Updating and profiling the natural product-likeness of Latin American compound libraries.

Compound databases of natural products play a crucial role in drug discovery and development projects and have implications in other areas, such as food chemical research, ecology and metabolomics. Recently, we put together the first version of the Latin American Natural Product database (LANaPDB) as a collective effort of researchers from six countries to ensemble a public and representative library of natural products in a geographical region with a large biodiversity. The present work aims to conduct a comparative and extensive profiling of the natural product-likeness of an updated version of LANaPDB and the individual ten compound databases that form part of LANaPDB. The natural product-likeness profile of the Latin American compound databases is contrasted with the profile of other major natural product databases in the public domain and a set of small-molecule drugs approved for clinical use. As part of the extensive characterization, we employed several chemoinformatics metrics of natural product likeness. The results of this study will capture the attention of the global community engaged in natural product databases, not only in Latin America but across the world.

HtrA-Dependent E-Cadherin Shedding Impairs the Epithelial Barrier Function in Primary Gastric Epithelial Cells and Gastric Organoids.

Impaired E-cadherin (Cdh1) functions are closely associated with cellular dedifferentiation, infiltrative tumor growth and metastasis, particularly in gastric cancer. The class-I carcinogen Helicobacter pylori (H. pylori) colonizes gastric epithelial cells and induces Cdh1 shedding, which is primarily mediated by the secreted bacterial protease high temperature requirement A (HtrA). In this study, we used human primary epithelial cell lines derived from gastroids and mucosoids from different healthy donors to investigate HtrA-mediated Cdh1 cleavage and the subsequent impact on bacterial pathogenesis in a non-neoplastic context. We found a severe impairment of Cdh1 functions by HtrA-induced ectodomain cleavage in 2D primary cells and mucosoids. Since mucosoids exhibit an intact apico-basal polarity, we investigated bacterial transmigration across the monolayer, which was partially depolarized by HtrA, as indicated by microscopy, the analyses of the transepithelial electrical resistance (TEER) and colony forming unit (cfu) assays. Finally, we investigated CagA injection and observed efficient CagA translocation and tyrosine phosphorylation in 2D primary cells and, to a lesser extent, similar effects in mucosoids. In summary, HtrA is a crucially important factor promoting the multistep pathogenesis of H. pylori in non-transformed primary gastric epithelial cells and organoid-based epithelial models.

Expanding the Chemical Space of Transforming Growth Factor-ß (TGFß) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives.

The TGFß type II receptor (TßRII) is a central player in all TGFß signaling downstream events, has been linked to cancer progression, and thus, has emerged as an auspicious anti-TGFß strategy. Especially its targeted degradation presents an excellent goal for effective TGFß pathway inhibition. Here, cellular structure-activity relationship (SAR) data from the TßRII degrader chemotype 1 was successfully transformed into predictive ligand-based pharmacophore models that allowed scaffold hopping. Two distinct 3,4-disubstituted indoles were identified from virtual screening: tetrahydro-4-oxo-indole 2 and indole-3-acetate 3. Design, synthesis, and screening of focused amide libraries confirmed 2r and 3n as potent TGFß inhibitors. They were validated to fully recapitulate the ability of 1 to selectively degrade TßRII, without affecting TßRI. Consequently, 2r and 3n efficiently blocked endothelial-to-mesenchymal transition and cell migration in different cancer cell lines while not perturbing the microtubule network. Hence, 2 and 3 present novel TßRII degrader chemotypes that will (1) aid target deconvolution efforts and (2) accelerate proof-of-concept studies for small-molecule-driven TßRII degradation in vivo.

The PATH to PPE Mastery - Programme for Assessment and Training in HCID (High Consequence Infectious Diseases) PPE (Personal Protective Equipment), Mastery.

