Search

Purpose The current idea of how oral mucositis (OM) develops is primarily based on hypotheses and the early events which precede clinically established OM remain to be demonstrated. Cryotherapy (CT) continues to have considerable promise in clinical settings to reduce chemotherapy-induced OM. Although being effective, the knowledge is scarce regarding the ideal temperature for prevention of OM. Thus, the present study had two main objectives: (i) to develop an animal model to investigate the early events of OM; (ii) to study at what cooling temperature these early events could be abolished. Methods Male Sprague–Dawley rats were anaesthetized and given an intravenous bolus dose with the cytostatic drug fluorouracil (5-FU). During the first hour following injection with 5-FU, the oral cavity of the rats was cooled to a mucosal temperature at the range of 15–30 ○C, or left uncooled (35 ○C), serving as control. After 3–5 days, the rats were euthanized, and the buccal mucosa was excised. Subsequently, mucosal thickness and expression of IL-6 and TNF-α were analyzed with immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Results Five days following treatment with 5-FU, a statistically significant thickening of the oral mucosa occurred, and a distinct expression of both IL-6 and TNF-α were observed. The cryo-treated groups (15–30 °C) displayed statistically significantly thinner mucosa as compared to the control group (35 °C). The ELISA showed an increase in expression of the proinflammatory cytokines IL-6 and TNF-α in tissues exposed to 5-FU that were treated with increasing temperatures (15–30 °C). Conclusion Bolus i.v. injection with 5-FU in rats can be used to create a functional animal model for chemotherapy-induced OM. Further, moderate temperature reduction is sufficient to reduce the early events which may precede clinically established OM.

Objective Restless legs syndrome (RLS) is known to be associated with multiple sclerosis (MS) and may be caused by MS lesions in specific cerebral brain regions. Applying a voxel-wise lesion analysis, we tried to identify the contribution of cerebral MS lesions to RLS. Methods In this retrospective study, we established a cohort of people with MS with documented RLS and controls of people with MS without RLS matched disease severity. Diagnosis of MS and RLS was based on the current guidelines. The MS lesions were analyzed on T2-weighted magnetic resonance imaging scans (1.5 or 3 T). After manual delineation, lesion maps were converted into stereotaxic space. We generated a lesion overlap and performed a Liebermeister test with 4000 permutations to compare the absence or presence of RLS voxel-wise between patients with and without lesions in a given voxel. Results Forty of the patients with RLS and MS fulfilled the inclusion criteria. The voxel-wise analysis yielded associations between RLS and MS in the subcortex of the left gyrus precentralis. Conclusion Our voxel-wise analysis shows associations in the subcortex of the left gyrus precentralis. Thus, our data suggests that a dysfunction of the efferent motor system due to cerebral lesions may contribute to the pathophysiology of RLS in MS.

Funder: Wellcome Trust, PurposeSurgical workflow analysis seeks to systematically break down operations into hierarchal components. It facilitates education, training, and understanding of surgical variations. There are known educational demands and variations in surgical practice in endoscopic transsphenoidal approaches to pituitary adenomas. Through an iterative consensus process, we generated a surgical workflow reflective of contemporary surgical practice.MethodsA mixed-methods consensus process composed of a literature review and iterative Delphi surveys was carried out within the Pituitary Society. Each round of the survey was repeated until data saturation and > 90% consensus was reached.ResultsThere was a 100% response rate and no attrition across both Delphi rounds. Eighteen international expert panel members participated. An extensive workflow of 4 phases (nasal, sphenoid, sellar and closure) and 40 steps, with associated technical errors and adverse events, were agreed upon by 100% of panel members across rounds. Both core and case-specific or surgeon-specific variations in operative steps were captured.ConclusionsThrough an international expert panel consensus, a workflow for the performance of endoscopic transsphenoidal pituitary adenoma resection has been generated. This workflow captures a wide range of contemporary operative practice. The agreed "core" steps will serve as a foundation for education, training, assessment and technological development (e.g. models and simulators). The "optional" steps highlight areas of heterogeneity of practice that will benefit from further research (e.g. methods of skull base repair). Further adjustments could be made to increase applicability around the world.

Background To assess the effect of sex and laterality on clinical features of primary rhegmatogenous retinal detachment (RRD). Method This study is a retrospective analysis of data prospectively collected. We extracted data from two online datasets over a 7-year period of patients older than 16 years who had undergone surgery for primary RRD. Data on baseline characteristics were analyzed to compare males versus females, and right versus left eyes. Results Of 8133 eyes analyzed, 4342 (53.4%) were right. The overall male predominance (63.7%) was more marked in the age range 50–69 years. Men were more commonly pseudophakic and presented more frequently with baseline posterior vitreous detachment (PVD). Female sex was significantly associated with baseline myopia, retinal holes as causative retinal break, and isolated inferior RD. Men had more frequent foveal involvement, greater RRD extent, greater numbers and larger sized retinal tears including dialysis and giant retinal tears. Regarding laterality, foveal involvement, larger retinal breaks, isolated temporal RD and temporal retinal breaks were more common in right eyes, whereas left eyes were more myopic at baseline and presented more frequently with isolated nasal RD and nasal retinal breaks. Conclusions This study confirmed the predominance of male sex and right laterality in RRD. Sex and laterality were associated with multiple presenting features of RRD including extent, break distribution, number, size and type, as well as RD distribution.

