargon of manufacturers they are not able to understand. On-line customers want personalised advice and adequate product offerings. Gaining sufficient information from the customer but also providing her with information at the right place is the key. Resulting from this fact, an automated communication process is needed that simulates the sales dialog between customers and human sales persons. This article proposes a method for question selection in e-sales dialogs based on the variance of the CBR system's inherent similarities. The method uses a similarity-influenced measure to reduce the number of questions required to find satisfactory products. Additionally, it is shown how questions can be selected on the level of abstraction appropriate to the customer's knowledge.

Tuberculosis is the deadliest bacterial disease globally, threatening the lives of millions every year. New antibiotic therapies that can shorten the duration of treatment, improve cure rates, and impede the development of drug resistance are desperately needed. Here, we used polymeric micelles to encapsulate four second-generation derivatives of the antitubercular drug pretomanid that had previously displayed much better in vivo activity against Mycobacterium tuberculosis than pretomanid itself. Because these compounds were relatively hydrophobic, we expected that such micellar formulations would increase drug bioavailability, reduce toxicities, and improve therapeutic outcomes. The polymeric micelles were based on polypept(o)ides (PeptoMicelles) and were stabilized in their hydrophobic core by Π-Π interactions, allowing the efficient encapsulation of aromatic pretomanid derivatives. The stability of these Π-Π stabilized PeptoMicelles was demonstrated in water, blood plasma, and lung surfactant by fluorescence cross-correlation spectroscopy and was further supported by prolonged circulation times of several days in the vasculature of zebrafish larvae. The pretomanid derivative with the best in vitro potency against Mycobacterium marinum ('drug D') was also the most efficacious PeptoMicelle formulation tested in the zebrafish larvae infection model, almost completely eradicating the bacteria at non-toxic doses. This lead formulation was further assessed against Mycobacterium tuberculosis in the susceptible C3HeB/FeJ mouse model, which develops human-like necrotic granulomas. Following intravenous administration, the drug D micellar formulation significantly reduced bacterial burden and inflammatory responses in the lungs and spleens of infected mice. Competing Interest Statement The authors have declared no competing interest.

The segmenting effect states that people learn better when multimedia instructions are presented in (meaningful and coherent) learner-paced segments, rather than as continuous units. This meta-analysis contains 56 investigations including 88 pairwise comparisons and reveals a significant segmenting effect with small to medium effects for retention and transfer performance. Segmentation also reduces the overall cognitive load and increases learning time. These four effects are confirmed for a system-paced segmentation. The meta-analysis tests different explanations for the segmenting effect that concern facilitating chunking and structuring due to segmenting the multimedia instruction by the instructional designer, providing more time for processing the instruction and allowing the learners to adapt the presentation pace to their individual needs. Moderation analyses indicate that learners with high prior knowledge benefitted more from segmenting instructional material than learners with no or low prior knowledge in terms of retention performance.

Background Consensus-orientated Delphi studies are increasingly used in various areas of medical research using a variety of different rating scales and criteria for reaching consensus. We explored the influence of using three different rating scales and different consensus criteria on the results for reaching consensus and assessed the test-retest reliability of these scales within a study aimed at identification of global treatment goals for total knee arthroplasty (TKA). Methods We conducted a two-stage study consisting of two surveys and consecutively included patients scheduled for TKA from five German hospitals. Patients were asked to rate 19 potential treatment goals on different rating scales (three-point, five-point, nine-point). Surveys were conducted within a 2 week period prior to TKA, order of questions (scales and treatment goals) was randomized. Results Eighty patients (mean age 68 ± 10 years; 70% females) completed both surveys. Different rating scales (three-point, five-point and nine-point rating scale) lead to different consensus despite moderate to high correlation between rating scales (r = 0.65 to 0.74). Final consensus was highly influenced by the choice of rating scale with 14 (three-point), 6 (five-point), 15 (nine-point) out of 19 treatment goals reaching the pre-defined 75% consensus threshold. The number of goals reaching consensus also highly varied between rating scales for other consensus thresholds. Overall, concordance differed between the three-point (percent agreement [p] = 88.5%, weighted kappa [k] = 0.63), five-point ( p  = 75.3%, k = 0.47) and nine-point scale ( p  = 67.8%, k = 0.78). Conclusion This study provides evidence that consensus depends on the rating scale and consensus threshold within one population. The test-retest reliability of the three rating scales investigated differs substantially between individual treatment goals. This variation in reliability can become a potential source of bias in consensus studies. In our setting aimed at capturing patients’ treatment goals for TKA, the three-point scale proves to be the most reasonable choice, as its translation into the clinical context is the most straightforward among the scales. Researchers conducting Delphi studies should be aware that final consensus is substantially influenced by the choice of rating scale and consensus criteria.

