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The two main phytocannabinoids—delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—have been extensively studied, and it has been shown that THC can induce transient psychosis. At the same time, CBD appears to have no psychotomimetic potential. On the contrary, emerging evidence for CBD's antipsychotic properties suggests that it may attenuate effects induced by THC. Thus, we investigated and compared the effects of THC and CBD administration on emotion, cognition, and attention as well as the impact of CBD pre-treatment on THC effects in healthy volunteers. We performed a placebo-controlled, double-blind, experimental trial (GEI-TCP II; ClinicalTrials.gov identifier: NCT02487381) with 60 healthy volunteers randomly allocated to four parallel intervention groups, receiving either placebo, 800 mg CBD, 20 mg THC, or both cannabinoids. Subjects underwent neuropsychological tests assessing working memory (Letter Number Sequencing test), cognitive processing speed (Digit Symbol Coding task), attention (d2 Test of Attention), and emotional state (adjective mood rating scale [EWL]). Administration of CBD alone did not influence the emotional state, cognitive performance, and attention. At the same time, THC affected two of six emotional categories—more precisely, the performance-related activity and extraversion—, reduced the cognitive processing speed and impaired the performance on the d2 Test of Attention. Interestingly, pre-treatment with CBD did not attenuate the effects induced by THC. These findings show that the acute intake of CBD itself has no effect per se in healthy volunteers and that a single dose of CBD prior to THC administration was insufficient to mitigate the detrimental impact of THC in the given setting. This is in support of a complex interaction between CBD and THC whose effects are not counterbalanced by CBD under all circumstances.
In this report, we present the contributions, outcomes, ideas, discussions and conclusions obtained at the PaleoMaps Workshop 2019, that took place at the Institute of Geography of the University of Cologne on 23 and 24 September 2019. The twofold aim of the workshop was: (1) to provide an overview of approaches and methods that are presently used to incorporate paleoenvironmental information in human–environment interaction modeling applications, and building thereon; (2) to devise new approaches and solutions that might be used to enhance the reconstruction of past human–environmental interconnections. This report first outlines the presented papers, and then provides a joint protocol of the often extensive discussions that came up following the presentations or else during the refreshment intervals. It concludes by adressing the open points to be resolved in future research avenues, e.g., implementation of open science practices, new procedures for reviewing of publications, and future concepts for quality assurance of the often complex paleoenvironmental data. This report may serve as an overview of the state of the art in paleoenvironment mapping and modeling. It includes an extensive compilation of the basic literature, as provided by the workshop attendants, which will itself facilitate the necessary future research.
Since 2010, an intensified ambulatory cardiology care programme has been implemented in southern Germany. To improve patient management, the structure of cardiac disease management was improved, guideline-recommended care was supported, new ambulatory medical services and a morbidity-adapted reimbursement system were set up. Our aim was to determine the effects of this programme on the mortality and hospitalisation of enrolled patients with cardiac disorders. We conducted a comparative observational study in 2015 and 2016, based on insurance claims data. Overall, 13,404 enrolled patients with chronic heart failure (CHF) and 19,537 with coronary artery disease (CAD) were compared, respectively, to 8,776 and 16,696 patients that were receiving usual ambulatory cardiology care. Compared to the control group, patients enrolled in the programme had lower mortality (Hazard Ratio: 0.84; 95% CI: 0.77–0.91) and fewer all-cause hospitalisations (Rate Ratio: 0.94; 95% CI: 0.90–0.97). CHF-related hospitalisations in patients with CHF were also reduced (Rate Ratio: 0.76; 95% CI: 0.69–0.84). CAD patients showed a similar reduction in mortality rates (Hazard Ratio: 0.81; 95% CI: 0.76–0.88) and all-cause hospitalisation (Rate Ratio: 0.94; 95% CI: 0.91–0.97), but there was no effect on CAD-related hospitalisation. We conclude that intensified ambulatory care reduced mortality and hospitalisation in cardiology patients.
Genetic code expansion facilitates position-selective modification of nucleic acids and proteins
(2020)
Transcription and translation obey to the genetic code of four nucleobases and 21 amino acids evolved over billions of years. Both these processes have been engineered to facilitate the use of non-natural building blocks in both nucleic acids and proteins, enabling researchers with a decent toolbox for structural and functional analyses. Here, we review the most common approaches for how labeling of both nucleic acids as well as proteins in a site-selective fashion with either modifiable building blocks or spectroscopic probes can be facilitated by genetic code expansion. We emphasize methodological approaches and how these can be adapted for specific modifications, both during as well as after biomolecule synthesis. These modifications can facilitate, for example, a number of different spectroscopic analysis techniques and can under specific circumstances even be used in combination.
