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A letter to the editor is presented which discusses the case of a 67-year old suffering rapidly progressive tingling and numbness, and shows the tendency for phemenological variety of paraneoplastic (auto) immune phenomena occurring in B-cell non-Hodgkin lymphoma (NHL).

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS., Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project., Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings., Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM)., Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s), 2023.)

Purpose: Effective chemotherapeutical agents for the treatment of meningiomas are still lacking. Previous in-vitro analyses revealed efficacy of decitabine (DCT), a DNA methyltransferase (DNMT) inhibitor established in the treatment of leukemia, in a yet undefined subgroup of meningiomas., Methods: Effects of DCT on proliferation and viability was analyzed in primary meningioma cells by immunofluorescence and MTT assays, and cases were classified as drug responders and non-responders. Molecular preconditions for efficacy were analyzed using immunofluorescence for Ki67, DNMT1, and five oncogenes (TRIM58, FAM84B, ELOVL2, MAL2, LMO3) previously found to be differentially methylated after DCT exposition, as well as by genome-wide DNA methylation analyses., Results: Efficacy of DCT (10µM) was found in eight (62%) of 13 meningioma cell lines 48 h after drug exposition (p < .05). DCT significantly reduced DNMT1 expression in all but two cell lines, and median ΔDNMT1 reduction 48 h after drug exposition was lower in DCT-resistant (-11.1%) than in DCT-sensitive (-50.5%, p = .030) cells. Rates of cell lines responsive to DCT exposition distinctly decreased to 25% after 72 h. No significant correlation of the patients´ age, sex, histological subtype, location of the paternal tumor, expression of Ki67, DNMT1 or the analyzed oncogenes with treatment response was found (p > .05, each). DCT efficacy was further independent of the methylation class and global DNA methylation of the paternal tumor., Conclusion: Early effects of DCT in meningiomas are strongly related with DNMT1 expression, while clinical, histological, and molecular predictors for efficacy are sparse. Kinetics of drug efficacy might indicate necessity of repeated exposition and encourage further analyses., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

New inhibitors of the bacterial transferase MraY from Aquifex aeolicus (MraY AA ), based on the aminoribosyl uridine central core of known natural MraY inhibitors, have been designed to generate interaction of their oxadiazole linker with the key amino acids (H324 or H325) of the enzyme active site, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin. A panel of ten compounds was synthetized notably thanks to a robust microwave-activated one-step sequence for the synthesis of the oxadiazole ring that involved the O -acylation of an amidoxime and subsequent cyclization. The synthetized compounds, with various hydrophobic substituents on the oxadiazole ring, were tested against the MraY AA transferase activity. Although with poor antibacterial activity, nine out of the ten compounds revealed the inhibition of the MraY AA activity in the range of 0.8 µM to 27.5 µM., Competing Interests: The authors declare no conflict of interest.

New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers. The synthesized compounds were tested against the MraY AA transferase activity, and the most active compound with an original ( S , S )-tartaric diamide linker inhibits MraY activity with an IC 50 equal to 0.37 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative strains; however, the compounds showed no antibacterial activity. Docking and molecular dynamics studies revealed that this new linker established two stabilizing key interactions with N190 and H325, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin.

Purpose: Glioma patients face a limited life expectancy and at the same time, they suffer from afflicting symptoms and undesired effects of tumor treatment. Apart from bone marrow suppression, standard chemotherapy with temozolomide causes nausea, emesis and loss of appetite. In this pilot study, we investigated how chemotherapy-induced nausea and vomiting (CINV) affects the patients' levels of depression and their quality of life., Methods: In this prospective observational multicentre study ( n = 87), nausea, emesis and loss of appetite were evaluated with an expanded MASCC questionnaire, covering 10 days during the first and the second cycle of chemotherapy. Quality of life was assessed with the EORTC QLQ-C30 and BN 20 questionnaire and levels of depression with the PHQ-9 inventory before and after the first and second cycle of chemotherapy., Results: CINV affected a minor part of patients. If present, it reached its maximum at day 3 and decreased to baseline level not before day 8. Levels of depression increased significantly after the first cycle of chemotherapy, but decreased during the further course of treatment. Patients with higher levels of depression were more severely affected by CINV and showed a lower quality of life through all time-points., Conclusion: We conclude that symptoms of depression should be perceived in advance and treated in order to avoid more severe side effects of tumor treatment. Additionally, in affected patients, delayed nausea was most prominent, pointing toward an activation of the NK 1 receptor. We conclude that long acting antiemetics are necessary totreat temozolomide-induced nausea., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dufner, Kessler, Just, Hau, Bumes, Pels, Grauer, Wiese, Löhr, Jordan and Strik.)