Background: High Consequence Infectious Diseases (HCIDs), have the potential to cause pandemics and require particular focus for preparedness due to their high mortality rates. The application of Personal Protective Equipment (PPE) for HCIDs is complex and carries significant risk of Health Care Worker (HCW) contamination if done incorrectly. Previous reviews have reported a lack of information on the nature of training provided and the ideal timing of repeat training to best retain skills. Simulation Based Mastery Learning (SBML) is a methodology for skill acquisition which encompasses deliberate practice and repeated assessment until the learner achieves a pre-set Mastery standard. SBML has been demonstrated to improve competence, skill retention and patient outcomes in other clinical procedures. SBML has not been previously studied or utilised in HCID PPE training. Aim: We aimed to increase the likelihood of safe clinical practice by evidencing that Lothian modified SBML for PPE effectively prepares our priority learners. Methods: A quasi-experimental within group post-test design was used. Learners undertook a modified SBML programme which included two-hour asynchronous and two-hour synchronous components. Findings: 11 learners (10 infectious diseases registrars and 1 infectious diseases consultant) were enrolled in the programme with 8 completing all stages, all of whom achieved the Mastery passing standard. The resources were highly rated by learners with the exemplar videos of skills highlighted as particularly useful. Self-assessed preparedness for each skill increased following pre-learning and synchronous sessions. Conclusion: Modified SBML can be used as an effective methodology for the training and assessment of HCWs in the donning and doffing of HCID PPE.

Scottish Index of Multiple Deprivation (SIMD) indicators as predictors of mortality among patients hospitalised with COVID-19 disease in the Lothian Region, Scotland during the first wave: a cohort study.

BACKGROUND: Sars-CoV-2, the causative agent of COVID-19, has led to more than 226,000 deaths in the UK and multiple risk factors for mortality including age, sex and deprivation have been identified. This study aimed to identify which individual indicators of the Scottish Index of Multiple Deprivation (SIMD), an area-based deprivation index, were predictive of mortality. METHODS: This was a prospective cohort study of anonymised electronic health records of 710 consecutive patients hospitalised with Covid-19 disease between March and June 2020 in the Lothian Region of Southeast Scotland. Data sources included automatically extracted data from national electronic platforms and manually extracted data from individual admission records. Exposure variables of interest were SIMD quintiles and 12 indicators of deprivation deemed clinically relevant selected from the SIMD. Our primary outcome was mortality. Age and sex adjusted univariable and multivariable analyses were used to determine measures of association between exposures of interest and the primary outcome. RESULTS: After adjusting for age and sex, we found an increased risk of mortality in the more deprived SIMD quintiles 1 and 3 (OR 1.75, CI 0.99-3.08, p = 0.053 and OR 2.17, CI 1.22-3.86, p = 0.009, respectively), but this association was not upheld in our multivariable model containing age, sex, Performance Status and clinical parameters of severity at admission. Of the 12 pre-selected indicators of deprivation, two were associated with greater mortality in our multivariable analysis: income deprivation rate categorised by quartile (Q4 (most deprived): 2.11 (1.20-3.77) p = 0.011)) and greater than expected hospitalisations due to alcohol per SIMD data zone (1.96 (1.28-3.00) p = 0.002)). CONCLUSIONS: SIMD as an aggregate measure of deprivation was not predictive of mortality in our cohort when other exposure measures were accounted for. However, we identified a two-fold increased risk of mortality in patients residing in areas with greater income-deprivation and/or number of hospitalisations due to alcohol. In areas where aggregate measures fail to capture pockets of deprivation, exploring the impact of specific SIMD indicators may be helpful in targeting resources to residents at risk of poorer outcomes from Covid-19.

Short-term outcomes and costs analysis of robotic-assisted versus laparoscopic cholecystectomy-a retrospective single-center analysis.

PURPOSE: Robotic-assisted surgery is an alternative technique for patients undergoing minimal invasive cholecystectomy (CHE). The aim of this study is to compare the outcomes and costs of laparoscopic versus robotic CHE, previously described as the major disadvantage of the robotic system, in a single Austrian tertiary center. METHODS: A retrospective single-center analysis was carried out of all patients who underwent an elective minimally invasive cholecystectomy between January 2010 and August 2020 at our tertiary referral institution. Patients were divided into two groups: robotic-assisted CHE (RC) and laparoscopic CHE (LC) and compared according to demographic data, short-term postoperative outcomes and costs. RESULTS: In the study period, 2088 elective minimal invasive cholecystectomies were performed. Of these, 220 patients met the inclusion criteria and were analyzed. One hundred ten (50%) patients underwent LC, and 110 patients RC. There was no significant difference in the mean operation time between both groups (RC: 60.2 min vs LC: 62.0 min; p = 0.58). Postoperative length of stay was the same in both groups (RC: 2.65 days vs LC: 2.65 days, p = 1). Overall hospital costs were slightly higher in the robotic group with a total of €2088 for RC versus €1726 for LC. CONCLUSIONS: Robotic-assisted cholecystectomy is a safe and feasible alternative to laparoscopic cholecystectomy. Since there are no significant clinical and cost differences between the two procedures, RC is a justified operation for training the whole operation team in handling the system as a first step procedure. Prospective randomized trials are necessary to confirm these conclusions.