Background Polypharmacy interventions are resource-intensive and should be targeted to those at risk of negative health outcomes. Our aim was to develop and internally validate prognostic models to predict health-related quality of life (HRQoL) and the combined outcome of falls, hospitalisation, institutionalisation and nursing care needs, in older patients with multimorbidity and polypharmacy in general practices.
Methods Design: two independent data sets, one comprising health insurance claims data (n=592 456), the other data from the PRIoritising MUltimedication in Multimorbidity (PRIMUM) cluster randomised controlled trial (n=502). Population: ≥60 years, ≥5 drugs, ≥3 chronic diseases, excluding dementia. Outcomes: combined outcome of falls, hospitalisation, institutionalisation and nursing care needs (after 6, 9 and 24 months) (claims data); and HRQoL (after 6 and 9 months) (trial data). Predictor variables in both data sets: age, sex, morbidity-related variables (disease count), medication-related variables (European Union-Potentially Inappropriate Medication list (EU-PIM list)) and health service utilisation. Predictor variables exclusively in trial data: additional socio-demographics, morbidity-related variables (Cumulative Illness Rating Scale, depression), Medication Appropriateness Index (MAI), lifestyle, functional status and HRQoL (EuroQol EQ-5D-3L). Analysis: mixed regression models, combined with stepwise variable selection, 10-fold cross validation and sensitivity analyses.
Results Most important predictors of EQ-5D-3L at 6 months in best model (Nagelkerke’s R² 0.507) were depressive symptoms (−2.73 (95% CI: −3.56 to −1.91)), MAI (−0.39 (95% CI: −0.7 to −0.08)), baseline EQ-5D-3L (0.55 (95% CI: 0.47 to 0.64)). Models based on claims data and those predicting long-term outcomes based on both data sets produced low R² values. In claims data-based model with highest explanatory power (R²=0.16), previous falls/fall-related injuries, previous hospitalisations, age, number of involved physicians and disease count were most important predictor variables.
Conclusions Best trial data-based model predicted HRQoL after 6 months well and included parameters of well-being not found in claims. Performance of claims data-based models and models predicting long-term outcomes was relatively weak. For generalisability, future studies should refit models by considering parameters representing well-being and functional status.
Background: Experienced and anticipated regret influence physicians’ decision-making. In medicine, diagnostic decisions and diagnostic errors can have a severe impact on both patients and physicians. Little empirical research exists on regret experienced by physicians when they make diagnostic decisions in primary care that later prove inappropriate or incorrect. The aim of this study was to explore the experience of regret following diagnostic decisions in primary care.
Methods: In this qualitative study, we used an online questionnaire on a sample of German primary care physicians. We asked participants to report on cases in which the final diagnosis differed from their original opinion, and in which treatment was at the very least delayed, possibly resulting in harm to the patient. We asked about original and final diagnoses, illness trajectories, and the reactions of other physicians, patients and relatives. We used thematic analysis to assess the data, supported by MAXQDA 11 and Microsoft Excel 2016.
Results: 29 GPs described one case each (14 female/15 male patients, aged 1.5–80 years, response rate < 1%). In 26 of 29 cases, the final diagnosis was more serious than the original diagnosis. In two cases, the diagnoses were equally serious, and in one case less serious. Clinical trajectories and the reactions of patients and relatives differed widely. Although only one third of cases involved preventable harm to patients, the vast majority (27 of 29) of physicians expressed deep feelings of regret.
Conclusion: Even if harm to patients is unavoidable, regret following diagnostic decisions can be devastating for clinicians, making them ‘second victims’. Procedures and tools are needed to analyse cases involving undesirable diagnostic events, so that ‘true’ diagnostic errors, in which harm could have been prevented, can be distinguished from others. Further studies should also explore how physicians can be supported in dealing with such events in order to prevent them from practicing defensive medicine.
Purpose: Sarcopenia, defined as a loss of muscle mass and quality, has been associated with impaired oncological outcome and treatment toxicities in several malignancies. However, its role in anal squamous cell carcinoma (ASCC) remains less well explored.
Methods/Materials: Planning CT scans were used to measure cross-sectional skeletal muscle area (SMA) to calculate the skeletal muscle index (SMI). The association of sarcopenia with clinical and treatment-related parameters, and toxicity was assessed in 114 patients with ASCC that underwent standard 5-Fluorouracil/Mitomycin C chemoradiotherapy (CRT). The prognostic impact of sarcopenia on local relapse-free survival (LRFS), disease-free survival (DFS), and overall survival was examined using a Cox regression analysis.
