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).

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.

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.

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.

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.

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.

Structural analysis revealed a novel conformation of the NTRC reductase domain from Chlamydomonas reinhardtii.

In plant chloroplasts, thiol regulation is driven by two systems. One relies on the activity of thioredoxins through their light dependent reduction by ferredoxin via a ferredoxin-thioredoxin reductase (FTR). In the other system, a NADPH-dependent redox regulation is driven by a NADPH-thioredoxin reductase C (NTRC). While the thioredoxin system has been deeply studied, a more thorough understanding of the function of this plant specific NTRC is desirable. NTRC is a single polypeptide harbouring a thioredoxin domain (Trx) at the C-terminus of a NADPH-dependent Thioredoxin reductase (TrxR). To provide functional and structural insights, we studied the crystal structure of the TrxR domain of the NTRC from Chlamydomonas reinhardtii (CrNTRC, Cre01.g054150.t1.2) and its Cys136Ser (C136S) mutant, which is characterized by the mutation of the resolving cysteine in the active site of the TrxR domain. Furthermore, we confirmed the role of NTRC as electron donor for 2-Cys peroxiredoxin (PRX) also in C. reinhardtii. The structural data of TrxR were employed to develop a scheme of action which addresses electron transfer between TrxR and Trx of NTRC and between NTRC and its substrates.

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.

Computational Ion Channel Research: from the Application of Artificial Intelligence to Molecular Dynamics Simulations.

Although ion channels are crucial in many physiological processes and constitute an important class of drug targets, much is still unclear about their function and possible malfunctions that lead to diseases. In recent years, computational methods have evolved into important and invaluable approaches for studying ion channels and their functions. This is mainly due to their demanding mechanism of action where a static picture of an ion channel structure is often insufficient to fully understand the underlying mechanism. Therefore, the use of computational methods is as important as chemical-biological based experimental methods for a better understanding of ion channels. This review provides an overview on a variety of computational methods and software specific to the field of ion-channels. Artificial intelligence (or more precisely machine learning) approaches are applied for the sequence-based prediction of ion channel family, or topology of the transmembrane region. In case sufficient data on ion channel modulators is available, these methods can also be applied for quantitative structureactivity relationship (QSAR) analysis. Molecular dynamics (MD) simulations combined with computational molecular design methods such as docking can be used for analysing the function of ion channels including ion conductance, different conformational states, binding sites and ligand interactions, and the influence of mutations on their function. In the absence of a three-dimensional protein structure, homology modelling can be applied to create a model of your ion channel structure of interest. Besides highlighting a wide range of successful applications, we will also provide a basic introduction to the most important computational methods and discuss best practices to get a rough idea of possible applications and risks.

Targeting Kca3.1 Channels in Cancer.

The Kca3.1 channels, previously designated as IK1 or SK4 channels and encoded by the KCNN4 gene, are activated by a rise of the intracellular Ca2+ concentration. These K+ channels are widely expressed in many organs and involved in many pathologies. In particular, Kca3.1 channels have been studied intensively in the context of cancer. They are not only a marker and a valid prognostic tool for cancer patients, but have an important share in driving cancer progression. Their function is required for many characteristic features of the aggressive cancer cell behavior such as migration, invasion and metastasis as well as proliferation and therapy resistance. In the context of cancer, another property of Kca3.1 is now emerging. These channels can be a target for novel small molecule-based imaging probes, as it has been validated in case of fluorescently labeled senicapoc-derivatives. The aim of this review is (i) to give an overview on the role of Kca3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using Kca3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to Kca3.1 channels in order to provide a deeper understanding of Kca3.1 channel pharmacology. Alltogether, Kca3.1 is an attractive therapeutic target so that senicapoc, originally developed for the treatment of sickle cell anemia, should be repurposed for the treatment of cancer patients.

SCOT: Rethinking the classification of secondary structure elements.

