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Drug Discovery Summit: 14 th Swiss Course on Medicinal Chemistry.
No full textThe 14th Swiss Course on Medicinal Chemistry took place again in October 2022 in Leysin and provided a great opportunity for young medicinal chemists from diverse backgrounds for an intense and interactive week dedicated to the latest developments in drug design
Populist radical-right attitudes, political involvement and selective information consumption: who tunes out and who prefers attitude-consonant information.
Get PDFFeasibility of the J-PET to monitor the range of therapeutic proton beams.
No full textPURPOSE
The aim of this work is to investigate the feasibility of the Jagiellonian Positron Emission Tomography (J-PET) scanner for intra-treatment proton beam range monitoring.
METHODS
The Monte Carlo simulation studies with GATE and PET image reconstruction with CASToR were performed in order to compare six J-PET scanner geometries. We simulated proton irradiation of a PMMA phantom with a Single Pencil Beam (SPB) and Spread-Out Bragg Peak (SOBP) of various ranges. The sensitivity and precision of each scanner were calculated, and considering the setup's cost-effectiveness, we indicated potentially optimal geometries for the J-PET scanner prototype dedicated to the proton beam range assessment.
RESULTS
The investigations indicate that the double-layer cylindrical and triple-layer double-head configurations are the most promising for clinical application. We found that the scanner sensitivity is of the order of 10-5 coincidences per primary proton, while the precision of the range assessment for both SPB and SOBP irradiation plans was found below 1 mm. Among the scanners with the same number of detector modules, the best results are found for the triple-layer dual-head geometry. The results indicate that the double-layer cylindrical and triple-layer double-head configurations are the most promising for the clinical application, CONCLUSIONS:: We performed simulation studies demonstrating that the feasibility of the J-PET detector for PET-based proton beam therapy range monitoring is possible with reasonable sensitivity and precision enabling its pre-clinical tests in the clinical proton therapy environment. Considering the sensitivity, precision and cost-effectiveness, the double-layer cylindrical and triple-layer dual-head J-PET geometry configurations seem promising for future clinical application
Patients on vitamin K treatment: is switching to direct-acting oral anticoagulation cost-effective? A target trial on a prospective cohort.
Get PDFAIMS
Direct-acting oral anticoagulants (DOACs) have, to a substantial degree, replaced vitamin K antagonists (VKA) as treatments for stroke prevention in atrial fibrillation (AF) patients. However, evidence on the real-world causal effects of switching patients from VKA to DOAC is lacking. We aimed to assess the empirical incremental cost-effectiveness of switching patients to DOAC compared with maintaining VKA treatment.
METHODS
The target trial approach was applied to the prospective observational Swiss-AF cohort, which enrolled 2415 AF patients from 2014 to 2017. Clinical data, healthcare resource utilisation and EQ-5D-based utilities representing quality of life were collected in yearly follow-ups. Health insurance claims were available for 1024 patients (42.4%). Overall survival, quality-of-life, costs from the Swiss statutory health insurance perspective and cost-effectiveness were estimated by emulating a target trial in which patients were randomly assigned to switch to DOAC or maintain VKA treatment.
RESULTS
228 patients switching from VKA to DOAC compared with 563 patients maintaining VKA treatment had no overall survival advantage over a 5-year observation period (HR 0.99, 95% CI 0.45, 1.55). The estimated gain in quality-adjusted life years (QALYs) was 0.003 over the 5-year period at an incremental costs of CHF 23 033 (€ 20 940). The estimated incremental cost-effectiveness ratio was CHF 425 852 (€ 387 138) per QALY gained.
CONCLUSIONS
Applying a causal inference method to real-world data, we could not demonstrate switching to DOACs to be cost-effective for AF patients with at least 1 year of VKA treatment. Our estimates align with results from a previous randomised trial
Comparison among ultra-thin coronary stents: a network meta-analysis.
No full textBACKGROUND
Ultrathin-strut DES have been related to potential improvement in stent-related outcomes compared to thicker-struts drug-eluting stents (DESs). However, comparisons among different ultrathin devices are lacking.
