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Introduction Few available data indicate that a mutation-based “neoadjuvant” therapy in advanced anaplastic thyroid carcinoma (ATC) might convert an initially unresectable primary tumor to resectable and optimize local tumor control. We evaluated a preoperative short-term “neoadjuvant” therapy with a BRAF-directed therapy or, in case of BRAF non-mutated tumors, an mKI/checkpoint inhibitor combination in three patients with ATC stage IVB and C. Methods In the context of preoperative diagnostics, immunohistochemistry (IHC) assessment and genetic analysis was started as soon as possible. The antiangiogenetic therapy with lenvatinib was immediately after diagnosis of ATC started as bridging therapy. In case of a BRAF-mutated ATC, a combination therapy of dabrafenib and trametinib, in case of BRAF-wildtype ATC a combination of pembrolizumab and lenvatinib was given for 4 weeks. If re-staging has shown a significant therapy response due to a decrease in size of > 50%, surgical resection was reconsidered. A primary tumor resection was performed first. As a second step, limited distant metastasis have been resected approximately 4 weeks after thyroid surgery. After postoperative recovery, the targeted systemic therapy was continued. Patients Two patients presented with BRAF-wildtype ATC stage IVC, one with BRAF-mutated ATC stage IVB. All patients were evaluated by surgery, nuclear medicine and oncology upon diagnosis of ATC. Results In all three cases, the “neoadjuvant” therapy induced a dramatic response and led to local resectability in primarily non-resectable ATC stage IVB or C. We have chosen for the first time a short-term “neoadjuvant” treatment period to reduce the risk of bleeding and/or fistula due to potential rapid tumor shrinkage. The results of surgery after only short-term “neoadjuvant” therapy showed two R0 und one R1 resections. Postoperative histopathological findings confirmed an extent of tumor necrosis or regressive fibrotic tissue between 60 and > 95% in our patients. Conclusions A short-term mutation-based “neoadjuvant” therapy can achieve local resectability in initially unresectable ATC stage IVB or C. A neoadjuvant treatment period of about 4 weeks seems to show similar response as a treatment duration of at least 3 months.

The fracture risk assessment tool (FRAX) is a tool which calculates an individual 10-year fracture risk based on epidemiological data in patients with a risk of osteporosis. The aim of this study was to evaluate the value of FRAX to estimate the risk of postoperative periprosthetic fractures (PPF) in patients following with total hip and knee arthroplasty. 167 patients (137 periprosthetic fractures in total hip arthroplasty and 30 periprosthetic fractures in total knee arthroplasty) were included in this study. Patients’ data was retrieved retrospectively. In each patient the 10-year probability of a major osteoporotic fracture (MOF) and an osteoporotic hip fracture (HF) was calculated using FRAX. According to the NOGG guideline 57% of total hip arthroplasty (THA) patients and 43.3% of total knee arthroplasty (TKA) patients were in need of osteoporosis treatment, whereas only 8% and 7% received an adequate one respectively. 56% of the patients with PPF after THA and 57% of the patients with PPF after TKA reported about a previous fracture. Significant associations between the 10-year probability of a MOF and HF calculated by FRAX and PPF in THA and TKA were seen. The results of the present study show that FRAX might have the potential to estimate the PPF in patients following THA and TKA. FRAX should be calculated before and after THA or TKA in order to assess the risk and counsel patients. The data show a clear undertreatment of patients with PPF in respect to osteoporosis.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal acquired thrombotic microangiopathy syndrome that frequently develops in the context of infectious diseases or systemic autoimmune conditions including connective tissue diseases. We report the case of a 42-year-old female suffering from severe iTTP associated with anti-Jo-1 positive antisynthetase syndrome, which was successfully treated with combination therapy of intravenous immune globulin, rituximab and plasma exchange. Based on a systematic review of the literature, two additional cases of idiopathic inflammatory myopathy-associated iTTP (secondary iTTP) were identified. In conclusion, iTTP may be a rare complication of IIM that clinicians should consider in cases of marked thrombocytopenia. Further work-up of this finding should include a peripheral blood smear (schistocyte count) and ADAMTS13 activity. The concomitant manifestation of these autoimmune conditions may require intensive immunosuppressive therapy.