Novel starting points for fragment-based drug design against mycobacterial thioredoxin reductase identified using crystallographic fragment screening.

The increasing number of people dying from tuberculosis and the existence of extensively drug-resistant strains has led to an urgent need for new antituberculotic drugs with alternative modes of action. As part of the thioredoxin system, thioredoxin reductase (TrxR) is essential for the survival of Mycobacterium tuberculosis (Mtb) and shows substantial differences from human TrxR, making it a promising and most likely selective target. As a model organism for Mtb, crystals of Mycobacterium smegmatis TrxR that diffracted to high resolution were used in crystallographic fragment screening to discover binding fragments and new binding sites. The application of the 96 structurally diverse fragments from the F2X-Entry Screen revealed 56 new starting points for fragment-based drug design of new TrxR inhibitors. Over 200 crystal structures were analyzed using FragMAXapp, which includes processing and refinement by largely automated software pipelines and hit identification via the multi-data-set analysis approach PanDDA. The fragments are bound to 11 binding sites, of which four are positioned at binding pockets or important interaction sites and therefore show high potential for possible inhibition of TrxR.

Similarity-based pairing improves efficiency of siamese neural networks for regression tasks and uncertainty quantification.

Siamese networks, representing a novel class of neural networks, consist of two identical subnetworks sharing weights but receiving different inputs. Here we present a similarity-based pairing method for generating compound pairs to train Siamese neural networks for regression tasks. In comparison with the conventional exhaustive pairing, it reduces the algorithm complexity from O(n2) to O(n). It also results in a better prediction performance consistently on the three physicochemical datasets, using a multilayer perceptron with the circular fingerprint as a proof of concept. We further include into a Siamese neural network the transformer-based Chemformer, which extracts task-specific features from the simplified molecular-input line-entry system representation of compounds. Additionally, we propose a means to measure the prediction uncertainty by utilizing the variance in predictions from a set of reference compounds. Our results demonstrate that the high prediction accuracy correlates with the high confidence. Finally, we investigate implications of the similarity property principle in machine learning.

Real-life Indications and Outcome of Electrocautery-enhanced Lumen-apposing Metal Stents in a Tertiary Center.

PURPOSE: Electrocautery-enhanced lumen-apposing stents (EC-LAMS) were originally designed for the drainage of the gallbladder, bile duct, and pancreas pseudocysts. Throughout the years, several off-label indications were established. This study aims to evaluate the indication, safety, efficacy, and outcome of all LAMS implanted in a single tertiary referral center. METHODS: From April 2016 to April 2022, all patients undergoing LAMS placement in a single tertiary center were included. We present a detailed analysis of indications, success rates, and complications based on a retrospective analysis of our prospectively maintained database. RESULTS: A total of 86 stents were placed in 77 patients between April 2016 and April 2022. Indications were walled-off pancreatic necrosis (25.6%), bile duct obstructions (16.3%), acute cholecystitis (15.1%), pancreas pseudocysts (15.1%), postoperative collections (10.5%), postoperative pancreatic fistulas (9.3%), and gastro-gastrostomy/jejunostomy (8.1%) to enable to perform an endoscopic retrograde cholangiopancreatography in patients with gastric bypass. Technical success was 97.7% (84 out of 86). A total of 10 (11.7%) adverse events were observed. In 3 patients (3.5%), severe complications occurred, which required acute surgery; one displacement was closed through clips. In 7 patients (8.2%), bleedings occurred during necrosectomy or from mucosal erosions at the stent side, respectively, that were treated with endoclips. CONCLUSIONS: EC-LAMS are safe and show a high technical success rate in all indications. In everyday clinical practice, the main indications are hepato-pancreato-biliary, and therefore an hepato-pancreato-biliary-surgical department should have EC-LAMS in their armamentarium.

Introduction to artificial intelligence and deep learning using interactive electronic programming notebooks.

Artificial intelligence (AI), or deep learning (DL), approaches have already found their way into our everyday lives. Furthermore, these methods are a central part of research in the life and natural sciences and have been applied in the form of machine learning for decades. In pharmaceutical and medicinal chemistry, and in computer-aided drug discovery, current developments are also changing the way drugs are developed. It is essential to familiarize students with AI methods already during their studies and prepare them for future tasks and challenges. We developed a set of interactive learning materials based on cheminformatics examples that can be used to establish such introductory AI courses in the life and natural sciences. These interactive notebooks are easily accessible without the need for installation, and no prior programming knowledge is required. Through these notebooks, students can easily study how AI/DL works and how these methods can be applied. This knowledge will foster a general competence when interacting with and evaluating future DL applications later in their career. The materials are freely available and publicly accessible through a GitHub repository in German and English.