Results: 29 (25.4%) patients had sarcopenia. Patients with sarcopenia had lower baseline hemoglobin levels (p = 0.002), worse Karnofsky Performance Status (p = 0.001) lower BMI (p < 0.001), and a significantly lower body surface area (p = 0.03), and lower incidence of involved lymph nodes (p = 0.03). Regarding acute toxicity, sarcopenia was associated with a significantly higher incidence of ≥grade 3leukopenia (OR: 3.5; 95% CI: 1.6–7.5, p = 0.007) and ≥grade 3 thrombopenia (OR: 5.1; 95% CI: 1.3–21, p = 0.018) after CRT. Despite higher hematologic toxicity in sarcopenic patients, total treatment time was similar between patients with and without sarcopenia (median 44 vs 45 days, p = 0.95). There was no significant prognostic impact of sarcopenia on either LRFS, DFS, or OS.
Conclusion: This is the largest study to assess the impact of sarcopenia on toxicity and oncological outcome in patients with ASCC. Increased clinician awareness of higher hematological toxicity risk is needed for sarcopenic patients with ASCC undergoing CRT to facilitate closer monitoring of side effects and earlier introduction of supportive measures. Further prospective studies are needed to elucidate the prognostic role and impact of sarcopenia on CRT-related toxicity in ASCC.
Background: Radiotherapy dose and target volume prescriptions for anal squamous cell carcinoma (ASCC) vary considerably in daily practice and guidelines, including those from NCCN, UK, Australasian, and ESMO. We conducted a pattern-of-care survey to assess the patient management in German speaking countries.
Methods: We developed an anonymous questionnaire comprising 18 questions on diagnosis and treatment of ASCC. The survey was sent to 361 DEGRO-associated institutions, including 41 university hospitals, 118 non-university institutions, and 202 private practices.
Results: We received a total of 101 (28%) surveys, including 20 (19.8%) from university, 36 (35.6%) from non-university clinics, and 45 (44.6%) from private practices. A total of 28 (27.8%) institutions reported to treat more than 5 patients with early-stage ASCC and 42 (41.6%) institutions treat more than 5 patients with locoregionally-advanced ASCC per year. Biopsy of suspicious inguinal nodes was advocated in only 12 (11.8%) centers. Screening for human immunodeficiency virus (HIV) is done in 28 (27.7%). Intensity modulated radiotherapy or similar techniques are used in 97%. The elective lymph node dose ranged from 30.6 Gy to 52.8 Gy, whereas 87% prescribed 50.4–55. 8 Gy (range: 30.6 to 59.4 Gy) to the involved lymph nodes. The dose to gross disease of cT1 or cT2 ASCC ranged from 50 to ≥60 Gy. For cT3 or cT4 tumors the target dose ranged from 54 Gy to more than 60 Gy, with 76 (75.2%) institutions prescribing 59.4 Gy. The preferred concurrent chemotherapy regimen was 5-FU/Mitomycin C, whereas 6 (6%) prescribed Capecitabine/Mitomycin C. HIV-positive patients are treated with full-dose CRT in 87 (86.1%) institutions. First assessment for clinical response is reported to be performed at 4–6 weeks after completion of CRT in 2 (2%) institutions, at 6–8 weeks in 20 (19.8%), and 79 (78%) institutions wait up to 5 months.
Conclusions: We observed marked differences in radiotherapy doses and treatment technique in patients with ASCC, and also variable approaches for patients with HIV. These data underline the need for an consensus treatment guideline for ASCC.
The Rnf complex is a Na+ coupled respiratory enzyme in a fermenting bacterium, Thermotoga maritima
(2020)
rnf genes are widespread in bacteria and biochemical and genetic data are in line with the hypothesis that they encode a membrane-bound enzyme that oxidizes reduced ferredoxin and reduces NAD and vice versa, coupled to ion transport across the cytoplasmic membrane. The Rnf complex is of critical importance in many bacteria for energy conservation but also for reverse electron transport to drive ferredoxin reduction. However, the enzyme has never been purified and thus, ion transport could not be demonstrated yet. Here, we have purified the Rnf complex from the anaerobic, fermenting thermophilic bacterium Thermotoga maritima and show that is a primary Na+ pump. These studies provide the proof that the Rnf complex is indeed an ion (Na+) translocating, respiratory enzyme. Together with a Na+-F1FO ATP synthase it builds a simple, two-limb respiratory chain in T. maritima. The physiological role of electron transport phosphorylation in a fermenting bacterium is discussed.
Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.