Purpose Despite excellent long-term overall survival rates, pediatric low-grade gliomas (pLGG) show high variety of clinical behavior regarding progress or senescence post incomplete resection (IR). This study retrospectively analyzes tumor growth velocity (TGV) of pLGG before surgery and after IR to investigate the impact of surgical extent, tumor location and molecular BRAF status on postoperative residual tumor growth behavior. Methods Of a total of 172 patients with pLGG receiving surgical treatment, 107 underwent IR (66%). Fifty-three vs 94 patients could be included in the pre- and post-operative cohort, respectively, and were observed over a mean follow-up time of 40.2 vs 60.1 months. Sequential three-dimensional MRI-based tumor volumetry of a total of 407 MRI scans was performed to calculate pre- and postoperative TGV. Results Mean preoperative TGV of 0.264 cm3/month showed significant deceleration of tumor growth to 0.085 cm3/month, 0.024 cm3/month and −0.016 cm3/month after 1st, 2nd, and 3rd IR, respectively (p 2.03 cm3 associated with a higher risk of progress post IR (sensitivity 78,6%, specificity 76.3%, AUC 0.88). Postoperative TGV of BRAF V600E-mutant LGG was significantly higher than of BRAF wild-type LGG (0.123 cm3/month vs. 0.016 cm3/month, p = 0.047). Conclusion This data suggests that extensive surgical resection may impact pediatric LGG growth kinetics post incomplete resection by inducing a significant deceleration of tumor growth. BRAF-V600E mutation may be a risk factor for higher postoperative TGV.

Since the potential for reducing CO2 emissions from fossil fuels is limited, suitable CO2-neutral fuels are required for applications which cannot reasonably be electrified, and therefore still rely on internal combustion engines in the future. Potential fuel candidates for CI engines are either paraffinic diesel fuels or new fuels like POMDME (polyoxymethylene dimethyl ether, short “OME”). Besides, also blends of these two types of fuels might be of interest. While many studies have been conducted on OME blends with fossil diesel fuel, the research on HVO–OME blends has been less extensive to date.In the current work, pure OME and HVO–OME blends are investigated in a single-cylinder research engine. The test results of the various fuel blend formulations are compared and evaluated, particularly with regard to soot-NOx trade-off behavior. The primary objective of the study is to examine whether the major potential of blending these two fuels is already largely exploited at low OME content, or if significant additional emission reduction potential can still be found with higher content blends, but still without the need to switch to pure OME operation. Furthermore, the fuel blend which is best suited for the realization of an ultra-low emission concept under the current technical conditions should be identified. In addition, three different injector designs were tested for operation on pure OME3-5, differing both in hydraulic flow and in the number of injection holes as well as their layout. The optimum configuration is evaluated with regard to emissions, normalized heat release and indicated efficiency.

Data science systems (DSSs) are a fundamental tool in many areas of research and are now developed by people with a myriad of backgrounds. This is coupled with a crisis in reproducibility of such DSSs despite the wide availability of powerful tools for data science and machine learning over the last decade. We believe that perverse incentives and a lack of widespread software engineering skills are among the many causes of this crisis and analyze why software engineering and building large complex systems is, in general, hard. Based on these insights, we identify how software engineering addresses those difficulties and how one might apply and generalize software engineering methods to make DSSs more fit for purpose. We advocate two key development philosophies: one should incrementally grow – not plan then build – DSSs, and one should use two types of feedback loops during development: one which tests the code’s correctness and another that evaluates the code’s efficacy.

The intermediate bacterial microbiota is a heterogeneous group that varies in the severity of the dysbiosis, from minor deficiency to total absence of vaginal Lactobacillus spp. We treated women with this vaginal dysbiosis in the first trimester of pregnancy using a vaginally applied lactobacilli preparation to restore the normal microbiota in order to delay the preterm delivery rate. Pregnant women with intermediate microbiota of the vagina and a Nugent score of 4 were enrolled in two groups: intermediate vaginal microbiota and a Nugent score of 4 with lactobacilli (IMLN4) and intermediate vaginal microbiota and a Nugent score of 4 without lactobacilli (IM0N4), with and without vaginal lactobacilli at baseline, respectively. Half of the women in each group received the treatment. Among women without lactobacilli (the IM0N4 group), the Nugent sore decreased by 4 points only in the women who received treatment, and gestational age at delivery and neonatal birthweight were both significantly higher in the treated subgroup than in the untreated subgroup (p = 0.047 and p = 0.016, respectively). This small study found a trend toward a benefit of treatment with vaginal lactobacilli during pregnancy.