METHODS
All randomized controlled trials comparing ultrathin (struts thickness < 70 µm) and thicker-struts DESs in an all-comers population were included. Target lesion failure (TLF), as defined by included trials, at 1-year follow-up was the primary endpoint. Overall mortality, myocardial infarction, target lesion revascularization (TLR), and stent thrombosis were the secondary endpoints. Arms of included trials were compared by means of network meta-analysis.
RESULTS
Nine studies encompassing 20081 patients were included, of which 9509 patients had an ultrathin DES: Orsiro (evaluated in 7 arms with 8086 patients), MiStent (one arm with 703 patients), or Supraflex (one arm with 720 patients). At 1-year follow-up, no significant differences were noted for TLF among these ultrathin DES. In particular, Orsiro was associated with a similar risk of TLF compared with Supraflex (RR, 1.07; 95% confidence interval, 0.59-1.78) and showed the highest probability of performing best in terms of TLF, myocardial infarction and TLR.
CONCLUSIONS
Ultrathin DESs are all associated with a comparable risk of TLF as compared with thicker-strut DESs. In terms of TLR and TLF risk, Orsiro was the one with the highest probability of best performances, either compared to other ultrathin DESs or to devices with thicker struts
The serotonin blocker Ketanserin reduces coral reef fish Ctenochaetus striatus aggressive behaviour during between-species social interactions.
No full textA multitude of species engages in social interactions not only with their conspecifics but also with other species. Such interspecific interactions can be either positive, like helping, or negative, like aggressive behaviour. However, the physiological mechanisms of these behaviours remain unclear. Here, we manipulated the serotonin system, a well-known neurohormone for regulating intraspecific aggressive behaviour, to investigate its role in interspecific aggression. We tested whether serotonin blockade affects the aggressive behaviour of a coral reef fish species (Ctenochaetus striatus) that engages in mutualistic interactions with another species, the cleaner fish (Labroides dimidiatus). Although this mutualistic cleaning relationship may appear positive, cleaner fish do not always cooperate and remove ectoparasites from the other coral reef fish ("clients") but tend to cheat and bite the client's protective layer of mucus. Client fish thus often apply control mechanisms, like chasing, to deter their cleaner fish partners from cheating. Our findings show that blocking serotonin receptors 5-HT2A and 5-HT2C with ketanserin reduced the client fish's aggressive behaviour towards cleaner fish, but in the context where the latter did not cheat. These results are evidence of the involvement of serotonin in regulating aggressive behaviour at the between-species social interactions level. Yet, the direction of effect we found here is the opposite of previous findings using a similar experimental set-up and ecological context but with a different client fish species (Scolopsis bilineatus). Together, it suggests that serotonin's role in aggressive behaviour is complex, and at least in this mutualistic ecological context, its function is species-dependent. This warrants, to some extent, careful interpretations from single-species studies looking into the physiological mechanisms of social behaviour
The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming 9th edition of the TNM Classification of Lung Cancer.
No full textINTRODUCTION
This study analyzed all metastatic categories of the current tumor, node, and metastasis (TNM) classification of non-small cell lung cancer to propose modifications of the M component in the next edition (9th) of the classification.
METHODS
A database of 124,581 patients diagnosed between 2011 and 2019 was established; of these, 14,937 with NSCLC in stage IVA-IVB were available for this analysis. Overall survival was calculated using the Kaplan-Meier method, and prognosis assessed using multivariable-adjusted Cox proportional hazards regression.
RESULTS
The 8th edition M categories demonstrated good discrimination in the 9th edition dataset. Assessments demonstrated that an increasing number of metastatic lesions was associated with decreasing prognosis; because this appears to be a continuum and adjustment for confounders was not possible, no specific lesion number was deemed appropriate for stage classification. Among tumors involving multiple metastases, decreasing prognosis was seen with an increasing number of organ systems involved. Multiple assessments, including after adjustment for potential confounders, demonstrated that patients with M1c patients who had metastases to a single extrathoracic organ system were prognostically distinct from M1c patients who had involvement of multiple extrathoracic organ systems.