The straightforward synthesis of aminoribosyl uridines substituted by a 5'-methylene-urea is described. Their convergent synthesis involves the urea formation from various activated amides and an azidoribosyl uridine substituted at the 5' position by an aminomethyl group. This common intermediate resulted from the diastereoselective glycosylation of a phthalimido uridine derivative with a ribosyl fluoride as a ribosyl donor. The inhibition of the MraY transferase activity by the synthetized 11 urea-containing inhibitors was evaluated and 10 compounds revealed MraY inhibition with IC 50 ranging from 1.9 μM to 16.7 μM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative bacteria. Four compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 μg mL -1 , including methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus faecium. Interestingly, one compound also revealed antibacterial activity against Pseudomonas aeruginosa with MIC equal to 64 μg mL -1 . Docking experiments predicted two modes of positioning of the active compounds urea chain in different hydrophobic areas (HS2 and HS4) within the MraY active site from Aquifex aeolicus. However, molecular dynamics simulations showed that the urea chain adopts a binding mode similar to that observed in structural model and targets the hydrophobic area HS2.

Rationale: The heterogeneous nature of gliomas makes the development and application of novel treatments challenging. In particular, infiltrating myeloid cells play a role in tumor progression and therapy resistance. Hence, a detailed understanding of the dynamic interplay of tumor cells and immune cells in vivo is necessary. To investigate the complex interaction between tumor progression and therapy-induced changes in the myeloid immune component of the tumor microenvironment, we used a combination of [ 18 F]FET (amino acid metabolism) and [ 18 F]DPA-714 (TSPO, GAMMs, tumor cells, astrocytes, endothelial cells) PET/MRI together with immune-phenotyping. The aim of the study was to monitor temozolomide (TMZ) treatment response and therapy-induced changes in the inflammatory tumor microenvironment (TME). Methods: Eighteen NMRI nu/nu mice orthotopically implanted with Gli36dEGFR cells underwent MRI and PET/CT scans before and after treatment with TMZ or DMSO (vehicle). Tumor-to-background (striatum) uptake ratios were calculated and areas of unique tracer uptake (FET vs. DPA) were determined using an atlas-based volumetric approach. Results: TMZ therapy significantly modified the spatial distribution and uptake of both tracers. [ 18 F]FET uptake was significantly reduced after therapy (-53 ± 84%) accompanied by a significant decrease of tumor volume (-17 ± 6%). In contrast, a significant increase (61 ± 33%) of [ 18 F]DPA-714 uptake was detected by TSPO imaging in specific areas of the tumor. Immunohistochemistry (IHC) validated the reduction in tumor volumes and further revealed the presence of reactive TSPO-expressing glioma-associated microglia/macrophages (GAMMs) in the TME. Conclusion: We confirm the efficiency of [ 18 F]FET-PET for monitoring TMZ-treatment response and demonstrate that in vivo TSPO-PET performed with [ 18 F]DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The synthesis of four CF 3 -proline analogues of the PLG peptide is reported. Our results show that the incorporation of trifluoromethylated amino acids (Tfm-AAs) at the N-terminal position of a peptide significantly increases its hydrophobicity. In addition, depending on the relative configuration and the position of the CF 3 group, Tfm-AAs can also promote passive diffusion transport., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This article has been withdrawn by the authors. This article did not comply with the editorial guidelines of MCP. Specifically, single peptide based protein identifications of 9-19% were included in the analysis and discussed in the results and conclusions. We wish to withdraw this article and resubmit a clarified, corrected manuscript for review., (Copyright © 2017, The American Society for Biochemistry and Molecular Biology.)