With the changing epidemiology of COVID-19 and its impact on our daily lives, there is still an unmet need of COVID-19 therapies treating early infections to prevent progression. The current study was a randomized, parallel, double-blind, placebo-controlled trial. Ninety SARS-CoV-2 positive patients were randomized into 3 groups receiving placebo, 0.02% or 0.1% azelastine nasal spray for 11 days, during which viral loads were assessed by quantitative PCR. Investigators assessed patients’ status throughout the trial including safety follow-ups (days 16 and 60). Symptoms were documented in patient diaries. Initial viral loads were log10 6.85 ± 1.31 (mean ± SD) copies/mL (ORF 1a/b gene). After treatment, virus load was reduced in all groups (p p = 0.007). In a subset of patients (initial Ct p = 0.005). Negative PCR results appeared earlier and more frequently in the azelastine treated groups: being 18.52% and 21.43% in the 0.1% and 0.02% groups, respectively, compared to 0% for placebo on day 8. Comparable numbers of adverse events occurred in all treatment groups with no safety concerns. The shown effects of azelastine nasal spray may thus be suggestive of azelastine’s potential as an antiviral treatment.Trial registration: The study was registered in the German Clinical Trial Register (DRKS-ID: DRKS00024520; Date of Registration in DRKS: 12/02/2021). EudraCT number: 2020-005544-34.

In vivo, the force–velocity relation (F–v–r) is typically derived from the torque–angular velocity relation (T–ω–r), which is subject to two factors that may influence resulting measurements: tendon compliance and preload prior to contraction. The in vivo plantar flexors’ T–ω–r was determined during preloaded maximum voluntary shortening contractions at 0–200°/s. Additionally, we used a two factor block simulation study design to independently analyze the effects of preload and tendon compliance on the resulting T–ω–r. Therefore, we replicated the in vivo experiment using a Hill-type muscle model of the gastrocnemius medialis. The simulation results matched a key pattern observed in our recorded in vivo experimental data: during preloaded contractions, torque output of the muscle was increased when compared with non-preloaded contractions from literature. This effect increased with increasing contraction velocity and can be explained by a rapidly recoiling tendon, allowing the contractile element to contract more slowly, thus developing higher forces compared with non-preloaded contractions. Our simulation results also indicate that a more compliant tendon results in increased ankle joint torques. The simulation and the experimental data clearly show that the deduction of the in vivo F–v–r from the T–ω–r is compromised due to the two factors preloading and tendon compliance.

Acknowledgements: This work was supported by the Wellcome Trust, United Kingdom, Investigator award 214298/Z/18/Z to R.F.W., a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant 464878930 to S.G., and a DFG Equipment grant INST 86/1831-1 to Prof. Markus Meissner. B.N.M.S. was supported by a Gates Cambridge Scholarship, and K.B. was supported by the Leverhulme Early Career Fellowship (ECF-2015-562) provided jointly by the Isaac Newton Trust and the Leverhulme Trust. M.S.R. and J.H. was supported by Wellcome Trust grants 086598 and 214272 to M.S.R. and a Wellcome Trust Strategic Award 100140 to the Cambridge Institute for Medical Research (CIMR). N.R.Z. was supported by Wellcome Trust grant WT 207455/Z/17/Z. C.M.K. was supported by a Canada Vanier Graduate Scholarship and J.B.D. is supported by the Canada Research Chair (Tier II) in Evolutionary Cell Biology and by the Natural Sciences and Engineering Research Council of Canada (RES0043758, RES0046091). Y.R-C. was supported by NIH awards F31AI152297 and T32AI007528. We thank VEuPathDB for their invaluable Informatics Resources, and Markus Meissner, Christine Hopp, Nicola Hodson, Julian Rayner, Mirko Singer and David Warhurst for useful discussions, and Cornelia Niemann and Karin Müller for assistance with electron microscopy., Apicomplexan parasites have immense impacts on humanity, but their basic cellular processes are often poorly understood. Where endocytosis occurs in these cells, how conserved this process is with other eukaryotes, and what the functions of endocytosis are across this phylum are major unanswered questions. Using the apicomplexan model Toxoplasma, we identified the molecular composition and behavior of unusual, fixed endocytic structures. Here, stable complexes of endocytic proteins differ markedly from the dynamic assembly/disassembly of these machineries in other eukaryotes. We identify that these endocytic structures correspond to the ‘micropore’ that has been observed throughout the Apicomplexa. Moreover, conserved molecular adaptation of this structure is seen in apicomplexans including the kelch-domain protein K13 that is central to malarial drug-resistance. We determine that a dominant function of endocytosis in Toxoplasma is plasma membrane homeostasis, rather than parasite nutrition, and that these specialized endocytic structures originated early in infrakingdom Alveolata likely in response to the complex cell pellicle that defines this medically and ecologically important ancient eukaryotic lineage.