MOTIVATION: Secondary structure classification is one of the most important issues in structure-based analyses due to its impact on secondary structure prediction, structural alignment and protein visualization. There are still open challenges concerning helix and sheet assignments which are currently not addressed by a single multi-purpose software. RESULTS: We introduce SCOT (Secondary structure Classification On Turns) as a novel secondary structure element assignment software which supports the assignment of turns, right-handed α-, 310- and π-helices, left-handed α- and 310-helices, 2.27- and polyproline II helices, ß-sheets and kinks. We demonstrate that the introduction of helix Purity values enables a clear differentiation between helix classes. SCOT's unique strengths are highlighted by comparing it to six state-of-the-art methods (DSSP, STRIDE, ASSP, SEGNO, DISICL and SHAFT). The assignment approaches were compared concerning geometric consistency, protein structure quality and flexibility dependency and their impact on secondary structure element-based structural alignments. We show that only SCOT's combination of hydrogen bonds, geometric criteria and dihedral angles enables robust assignments independent of the structure quality and flexibility. We demonstrate that this combination and the elaborate kink detection lead to SCOT's clear superiority for protein alignments. As the resulting helices and strands are provided in a PDB conform output format, they can immediately be used for structure alignment algorithms. Taken together, the application of our new method and the straight-forward visualization using the accompanying PyMOL scripts enable the comprehensive analysis of regular backbone geometries in proteins. AVAILABILITY AND IMPLEMENTATION: https://this-group.rocks. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Diastereoselective synthesis of conformationally restricted KOR agonists.

In order to analyze the bioactive conformation of flexible KOR agonists the ethylenediamine KOR pharmacophore was conformationally constrained by incorporation into a bicyclic system. For this purpose, 2-azabicyclo[3.2.1.]octan-7-amines were designed, synthesized and pharmacologically evaluated. The primary amine 14 as first key intermediate was prepared in a six-step synthesis starting with methyl cyclopent-3-enecarboxylate 9. Whereas phenylacetamides failed to provide bicyclic compounds, the intramolecular nucleophilic substitution of the sulfonamide 25 was initiated by deprotonation with NaH affording the bicyclic compound 26 in 72% yield. The three-step introduction of the pharmacophoric pyrrolidine ring started with nucleophilic substitution of exo-configured tosylate 26 with NaN3, which unexpectedly occurred under retention of configuration leading to exo-configured azide 31. The final KOR agonists 35 and 36 with exo-configured amino moieties were obtained by removal of the N-tosyl moiety of 33 and introduction of the second pharmacophoric element by acylation with dihalophenylacetyl chlorides. The KOR affinity of the pyrrolidine 35a is in the high nanomolar range (Ki = 862 nM). The low KOR affinity is explained by a non-appropriate dihedral angle of 137°/141° of the N(pyrrolidine)-C-C-N(acyl) system. As observed for stereoisomers of potent KOR agonists, phenylacetamide 35a and more importantly sulfonamides 33a and 33b show moderate affinity at σ1 receptors (Ki = 109-208 nM).

Using Domain-Specific Fingerprints Generated Through Neural Networks to Enhance Ligand-Based Virtual Screening.

Similarity-based virtual screening is a fundamental tool in the early drug discovery process and relies heavily on molecular fingerprints. We propose a novel strategy of generating domain-specific fingerprints by training neural networks on target-specific bioactivity datasets and using the activation as a new molecular representation. The neural network is expected to combine information of already known bioactive compounds with unique information of the molecular structure and by doing so enrich the fingerprint. We evaluate this strategy on a large kinase-specific bioactivity dataset. A comparison of five neural network architectures and their fingerprints to the well-established extended-connectivity fingerprint (ECFP) and an autoencoder shows that our neural fingerprint produces better results in the similarity search. Most importantly, the neural fingerprint performs well even when specific targets are not included during training. Surprisingly, while Graph Neural Networks (GNNs) are thought to offer an advantageous alternative, the best performing neural fingerprints were based on traditional fully connected layers using the ECFP4 as the input. The neural fingerprint is freely available at: https://github.com/kochgroup/kinase_nnfp.

Diagnostic performance of the combined nasal and throat swab in patients admitted to hospital with suspected COVID-19.