An estimated half of all mobile phone users in Kenya use WhatsApp, an instant messaging platform that provides users an affordable way to send and receive text messages, photos, and other media at the one-to-one, one-to-many, many-to-one, or many-to-many levels. A mobile learning intervention aimed at strengthening supervisory support for community health workers (CHWs) in Kibera and Makueni, Kenya, created a WhatsApp group for CHWs and their supervisors to support supervision, professional development, and team building. We analyzed 6 months of WhatsApp chat logs (from August 19, 2014, to March 1, 2015) and conducted interviews with CHWs and their supervisors to understand how they used this instant messaging tool. During the study period, 1,830 posts were made by 41participants. Photos were a key component of the communication among CHWs and their supervisors: 430 (23.4%) of all posts contained photos or other media. Of the remaining 1,400 text-based posts, 87.6% (n = 1,227) related to at least 1 of 3 defined supervision objectives: (1) quality assurance, (2) communication and information, or (3) supportive environment. This supervision took place in the context of posts about the roll out of the new mobile learning intervention and the delivery of routine health care services, as well as team-building efforts and community development. Our preliminary investigation demonstrates that with minimal training, CHWs and their supervisors tailored the multi-way communication features of this mobile instant messaging technology to enact virtual one-to-one, group, and peer-to-peer forms of supervision and support, and they switched channels of communication depending on the supervisory objectives. We encourage additional research on how health workers incorporate mobile technologies into their practices to develop and implement effective supervisory systems that will safeguard patient privacy, strengthen the formal health system, and create innovative forms of community-based, digitally supported professional development for CHWs., (© Henry et al.)

Background: Community health workers (CHWs) are used increasingly in the world to address shortages of health workers and the lack of a pervasive national health system. However, while their role is often described at a policy level, it is not clear how these ideals are instantiated in practice, how best to support this work, or how the work is interpreted by local actors. CHWs are often spoken about or spoken for, but there is little evidence of CHWs' own characterisation of their practice, which raises questions for global health advocates regarding power and participation in CHW programmes. This paper addresses this issue., Design: A case study approach was undertaken in a series of four steps. Firstly, groups of CHWs from two communities met and reported what their daily work consisted of. Secondly, individual CHWs were interviewed so that they could provide fuller, more detailed accounts of their work and experiences; in addition, community health extension workers and community health committee members were interviewed, to provide alternative perspectives. Thirdly, notes and observations were taken in community meetings and monthly meetings. The data were then analysed thematically, creating an account of how CHWs describe their own work, and the tensions and challenges that they face., Results: The thematic analysis of the interview data explored the structure of CHW's work, in terms of the frequency and range of visits, activities undertaken during visits (monitoring, referral, etc.) and the wider context of their work (links to the community and health service, limited training, coordination and mutual support through action and discussion days, etc.), and provided an opportunity for CHWs to explain their motivations, concerns and how they understood their role. The importance of these findings as a contribution to the field is evidenced by the depth and detail of their descriptive power. One important aspect of this is that CHWs' accounts of both successes and challenges involved material elements: leaky tins and dishracks evidenced successful health interventions, whilst bicycles, empty first aid kits and recruiting stretcher bearers evidenced the difficulties of resourcing and geography they are required to overcome., Conclusion: The way that these CHWs described their work was as healthcare generalists, working to serve their community and to integrate it with the official health system. Their work involves referrals, monitoring, reporting and educational interactions. Whilst they face problems with resources and training, their accounts show that they respond to this in creative ways, working within established systems of community power and formal authority to achieve their goals, rather than falling into a 'deficit' position that requires remedial external intervention. Their work is widely appreciated, although some households do resist their interventions, and figures of authority sometimes question their manner and expertise. The material challenges that they face have both practical and community aspects, since coping with scarcity brings community members together. The implication of this is that programmes co-designed with CHWs will be easier to implement because of their relevance to their practices and experiences, whereas those that assume a deficit model or seek to use CHWs as an instrument to implement external priorities are likely to disrupt their work.