Background Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors with a broad range of local and systemic treatment options. Still a lack of data regarding treatment sequences exists. The aim of this study was to analyse outcomes in GEP-NETs depending on stage and treatment steps and compare our treatment decisions to the latest treatment recommendations of European Society of Medical Oncology (ESMO) 2020 for GEP-NETs. Methods Patients were included in this retrospective single-center analysis from 2012—2016. All patients suffering from a GEP-NET, who were screened, treated or evaluated at ENETS Center in Zurich, Switzerland were included in analysis. Patients with any other diagnosis of NET were not included. We used Kaplan Meier estimator as well as Cox regression to compare survival rates between different sites of localization, grades or stages and treatment sequences. Results Overall, we identified 256 GEP-NETs, most in advanced stage (62%) and located in small intestine tract or pancreatic gland. Survival depended on stage, grade, primary site and duration of response for the early systemic treatment. On average patients underwent 2.6 different treatment modalities, mostly depending on stage and higher tumor grade. Surgery was performed early but also in advanced stages, usually followed by Somatostatine-Agonist modalities. In distant disease (Stage IV), we investigated a positive effect of PFS after treatment with Somatostatine Analogues (SSA) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.21 – 0.97; p = 0.04) and systemic treatment (HR, 0.51; 95% CI, 0.26 – 0.99; p = 0.047) if patients underwent prior surgery or endoscopic resection. Kaplan Meier distributions predict shorter OS in distant disease (Stage IV), (Figure. 1; HR, 2.06; 95% CI, 1.46 – 2.89; log-rank test, p 0.001). Conclusion This retrospective analysis presents a great overview of all patients’, disease and treatment characteristics of GEP-NETs at ENETS Center in Zurich, Switzerland. We illustrated survival (PFS) depending on implemented therapies. According to these findings, we formed a suggested treatment algorithm for advanced GEP-NETs, which does not differ from the latest treatment recommendation by ESMO guidelines for GEP-NETs. The results of this project may define GEP-NET patients’ selection for upcoming clinical prospective studies.

BACKGROUND: Metabolomics is a highly multidisciplinary and non-standardised research field. Metabolomics researchers must possess and apply extensive cross-disciplinary content knowledge, subjective experience-based judgement, and the associated diverse skill sets. Accordingly, appropriate educational and training initiatives are important in developing this knowledge and skills base in the metabolomics community. For these initiatives to be successful, they must consider both pedagogical best practice and metabolomics-specific contextual challenges. AIM OF REVIEW: The aim of this review is to provide consolidated pedagogical guidance for educators and trainers in metabolomics educational and training programmes. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this review, we discuss the principles of pedagogical best practice as they relate to metabolomics. We then discuss the challenges and considerations in developing and delivering education and training in metabolomics. Finally, we present examples from our own teaching practice to illustrate how pedagogical best practice can be integrated into metabolomics education and training programmes.

We use a dense seismic network on the Reykjanes Peninsula, Iceland, to image a group of earthquakes at 10–12 km depth, 2 km north-east of 2021 Fagradalsfjall eruption site. These deep earthquakes have a lower frequency content compared to earthquakes located in the upper, brittle crust and are similar to deep long period (DLP) seismicity observed at other volcanoes in Iceland and around the world. We observed several swarms of DLP earthquakes between the start of the study period (June 2020) and the initiation of the 3-week-long dyke intrusion that preceded the eruption in March 2021. During the eruption, DLP earthquake swarms returned 1 km SW of their original location during periods when the discharge rate or fountaining style of the eruption changed. The DLP seismicity is therefore likely to be linked to the magma plumbing system beneath Fagradalsfjall. However, the DLP seismicity occurred ~ 5 km shallower than where petrological modelling places the near-Moho magma storage region in which the Fagradalsfjall lava was stored. We suggest that the DLP seismicity was triggered by the exsolution of CO2-rich fluids or the movement of magma at a barrier to the transport of melt in the lower crust. Increased flux through the magma plumbing system during the eruption likely adds to the complexity of the melt migration process, thus causing further DLP seismicity, despite a contemporaneous magma channel to the surface.

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by BCR-ABL1-derived permanent proliferation of myeloid progenitor cells. BCR-ABL1 tyrosine kinase inhibitors (TKI) are effective first-line therapeutic options to suppress tumor proliferation. However, TKI therapy is not always curative and drug-related side effects as well as drug resistance may evolve over time, necessitating salvage therapies. In this case report we present a 68-year-old woman who developed second- and third-generation TKI therapy resistance with BCR-ABL1T315I and BCR-ABL1E255V mutation. Considering contraindication for hematopoietic stem cell transplantation, we treated the patient in an individual treatment attempt with a third-generation TKI ponatinib in combination with palbociclib, a CDK4/CDK6 inhibitor, which has been shown to effectively inhibit proliferation of BCR-ABL1T315I-mutated cells in vitro. Our case study shows strong antineoplastic effects using this combination in an advanced CML patient resistant to ponatinib monotherapy as a fourth-line treatment. Combined administration of ponatinib/palbociclib at full dose showed almost a tenfold decrease (42.6 to 4.4 IS%) of BCR-ABL1-positive cells but with simultaneous hematopoietic toxicity, necessitating dose reduction. This combination treatment showed high clinical activity. However, biological activity needs to be further characterized in prospective clinical trials.