BACKGROUND: Accurate diagnosis in patients with suspected coronavirus disease 2019 (COVID-19) is essential to guide treatment and limit spread of the virus. The combined nasal and throat swab is used widely, but its diagnostic performance is uncertain. METHODS: In a prospective, multi-centre, cohort study conducted in secondary and tertiary care hospitals in Scotland, we evaluated the combined nasal and throat swab with reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in consecutive patients admitted to hospital with suspected COVID-19. Diagnostic performance of the index and serial tests was evaluated for a primary outcome of confirmed or probable COVID-19, and a secondary outcome of confirmed COVID-19 on serial testing. The diagnosis was adjudicated by a panel, who recorded clinical, laboratory and radiological features blinded to the test results. RESULTS: We enrolled 1368 consecutive patients (median age 68 [interquartile range, IQR 53-80] years, 47% women) who underwent a total of 3822 tests (median 2 [IQR 1-3] tests per patient). The primary outcome occurred in 36% (496/1368), of whom 65% (323/496) and 35% (173/496) had confirmed and probable COVID-19, respectively. The index test was positive in 255/496 (51%) patients with the primary outcome, giving a sensitivity and specificity of 51.4% (95% confidence interval [CI] 48.8 to 54.1%) and 99.5% (95% CI 99.0 to 99.8%). Sensitivity increased in those undergoing 2, 3 or 4 tests to 60.1% (95% CI 56.7 to 63.4%), 68.3% (95% CI 64.0 to 72.3%) and 77.6% (95% CI 72.7 to 81.9%), respectively. The sensitivity of the index test was 78.9% (95% CI 74.4 to 83.2%) for the secondary outcome of confirmed COVID-19 on serial testing. CONCLUSIONS: In patients admitted to hospital, a single combined nasal and throat swab with RT-PCR for SARS-CoV-2 has excellent specificity, but limited diagnostic sensitivity for COVID-19. Diagnostic performance is significantly improved by repeated testing.

Prospective randomized controlled trial on comparison of standard CO2 pressure pneumoperitoneum insufflator versus AirSeal®.

BACKGROUND: AirSeal® is a valve-free insufflation system that enables a stable pneumoperitoneum with continuous smoke evacuation and CO2 recirculation during laparoscopic surgery. Comparative evidence on the use of AirSeal® and standard CO2 insufflator in laparoscopic general surgery procedures is scarce. The aim of this study was to compare surgical outcomes between AirSeal® and standard CO2 insufflators in patients undergoing the most frequently performed laparoscopic procedures. METHODS: One hundred and ninety-eight patients undergoing elective laparoscopic cholecystectomy, colorectal surgery and hernia repair were randomized to either AirSeal® (group A) or standard pressure CO2 insufflator (group S). The primary endpoints were operative time and level of postoperative shoulder tip pain (Visual Analog Scale). Secondary outcomes included Clavien-Dindo grade complications, surgical side effect and length of hospital stay. RESULTS: Patients were randomized to either group A (n = 101) or group S (n = 97) and were analyzed by intention-to-treat. There was no significant difference in mean operative time between the groups (median [IQR]; 71 min [56-94] in group A vs. 69 min [52-93] in group S; p = 0.434). Shoulder tip pain levels were significantly lower in group S (VAS 0 [0-3] in group S vs. 2 [0-4] in group A; p = 0.001). There was no significant difference in complications, surgical side effects (subcutaneous emphysema was not observed in any group) and length of hospital stay. CONCLUSION: This randomized controlled trial showed that using the AirSeal® system did not reduce operative time and was associated with a higher postoperative shoulder tip pain compared to standard CO2 insufflator for short elective surgeries. ClinicalTrials.gov (NCT01740011).

[Reflux Symptoms - No Difference in Severity and Intensity in Patients with and without Functional Verified Gastroesophageal Reflux Disease]. / Refluxsymptomatik ­ kein Unterschied in Ausprägung und Schweregrad bei Patienten mit und ohne funktionell bewiesene gastroösophageale Refluxerkrankung.

BACKGROUND: Patients with gastroesophageal reflux disease (GERD) often suffer greatly from their symptoms. The aim of this study was to determine if there is a difference in quality of life and gastrointestinal symptom complexes between patients with purely functional complaints and patients with objective GERD. MATERIAL AND METHODS: We included all patients with typical reflux symptoms, who had a GERD examination in 2017 at our department. All patients underwent high resolution manometry, 24-h-pH-metry impedance measurement and gastroscopy. Quality of life was assessed using the Gastrointestinal Quality of Life Index (GIQLI) and gastrointestinal symptoms were rated by a symptom checklist (SCL), assessing the severity and intensity of 14 different symptoms. Based on the results of the 24-h-pH-metry impedance measurement, patients were divided into 2 groups: patients with functional reflux symptoms and patients with true GERD. These two groups were compared. RESULTS: Complete data were available in 162 patients, of whom 86 (52.2%) were objectively suffering from reflux (DeMeester score mean: 37.85; SD ± 29.11) and 76 (46.1%) had a normal DeMeester score (Mean: 7.01; SD ± 4.09). No significant difference in quality of life was found between the two groups (mean GIQLI of GERD patients: 94.81, SD ± 22.40, and mean GIQLI of patients with functional reflux symptoms: 95.26, SD ± 20.33, p = 0.988). Furthermore, no significant difference could be found in the evaluated symptoms (mean general SCL score of GERD patients: 46.97; SD ± 29.23; patients with functional reflux symptoms: 48.03; SD ± 29.17, p = 0.827). CONCLUSION: Patients with functional complaints suffer just as much from their symptoms as patients with objectively diagnosed GERD. Differentiation between gastroesophageal reflux disease and functional reflux symptoms is only possible by means of functional diagnostic testing.