Object: Histology is the gold standard for confirming thermally induced necrosis. Generally, however, no specimen is obtained from thermal ablation therapy for pathological examination. The aim of this study was to provide evidence for the relationship between temperatures reached and resulting tissue coagulation during laser ablation in a near-physiological ex vivo lung tumor model by combining viability staining and direct temperature measurement., Materials and Methods: In all, 17 human lung specimens with primary non-small-cell lung cancer (NSCLC) were examined in this study. Organs were resected with curative intent from patients of either gender (5 female, 12 male) with an average age of 65 years (51-78). Here, 11/17 specimens were subjected to interstitial laser thermal ablation in an ex vivo lung perfusion and ventilation model after surgery. A control group of 6/17 specimens was tested for viability without laser ablation. Tissue temperature was measured invasively in real-time during the ablation process using thermocouples. Afterwards, representative slices of all 17 specimens were tested for viability with triphenyltetrazolium chloride (TTC). Maximum tissue temperature Tmax[°C] measured at a distance of 10 and 20 mm from the laser tip and time of temperature exposure were correlated with the diameter of the induced coagulation as ascertained with viability staining. CH evaluated the results., Results: Mean maximum temperature was 75.9°C ± 14.4°C at a distance of 10 mm from the laser tip and 50.3°C ± 14.6°C at a distance of 20 mm, respectively. The mean distance between the coagulation margin and the laser tip was 17.8 mm ± 7.3 mm., Conclusion: We found that coagulation size correlated positively with temperature. There was a clear trend towards the correlation of time over 44°C and ablation depth. Maximum temperatures did not significantly correlate with coagulation size. Laser ablation of lung tumors using the IHLP (isolated human lung perfusion) model represents a possible method for evaluating ex vivo the interrelationships of temperature, time of temperature exposure, and resulting coagulation.

Introduction: Donor blood supplies are diminishing, becoming more costly and these transfusions lead to higher mortality in cardiac patients. The transfusion risks and the literature highlight the need for an alternative similar to cell salvage to be routinely considered. The Xtra is the first cell saver to be launched since 2001 and will undoubtedly initiate evolution towards the 'next generation' of cell savers. It is also the first to be launched in a new era where the demand for electronic perfusion data management (EPDM) has grown., Results: The user interface (UI) was easy to use. The increased data entry options improved the quality of the recordable data. The integrated data management system (DMS) was comprehensive. Data was easy to manage and enabled central data compilation, which reduces repeated data, the risk of inconsistent data inventory and provides the potential for research and analyses. The haematocrit of the processed blood is a key quality indicator for cell salvage. The comparison of the manufacturer's integrated protocol, Popt, to our team's own protocol showed that Popt delivered a higher haematocrit on its '1st bowl' (59.1% compared to 57.3%) and its 'total process' end product haematocrit was 0.68% higher. The Popt cycle took an average of 330s, whereas our own settings completed in just over 300s., Conclusion: The Xtra is a device which will lead the evolution of 'next generation' cell saver technology. The user interface and data management system provide export options and the ability to record the level of data required for good EPDM. This is essential to 'future proof' cell salvage technology. The manufacturer's integrated protocol achieved a higher end product haematocrit than our perfusion team's best practice. The design of the Xtra is contemporary, but the DMS equips this cell saver for the new era that faces both Perfusion and Cardiac Surgery.

Purpose: Few centers have attempted aortic surgery using miniaturized cardiopulmonary bypass (MCPB) systems due to concerns of air handling. The extra corporeal circuit optimized (ECCO) total MCPB system uses a venous air removal device and a parallel soft-shell reservoir that allows for venting of the heart. At our institution, total MCPB is used for all coronary artery bypass graft patients. Our objective was to assess the suitability of the ECCO total MCPB system during aortic surgery., Description: Fifty consecutive and unselected aortic procedures using the ECCO system were undertaken. Surgical feasibility, air removal ability, and blood transfusion requirements were audited to determine the efficacy of this technique., Evaluation: The bypass time was 81.6 +/- 28.0 minutes and the ischemic time was 56.7 +/- 18.9 minutes. Total MCPB handled 1,910 +/- 404 mL of vented blood with 96 venous air removal device activations noted. The blood product transfusion rate was 12%, which was below the surgical transfusion rate for our unit. There were no complications., Conclusions: Aortic surgery can be undertaken safely and effectively using the ECCO total MCPB system.