Background: T lymphocyte collection through leukapheresis is an essential step for chimeric antigen receptor T (CAR-T) cell therapy. Timing of apheresis is challenging in heavily pretreated patients who suffer from rapid progressive disease and receive T cell impairing medication. Methods: A total of 75 unstimulated leukaphereses were analyzed including 45 aphereses in patients and 30 in healthy donors. Thereof, 41 adult patients with Non-Hodgkin’s lymphoma (85%) or acute lymphoblastic leukemia (15%) underwent leukapheresis for CAR-T cell production. Results: Sufficient lymphocytes were harvested from all patients even from those with low peripheral lymphocyte counts of 0.18/nL. Only four patients required a second leukapheresis session. Leukapheresis products contained a median of 98 × 108 (9 - 341 × 108) total nucleated cells (TNC) with 38 × 108 (4 - 232 × 108) CD3+ T cells. Leukapheresis products from healthy donors as well as from patients in complete remission were characterized by high TNC and CD3+ T lymphocyte counts. CAR-T cell products could be manufactured for all but one patient. Conclusions: Sufficient yield of lymphocytes for CAR-T cell production is feasible also for patients with low peripheral blood counts. Up to 12–15 L blood volume should be processed in patients with absolute lymphocyte counts ≤ 1.0/nL.

Background Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). Methods Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 10 6 and 50 × 10 6 CARTs/m 2 . Leukapheresis, manufacturing and administration of CARTs were performed in-house. Results For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. Conclusion In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.clinicaltrials.gov as NCT03676504.

Introduction Cardiovascular disease (CVD) is the leading cause of death and the mortality rate and prognosis of CVD in women are worse compared to men. Adverse Pregnancy Outcomes (APOs) are frequently overlooked sex-specific risk factors for CVD and affect up to one in five pregnant women. This study evaluated healthcare providers'(HCPs) awareness of the long-term cardiovascular risk associated with gestational diabetes mellitus and hypertensive disorders of pregnancy. Methods A cross-sectional survey was conducted in Austria between March and August 2022 to assess HCPs’ knowledge, follow-up recommendations, and counseling regarding cardiovascular risk following APOs. The respondents were divided into general medicine, Obstetrics and Gynecology (O&G), general internal medicine, and cardiology. Results Of the 175 responses, 20% ( n  = 35) were from general medicine, 39% ( n  = 68) from O&G, 39% ( n  = 69) from general internal medicine and cardiology, and 2% ( n  = 3) from other specialties. Although most respondents were aware of increased CVD risk following APOs, significant knowledge gaps were identified, particularly concerning the prevalence and timing of CVD onset after APOs. Over 50% do not counsel women with APOs on cardiovascular risk reduction strategies and approximately half do not counsel on the risk of recurrence of APOs. Less than 20% provide women with written follow-up information. Differences in expertise were observed among specialties, with O&G demonstrating the highest level of knowledge. Conclusion This study identified knowledge gaps among HCPs in postpartum care for women with APOs highlighting the importance of standardized follow-up programs and the need for targeted education for HCPs. Graphical abstract