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Abstract Malaria remains one of the highest causes of morbidity and mortality, with 249 million cases and over 608,000 deaths in 2022. Insecticides, which target the Anopheles mosquito vector, are the primary method to control malaria. The widespread nature of resistance to the most important insecticide class, the pyrethroids, threatens the control of this disease. To reverse the stall in malaria control there is urgent need for new vector control tools, which necessitates understanding the molecular basis of pyrethroid resistance. In this study we utilised multi-omics data to identify uridine-diphosphate (UDP)-glycosyltransferases (UGTs) potentially involved in resistance across multiple Anopheles species. Phylogenetic analysis identifies sequence similarities between Anopheline UGTs and those involved in agricultural pesticide resistance to pyrethroids, pyrroles and spinosyns. Expression of five UGTs was characterised in An. gambiae and An. coluzzii to determine constitutive over-expression, induction, and tissue specificity. Furthermore, a UGT inhibitor, sulfinpyrazone, restored susceptibility to pyrethroids and DDT in An. gambiae, An. coluzzii, An. arabiensis and An. funestus, the major African malaria vectors. Taken together, this study provides clear association of UGTs with pyrethroid resistance as well as highlighting the potential use of sulfinpyrazone as a novel synergist for vector control.

BackgroundThe hepatitis E virus (HEV) can cause acute viral hepatitis with or without neurological manifestations, and occasionally progresses to chronic infection in immunocompromised individuals. The management of chronic HEV infection in cancer patients may be challenging due to the complex immunological constellation. Furthermore, the diagnostic workflow and the impact on quality of life of neurological HEV manifestations in immunocompromised patients have not been sufficiently delineated previously.Case descriptionA 61-year-old male with systemically treated chronic lymphocytic leukemia (CLL) experienced a slowly progressive atrophy of the spinal cord due to a chronic HEV infection. Despite continuous antiviral treatment with ribavirin, the patient’s neurological condition continued to deteriorate, particularly following subsequent attempts to treat CLL. Treatment with obinutuzumab resulted in acute bowel and urinary retention and a further deterioration of motor skills, prompting the discontinuation of obinutuzumab. The patient’s neurological status improved after the administration of intravenous immunoglobulins.ConclusionThis case study provides a comprehensive long-term follow-up of a cancer patient with chronic HEV infection and associated CNS involvement, which resulted in progressive neurological disability over several years. The challenges faced in diagnosing new neurological symptoms in patients undergoing immunosuppressive cancer treatment underscore the need for an interdisciplinary diagnostic approach that includes HEV testing. We propose a diagnostic pathway for future validation in immunocompromised cohorts presenting with neurological symptoms, emphasizing its potential to enhance clinical outcomes.

Background: Teriflunomide is a once-daily oral disease-modifying therapy (DMT) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Only limited information is available about its real-world use and changes over time. Objectives: To collect real-world data on teriflunomide use in clinical routine (and comparison to the previously conducted study TAURUS-MS). Design: National, open, non-interventional, prospective, multicenter study. Methods: TAURUS-MS II was conducted at 220 German sites between July 2017 and March 2022, including RRMS patients treated with teriflunomide. Data on patient demographics, MS history, previous treatment, therapy satisfaction, and safety were collected. Results: In total, 752 patients were included (65% female) with a mean age (±standard deviation) of 43 ± 11 years. Sixty-six percent had DMT before, and 46% had discontinued their last pretreatment ≤6 months prior to study entry. Among the latter, previous DMTs were interferon (21%), glatiramer acetate (11%), and dimethyl fumarate (9%), and reasons for discontinuation were adverse events (AEs; 55%) and insufficient efficacy (16%). Over 24 months, the mean treatment Satisfaction Questionnaire for Medication scores improved by 6 ± 29 points on effectiveness, 8 ± 20 on convenience, and 12 ± 25 on global satisfaction. The mean number of MS relapses decreased from 0.81 ± 0.81 in the 24 months prior to 0.27 ± 0.57 within 24 months after study entry. Non-serious AEs occurred in 423 patients (56%) and serious AEs in 49 patients (7%). Most reported AEs were alanine aminotransferase increase (11%), hypertension (8%), and alopecia (7%). Compared to TAURUS-MS, patients in TAURUS-MS II were younger, had a higher employment rate, and a higher share of treatment-naïve patients. Conclusion: Mean number of relapses was significantly reduced. Patient satisfaction was significantly improved compared to previous DMT. Tolerability was comparable to previous trials. Trial registration: Bundesinstitut für Arzneimittel und Medizinprodukte public database for non-interventional studies, number 7138.