[Planning and Design of a Prospective Randomised Multi-Centre Trial on the Repair of Large Hiatal Hernias with Sutures vs. Pledgeted Sutures vs. Absorbable Mesh]. / Vorstellung einer prospektiv randomisierten Multicenterstudie zum Vergleich der Hiatusplastik mit Nähten vs. Nähte mit Pledgets vs. resorbierbares Netz bei großen Hiatushernien.

BACKGROUND: The hernia recurrence rate after surgical treatment of large hiatal hernias is still very high. The optimal technique to reduce the recurrence rate is still under debate. The aim of this work is to clarify whether pledgeted reinforced sutures or a resorbable mesh can reduce the recurrence rate compared to hiatus closure with only sutures. MATERIALS AND METHODS: An Austria-wide, multi-centre, prospective, randomised study was planned. The study protocol was prepared by the main test centre (University Clinic for General, Visceral and Thoracic Surgery, Paracelsus Medical University Salzburg). The study includes patients who are scheduled to undergo laparoscopic or robot-assisted surgery for a large symptomatic hiatal hernia. A large hiatal hernia is defined as > 5 cm in manometry or gastroscopy or at least ⅓ of the stomach lying intrathoracically. The primary study endpoint is defined as the hernia recurrence rate, objectively assessed by gastroscopy. After inclusion in the study, patients will be followed up for 6 months, 1 year, 3 years and 5 years after the operation, using standardised questionnaires and gastroscopy. The power calculation showed a requirement of 55 patients per group. Preoperative randomisation and data management are software-based. RESULTS: The study approval by the leading ethics committee is currently pending and the study itself has been registered on ClinicalTrials.gov since October 2020. The Clinical Trials Registration Number is NCT04591860. Five clinics are participating in the study at the moment and all centres are actively enrolling patients. The duration of the study is set until January 2027. CONCLUSION: This study is the world's first prospective randomised study that examines the value of pledgets and resorbable mesh to reduce the recurrence rate after treatment of large hiatal hernias. The results will help to find the optimal technique to close the hiatus of large hiatal hernias.

Case report: meningitis as a presenting feature of anti-NMDA receptor encephalitis.

BACKGROUND: Meningitis is a very rare atypical presenting feature of anti-NMDA receptor encephalitis. In our case report, we describe an unusual clinical presentation of anti-NMDA receptor encephalitis with a biphasic pattern of meningitis followed by encephalitis and discuss potential mechanisms underlying this presentation. We aim to widen the differential diagnosis to be considered in a patient presenting with clinical meningitis and pyrexia. CASE PRESENTATION: This is a case of a 33-year old Caucasian woman who initially presented with a lymphocytic meningitis attributed to a viral infection. She subsequently developed fluctuating consciousness, agitation, visual hallucinations, dyskinetic movements, a generalized tonic-clonic seizure, and autonomic instability. Investigations revealed a diagnosis of anti-NMDA receptor encephalitis secondary to a previously unidentified ovarian teratoma. She made an excellent recovery with immunotherapy and removal of the teratoma. CONCLUSION: Clinicians should consider autoimmune encephalitides in individuals with meningitis, particularly where extensive investigations fail to identify a causative pathogen and there is rapid development of an encephalitic phenotype.

Two cases of imported respiratory diphtheria in Edinburgh, Scotland, October 2019.

We report two cases of respiratory toxigenic Corynebacterium diphtheriae infection in fully vaccinated UK born adults following travel to Tunisia in October 2019. Both patients were successfully treated with antibiotics and neither received diphtheria antitoxin. Contact tracing was performed following a risk assessment but no additional cases were identified. This report highlights the importance of maintaining a high index of suspicion for re-emerging infections in patients with a history of travel to high-risk areas outside Europe.

Coronavirus disease (COVID-19) Community Testing Team in Scotland: A 14-day review, 6 to 20 February 2020.

In response to the outbreak of COVID-19, we set up a team to carry out sampling in the community. This enabled individuals to remain in self-isolation in their own homes and to prevent healthcare settings and services from being overwhelmed by admissions for sampling of suspected cases. There is evidence that this is a cost effective, safe and necessary service to complement COVID-19 testing in hospitals.