Prognostic value of [18F]FDG PET/CT on treatment response and progression-free survival of gastroesophageal cancer patients undergoing perioperative FLOT chemotherapy.

PURPOSE: To evaluate the prognostic role of [18F]FDG PET/CT metabolic parameters in gastric cancer (GC) and gastroesophageal adenocarcinoma (GEJAC) patients receiving neoadjuvant chemotherapy. METHOD: In this retrospective study, 31 patients with biopsy-proven GC or GEJAC were included between August 2016 and March 2020. [18F]FDG PET/CT was performed before the neoadjuvant chemotherapy. Primary tumours' semi-quantitative metabolic parameters were extracted. All patients received a perioperative FLOT regimen thereafter. Post-chemotherapy [18F]FDG PET/CT was performed in most patients (17/31). All patients underwent surgical resection. Histopathology response to treatment and progression-free survival (PFS) were evaluated. Two-sided p-values < 0.05 were considered statistically significant. RESULTS: Thirty-one patients (mean age = 62 ± 8), including 21 GC and 10 GEJAC patients, were evaluated. 20/31(65%) patients were histopathology responders to neoadjuvant chemotherapy, including twelve complete and eight partial responders. During the median follow-up of 42.0 months, nine patients experienced recurrence. The median PFS was 60(95% CI:32.9-87.1) months. Pre-neoadjuvant chemotherapy SULpeak was significantly correlated with pathological response to treatment (p-value = 0.03;odds ratio = 16.75). In survival analysis, SUVmax (p-value = 0.01;hazard ratio[HR] = 1.55), SUVmean (p-value = 0.04;HR = 2.73), SULpeak (p-value < 0.001;HR = 1.91) and SULmean (p-value = 0.04;HR = 4.22) in the post-neoadjuvant chemotherapy pre-operative [18F]FDG PET/CT showed significant correlation with PFS. Additionally, aspects of staging were significantly correlated with PFS (p-value = 0.01;HR = 2.21). CONCLUSIONS: Pre-neoadjuvant chemotherapy [18F]FDG PET/CT parameters, especially SULpeak, could predict the pathological response to treatment in GC and GEJAC patients. Additionally, in survival analysis, post-chemotherapy metabolic parameters significantly correlated with PFS. Thus, performing [18F]FDG PET/CT before chemotherapy may help to identify patients at risk for inadequate response to perioperative FLOT and, after chemotherapy, may predict clinical outcomes.

Body composition dynamics and impact on clinical outcome in gastric and gastro-esophageal junction cancer patients undergoing perioperative chemotherapy with the FLOT protocol.

PURPOSE: Perioperative chemotherapy with FLOT constitutes a standard of care approach for locally advanced, resectable gastric or gastro-esophageal junction (GEJ) cancer. We aimed at investigating anthropometric, CT-based and FDG-PET-based body composition parameters and dynamics during this multidisciplinary approach and the impact on clinical outcomes. METHODS: This retrospective, single-center study was based on medical records and (FDG-PET)-CT images among gastric/GEJ cancer patients undergoing perioperative FLOT chemotherapy. RESULTS: Between 2016 and 2021, 46 gastric/GEJ cancer patients started perioperative FLOT at our tertiary cancer center (Salzburg, Austria). At a median follow-up of 32 months median PFS was 47.4 months and median OS was not reached. The skeletal muscle index (SMI, cm2/m2) turned out to be the only body composition parameter with a statistically significant decrease during pre-operative FLOT (51.3 versus 48.8 cm2/m2, p = 0.02). Neither pre-FLOT body mass index (BMI), nor SMI had an impact on the duration of pre-operative FLOT, the time interval from pre-operative FLOT initiation to surgery, the necessity of pre-operative or post-operative FLOT de-escalation or the likelihood of the start of postoperative chemotherapy. Pre-FLOT BMI (overweight versus normal, HR: 0.11, 95% CI: 0.02-0.65, p = 0.02) and pre-FLOT SMI (sarcopenia versus no sarcopenia, HR: 5.08, 95% CI: 1.27-20.31, p = 0.02) were statistically significantly associated with PFS in the multivariable analysis. CONCLUSION: The statistically significant SMI loss during pre-operative FLOT and the meaningful impact of baseline SMI and BMI on PFS argue for the implementation of a nutritional screening and support program prior to the initiation of pre-operative FLOT in clinical routine.