Abstract A relevant number of cancer patients who receive potentially neurotoxic cytostatic agents develop a chemotherapy-induced peripheral neuropathy over time. Moreover, the increasing use of immunotherapies and targeted agents leads to a raising awareness of treatment-associated peripheral neurotoxicity, e.g., axonal and demyelinating neuropathies such as Guillain–Barré-like syndromes. To date, the differentiation of these phenomena from concurrent neurological co-morbidities or (para-)neoplastic nerve affection as well as their longitudinal monitoring remain challenging. Neuromuscular ultrasound (NMUS) is an established diagnostic tool for peripheral neuropathies. Performed by specialized neurologists, it completes clinical and neurophysiological diagnostics especially in differentiation of axonal and demyelinating neuropathies. No generally approved biomarkers of treatment-induced peripheral neurotoxicity have been established so far. NMUS might significantly extend the repertoire of diagnostic and neuromonitoring methods in this growing patient group in short term. In this article, we present enlargements of the dorsal roots both in cytostatic and in immunotherapy-induced neurotoxicity for the first time. We discuss related literature regarding new integrative applications of NMUS for cancer patients by reference to two representative case studies. Moreover, we demonstrate the integration of NMUS in a diagnostic algorithm for suspected peripheral neurotoxicity independently of a certain cancer treatment regimen emphasizing the emerging potential of NMUS for clinical routine in this interdisciplinary field and prospective clinical trials.

Background: Adjuvant radiotherapy (RT) is an integral component of a multidisciplinary treatment strategy for early-stage breast cancer. It significantly reduces the incidence of loco-regional recurrence but also of distant events. Distant events are due to tumor cells disseminated from the primary tumor into lymphatic fluid or blood, circulating epithelial tumor cells (CETC/CTC), which can reach distant tissues and regrow into metastases. The purpose of this study is to determine changes in the number of CETC/CTC in the course of adjuvant RT, and to evaluate whether they are correlated to local recurrence and distant metastases in breast cancer patients. Methods: Blood from 165 patients irradiated between 2002 and 2012 was analyzed 0–6 weeks prior to and 0–6 weeks after RT using the maintrac® method, and patients were followed over a median period of 8.97 (1.16–19.09) years. Results: Patients with an increase in CETC/CTC numbers over the course of adjuvant RT had a significantly worse disease-free survival (p = 0.004) than patients with stable or decreasing CETC/CTC numbers. CETC/CTC behavior was the most important factor in predicting subsequent relapse-free survival. In particular, patients who had received neoadjuvant chemotherapy were disproportionately more likely to develop metastases when cell counts increased over the course of RT (p = 0.003; hazard ratio 4.886). Conclusions: Using the maintrac® method, CETC/CTC were detected in almost all breast cancer patients after surgery. The increase in CETC/CTC numbers over the course of RT represents a potential predictive biomarker to judge relative risk/benefit in patients with early breast cancer. The results of this study highlight the need for prospective clinical trials on CETC/CTC status as a predictive criterion and for individualization of treatment. Clinical Trial registration: The trial is registered (2 May 2019) at trials.gov under NCT03935802.

Abstract Neuro-oncology, with its various conservative, surgical, and interventional disciplines, is ideally suited to teach basic knowledge, skills, and attitudes important to medical practice in general. However, training is less about teaching specific treatment protocols and more about fostering skills for interdisciplinary collaboration, development of treatment recommendations, communication skills, and an ethical stance. To adequately teach this content, new and innovative formats are needed to test and learn high levels of student interaction, communication, and collaboration. New teaching concepts such as inverted teaching formats as well as the use of modern media technology can be helpful to improve networking between disciplines and to improve the quality of medical education.

Abstract Background High-content screening (HCS) experiments generate complex data from multiple object features for each cell within a treated population. Usually, these data are analyzed by using population-averaged values of the features of interest, increasing the amount of false positives and the need for intensive follow-up validation. Therefore, there is a strong need for novel approaches with reproducible hit prediction by identifying significantly altered cell populations. Results Here we describe SOPRA, a workflow for analyzing image-based HCS data based on regression analysis of non-averaged object features from cell populations, which can be run on hundreds of samples using different cell features. Following plate-wise normalization, the values are counted within predetermined binning intervals, generating unique frequency distribution profiles (histograms) for each population, which are then normalized to control populations (control-based normalization). These control-normalized frequency distribution profiles are analyzed using the Bioconductor R-package maSigPro, originally developed to analyze time profiles. However, statistically significant altered frequency distributions are also identified by maSigPro when integrating it into the SOPRA workflow. Finally, significantly changed profiles can be used to generate a heatmap from which altered cell populations with similar phenotypes can be identified, enabling the detection of siRNAs and compounds with the same ‘on-target’ profile and reducing the number of false positive hits. Conclusions SOPRA is a novel analysis workflow for the detection of statistically significant normalized frequency distribution profiles of cellular features generated in high-throughput RNAi screens. For the validation of the SOPRA software workflow, a screen for cell cycle progression was used. We were able to identify such profiles for siRNA-mediated gene perturbations and chemical inhibitors of different cell cycle stages. The SOPRA software is freely available from Github.