CONCLUSIONS
These data validate the 8th edition M1a and M1b categories, that are recommended to be maintained. We propose the M1c category be divided into M1c1 (involvement of a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems)
Predictive Algorithm for Surgery Recommendation in Thoracolumbar Burst Fractures Without Neurological Deficits.
Get PDFSTUDY DESIGN
Predictive algorithm via decision tree.
OBJECTIVES
Artificial intelligence (AI) remain an emerging field and have not previously been used to guide therapeutic decision making in thoracolumbar burst fractures. Building such models may reduce the variability in treatment recommendations. The goal of this study was to build a mathematical prediction rule based upon radiographic variables to guide treatment decisions.
METHODS
Twenty-two surgeons from the AO Knowledge Forum Trauma reviewed 183 cases from the Spine TL A3/A4 prospective study (classification, degree of certainty of posterior ligamentous complex (PLC) injury, use of M1 modifier, degree of comminution, treatment recommendation). Reviewers' regions were classified as Europe, North/South America and Asia. Classification and regression trees were used to create models that would predict the treatment recommendation based upon radiographic variables. We applied the decision tree model which accounts for the possibility of non-normal distributions of data. Cross-validation technique as used to validate the multivariable analyses.
RESULTS
The accuracy of the model was excellent at 82.4%. Variables included in the algorithm were certainty of PLC injury (%), degree of comminution (%), the use of M1 modifier and geographical regions. The algorithm showed that if a patient has a certainty of PLC injury over 57.5%, then there is a 97.0% chance of receiving surgery. If certainty of PLC injury was low and comminution was above 37.5%, a patient had 74.2% chance of receiving surgery in Europe and Asia vs 22.7% chance in North/South America. Throughout the algorithm, the use of the M1 modifier increased the probability of receiving surgery by 21.4% on average.
CONCLUSION
This study presents a predictive analytic algorithm to guide decision-making in the treatment of thoracolumbar burst fractures without neurological deficits. PLC injury assessment over 57.5% was highly predictive of receiving surgery (97.0%). A high degree of comminution resulted in a higher chance of receiving surgery in Europe or Asia vs North/South America. Future studies could include clinical and other variables to enhance predictive ability or use machine learning for outcomes prediction in thoracolumbar burst fractures
Drug-Coated Balloons for Treatment of Internal Carotid Artery Restenosis After Stenting: A Single-Center Mid-Term Outcome Study.
Get PDFPURPOSE
Endovascular and surgical treatments of stenosis of the extracranial internal carotid artery (ICA) are common procedures, yet both introduce a risk of restenosis due to endothelial hyperplasia. Drug-coated balloons (DCBs) are designed to decrease neointimal hyperplasia, however rarely used in the neurovascular setting. This study retrospectively analyzes mid-term results of DCB-treated in-stent restenosis (ISR) of the ICA.
MATERIALS AND METHODS
The medical history, comorbidities, and periprocedural data of patients receiving DCB treatment for > 50% ISR of the ICA after carotid artery stenting were analyzed. Follow-up after DCB treatment was performed with Doppler ultrasound. Suspicious cases were checked with CT- or MR-angiography and-if there was agreement between the modalities-validated with digital subtraction angiography. Potential risk factors for restenosis and differences in outcomes after PTA with three types of DCB balloons were evaluated.
RESULTS
DCB treatment was performed in 109 cases, 0.9% of which involved in-hospital major stroke; no minor strokes occurred. A total of 17 patients (15.6%) had recurrent ISR after DCB treatment, after a mean time of 30.2 months (7-85 months). Tobacco use was significantly associated with a higher incidence of recurrent ISR.
CONCLUSION
DCB angioplasty for ISR is an effective treatment that may delay and decrease restenosis. Treating comorbidities and adopting lifestyle changes may additionally help prevent ISR
Is there a shift from cardiovascular to cancer death in lipid-lowering trials? A systematic review and meta-analysis.
Get PDFBACKGROUND
Lipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk.
METHODS
We performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs.
RESULTS
We included 27 trials with 188'259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97-1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00-1.23), while the RR for CV death was 0.96 (0.91-1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99-1.47).
CONCLUSION
LLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations.
PROSPERO REGISTRATION
CRD42021271658
Data sources:
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