Novel technique of flexible endoscopic therapy of Zenker's diverticulum using a pulsed Holmium laser-a retrospective single-center analysis.

BACKGROUND: In recent years, flexible endoscopic therapy of Zenker's diverticulum seems to become the standard approach. The aim of this study was to assess the safety, efficacy and short-term outcome of flexible endoscopic diverticulotomy of Zenker's diverticulum with a pulsed Holmium laser (PHL). PATIENTS AND METHODS: All patients treated with endoscopic laser-diverticulotomy using a PHL between February 2013 and November 2021 at the University Hospital Salzburg were extracted from our prospectively maintained endoscopic database. Demographic data, size of Zenker's diverticulum, procedure duration, complications, short-term outcome and rate of recurrence were evaluated. RESULTS: In the study period, 45 procedures in 36 patients were performed. Mean depth of the Zenker diverticulum was 21 mm (10-60 mm), mean procedure time was 31 min (15-60 min), intraprocedural adverse events occurred in 2 out of 45 patients (5%) which were both managed endoscopically, post-procedural stenosis occurred in 1 patient (2%). In the follow-up examinations (mean follow-up after 6.4 months), 27 out of 36 patients (75%) were symptom-free, 6 patients (17%) reported an improvement of dysphagia. 3 patients (9%) suffered from persistent dysphagia. After initial symptom relief, a recurrent diverticulum occurred in 5 patients. Endoscopic re-intervention with PHL was done in these cases. CONCLUSIONS: Flexible endoscopic treatment of primary and recurrent Zenker's diverticulum using a PHL is a promising, safe and effective treatment with, in our opinion, technical advantages in comparison to the CO2 laser. Further controlled prospective trials are needed.

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE).

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).

Imaging of KCa 3.1 Channels in Tumor Cells with PET and Small-Molecule Fluorescent Probes.

The Ca2+ activated K+ channel KCa 3.1 is overexpressed in several human tumor cell lines, e. g. clear cell renal carcinoma, prostate cancer, non-small cell lung cancer. Highly aggressive cancer cells use this ion channel for key processes of the metastatic cascade such as migration, extravasation and invasion. Therefore, small molecules, which are able to image this KCa 3.1 channel in vitro and in vivo represent valuable diagnostic and prognostic tool compounds. The [18 F]fluoroethyltriazolyl substituted senicapoc was used as positron emission tomography (PET) tracer and showed promising properties for imaging of KCa 3.1 channels in lung adenocarcinoma cells in mice. The novel senicapoc BODIPY conjugates with two F-atoms (9 a) and with a F-atom and a methoxy moiety (9 b) at the B-atom led to the characteristic punctate staining pattern resulting from labeling of single KCa 3.1 channels in A549-3R cells. This punctate pattern was completely removed by preincubation with an excess of senicapoc confirming the high specificity of KCa 3.1 labeling. Due to the methoxy moiety at the B-atom and the additional oxyethylene unit in the spacer, 9 b exhibits higher polarity, which improves solubility and handling without reduction of fluorescence quantum yield. Docking studies using a cryo-electron microscopy (EM) structure of the KCa 3.1 channel confirmed the interaction of 9 a and 9 b with a binding pocket in the channel pore.

The role of hormones in symptoms and pathophysiology of reflux and esophageal motility disorders.