Background and purpose Initial cardiovascular fingolimod effects might compromise baroreflex responses to rapid blood pressure (BP) changes during common Valsalva-like maneuvers. This study evaluated cardiovascular responses to Valsalva maneuver (VM)-induced baroreceptor unloading and loading upon fingolimod initiation. Patients and methods Twenty-one patients with relapsing-remitting multiple sclerosis performed VMs before and 0.5, 1, 2, 3, 4, 5, and 6 hours after fingolimod initiation. We recorded heart rate (HR) as RR intervals (RRI), systolic and diastolic BP (BPsys, BPdia) during VM phase 1, VM phase 2 early, VM phase 2 late, and VM phase 4. Using linear regression analysis between decreasing BPsys and RRI values during VM phase 2 early, we determined baroreflex gain (BRG) reflecting vagal withdrawal and sympathetic activation upon baroreceptor unloading. To assess cardiovagal activation upon baroreceptor loading, we calculated Valsalva ratios (VR) between maximal and minimal RRIs after strain release. Analysis of variance or Friedman tests with post hoc analysis compared corresponding parameters at the eight time points (significance: p Results RRIs at VM phase 1, VM phase 2 early, and VM phase 2 late were higher after than before fingolimod initiation, and maximal after 4 hours. Fingolimod did not affect the longest RRIs upon strain release, but after 3, 5, and 6 hours lowered the highest BPsys values during overshoot and all BPdia values, and thus reduced VRs. BRG was slightly higher after 3 and 5 hours, and significantly higher after 4 hours than before fingolimod initiation. Conclusions VR-decreases 3–6 hours after fingolimod initiation are physiologic results of fingolimod-associated attenuations of BP and HR increases at the end of strain and do not suggest impaired cardiovagal activation upon baroreceptor loading. Stable and at the time of HR nadir significantly increased BRGs indicate improved responses to baroreceptor unloading. Thus, cardiovascular fingolimod effects do not impair autonomic responses to sudden baroreceptor loading or unloading but seem to be mitigated by baroreflex resetting.

Although parasitism is one of the most prevalent interactions in nature, studies of aquatic food webs rarely include parasites. Syndiniales (Dinophyceae, Alveolata) is a diverse parasitic group of dinoflagellates, common in all marine environments, and are described as dominant components of pelagic ecosystems. However, their temporal dynamics, prevalence, and host-specificity are poorly known. Using DNA metabarcoding to explore trophic interactions of zooplankton, we found a high proportion of Syndiniales sequence reads associated with the targeted consumers. We observed the occurrence of Syndiniales in copepods, cladocerans, appendicularians, and polychaete larvae, ranging between 11 and 36% relative read abundance, encompassing 11 main putative clades. Zooplankton–Syndiniales interactions showed variability in occurrence across the taxa, but also certain host-specificity. The study suggests that the observed copepod–Syndiniales interactions can be both direct parasitic infections and the result of trophic transmission through potentially infected prey by Syndiniales. Given the quantitative importance of Syndiniales and zooplankton in marine environments, our findings emphasize that their interactions should be recognized as key players in the structure and connectivity of plankton food webs.

Fish larvae supply in nearshore vegetated habitats, such as seagrass meadows and mangroves, contributes significantly to sustainable fish stocks. Yet, little information is available on distribution patterns of fish larvae in mangrove and seagrass habitats of the western Indian Ocean. The present study investigated the abundance, diversity and assemblage composition of fish larvae in mangrove creeks, inshore seagrass meadows (located adjacent to mangroves) and nearshore seagrass meadows (located in-between mangroves and coral reefs) in two coastal seascapes of Zanzibar (Tanzania) across seasons for 1 year. The highest mean abundances of fish larvae were recorded in mangrove creeks, while nearshore- and inshore seagrass meadows showed similar mean abundance levels. Generally, fish larvae representing 42 families were identified, with the fourteen most abundant families comprising 83% of all specimens. Fish larvae communities were dominated by specimens of the postflexion growth stage in all habitats, except in mangrove creeks in one of the two seascapes (i.e. Chwaka Bay) from April through June when abundances of the preflexion and very small-sized individuals were exceptionally high. Slightly higher fish larvae abundances were observed in mangroves during the southeast monsoon compared to the northeast monsoon, and there were also differences across months within monsoon periods for all three habitats studied. Assemblage composition of larvae did, however, not vary significantly in time or space. Our findings suggest that mangroves and seagrass meadows are highly linked shallow-water habitats with high retention of fish larvae contributing to similarity in assemblage compositions across shallow coastal seascapes. Conservation and management efforts should prioritize connected shallow-water seascapes for protection of fish larvae and to uphold sustainable coastal fisheries.