PURPOSE: A few studies suggest that hormones play a role in the motility of the lower esophagus, but data is rare. In this prospective study we evaluated the correlation between hormones (TSH, fT3, fT4, calcitonin, gastrin, and VIP) and gastroesophageal reflux disease (GERD), esophageal motility disorders, and gastrointestinal symptoms. METHODS: 100 consecutive patients with reflux symptoms and dysphagia were hospitalized for diagnostic evaluation. Self-reporting questionnaires were handed out and patients routinely underwent serum analysis (TSH, fT3, fT4, calcitonin, gastrin, and VIP), 24-hour-pH-impendance monitoring, and high-resolution manometry. RESULTS: Motility disorders were found in 38 out of 86 patients. There were no correlations between hormones, the DeMeester Score, and the lower esophageal sphincter pressure. A strong inverse relation between calcitonin and the Integrated Relaxation Pressure of the esophagogastric junction was found (r=-0.492; p<0.001). No correlations were found between hormone levels and the responses given in the questionnaires. Positive correlations, however, were found between VIP and gastrointestinal symptoms, as well as correlations between fT3 and dysphagia. Within the group with minor motility disorders, TSH and fT4 correlated with outcomes of the SCL-questionnaire. fT4 correlated with the typical symptoms, as well as the gastrointestinal symptoms (diarrhea, constipation, flatulence). TSH correlated with the typical symptoms. Moreover, a correlation between VIP and gas-bloat-symptoms was found within group II CONCLUSIONS: No correlation between TSH, fT3, fT4, gastrin, VIP, calcitonin, and GERD in the sense of acid reflux was found, although calcitonin seems to have an effect on the lower esophageal sphincter.

How We Treat Localized Rectal Cancer-An Institutional Paradigm for Total Neoadjuvant Therapy.

Total neoadjuvant therapy (TNT)-the neoadjuvant employment of radiotherapy (RT) or chemoradiation (CRT) as well as chemotherapy (CHT) before surgery-may lead to increased pathological complete response (pCR) rates as well as a reduction in the risk of distant metastases in locally advanced rectal cancer. Furthermore, increased response rates may allow organ-sparing strategies in a growing number of patients with low rectal cancer and upfront immunotherapy has shown very promising early results in patients with microsatellite instability (MSI)-high/mismatch-repair-deficient (dMMR) tumors. Despite the lack of a generally accepted treatment standard, we strongly believe that existing data is sufficient to adopt the concept of TNT and immunotherapy in clinical practice. The treatment algorithm presented in the following is based on our interpretation of the current data and should serve as a practical guide for treating physicians-without any claim to general validity.

Performance status: A key factor in predicting mortality in the first wave of COVID-19 in South-East Scotland.

BACKGROUND: COVID-19 mortality risk factors have been established in large cohort studies; long-term mortality outcomes are less documented. METHODS: We performed multivariable logistic regression to identify factors associated with in-patient mortality and intensive care unit (ICU) admission in symptomatic COVID-19 patients admitted to hospitals in South-East Scotland from 1st March to 30th June 2020. One-year mortality was reviewed. RESULTS: Of 726 patients (median age 72; interquartile range: 58-83 years, 55% male), 104 (14%) required ICU admission and 199 (27%) died in hospital. A further 64 died between discharge and 30th June 2021 (36% overall 1-year mortality). Stepwise logistic regression identified age >79 (odds ratio (OR), 4.77 (95% confidence interval (CI), 1.96-12.75)), male sex (OR, 1.83 (95% CI, 1.21-2.80)) and higher European Cooperative Oncology Group/World Health Organization performance status as associated with higher mortality risk. DISCUSSION: Poor functional baseline was the predominant independent risk factor for mortality in COVID-19. More than one-third of individuals had died by 1 year following admission.

Imaging of the calcium activated potassium channel 3.1 (KCa 3.1) in vivo using a senicapoc-derived positron emission tomography tracer.

The calcium-activated potassium channel 3.1 (KCa 3.1) is overexpressed in many tumor entities and has predictive power concerning disease progression and outcome. Imaging of the KCa 3.1 channel in vivo using a radiotracer for positron emission tomography (PET) could therefore establish a potentially powerful diagnostic tool. Senicapoc shows high affinity and excellent selectivity toward the KCa 3.1 channel. We have successfully pursued the synthesis of the 18 F-labeled derivative [18 F]3 of senicapoc using the prosthetic group approach with 1-azido-2-[18 F]fluoroethane ([18 F]6) in a "click" reaction. The biological activity of the new PET tracer was evaluated in vitro and in vivo. Inhibition of the KCa 3.1 channel by 3 was demonstrated by patch clamp experiments and the binding pose was analyzed by docking studies. In mouse and human serum, [18 F]3 was stable for at least one half-life of [18 F]fluorine. Biodistribution experiments in wild-type mice were promising, showing rapid and predominantly renal excretion. An in vivo study using A549-based tumor-bearing mice was performed. The tumor signal could be delineated and image analysis showed a tumor-to-muscle ratio of 1.47 ± 0.24. The approach using 1-azido-2-[18 F]fluoroethane seems to be a good general strategy to achieve triarylacetamide-based fluorinated PET tracers for imaging of the KCa 3.1 channel in vivo.