Carpogenic germination of Sclerotinia sclerotiorum sclerotia in Brassica oleracea var gemmifera (VN: Brussels sprouts) in North Patagonia, Argentina.

In August 2018, symptoms of apical and basal rot resembling those caused by Sclerotinia sclerotiorum infection were observed in a commercial Brussels sprouts field in North Patagonia, Argentina. The incidence of apical and basal rot was 23.30% and 2.30%, respectively. Carpogenic germination of sclerotia was detected in shaded, highly humid soil areas. To our knowledge, this is the first report of carpogenic germination of sclerotia from S. sclerotiorum in North Patagonia.

Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors.

Heterozygous activin receptor-like kinase 1 (ALK1) mutations are associated with two vascular diseases: hereditary hemorrhagic telangiectasia (HHT) and more rarely pulmonary arterial hypertension (PAH). Here, we aimed to understand the impact of ALK1 mutations on BMP9 and BMP10 transcriptomic responses in endothelial cells. Endothelial colony-forming cells (ECFCs) and microvascular endothelial cells (HMVECs) carrying loss of function ALK1 mutations were isolated from newborn HHT and adult PAH donors, respectively. RNA-sequencing was performed on each type of cells compared to controls following an 18 h stimulation with BMP9 or BMP10. In control ECFCs, BMP9 and BMP10 stimulations induced similar transcriptomic responses with around 800 differentially expressed genes (DEGs). ALK1-mutated ECFCs unexpectedly revealed highly similar transcriptomic profiles to controls, both at the baseline and upon stimulation, and normal activation of Smad1/5 that could not be explained by a compensation in cell-surface ALK1 level. Conversely, PAH HMVECs revealed strong transcriptional dysregulations compared to controls with > 1200 DEGs at the baseline. Consequently, because our study involved two variables, ALK1 genotype and BMP stimulation, we performed two-factor differential expression analysis and identified 44 BMP9-dysregulated genes in mutated HMVECs, but none in ECFCs. Yet, the impaired regulation of at least one hit, namely lunatic fringe (LFNG), was validated by RT-qPCR in three different ALK1-mutated endothelial models. In conclusion, ALK1 heterozygosity only modified the BMP9/BMP10 regulation of few genes, including LFNG involved in NOTCH signaling. Future studies will uncover whether dysregulations in such hits are enough to promote HHT/PAH pathogenesis, making them potential therapeutic targets, or if second hits are necessary.

Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.

BACKGROUND: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD. OBJECTIVES: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance. DESIGN: A phase 3, double-blind, placebo-controlled, randomized clinical trial. SETTING: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. PARTICIPANTS: Cognitively normal older adults aged 65 to 83. INTERVENTION: Pioglitazone tablet. MEASUREMENTS: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40'523 genotypes. RESULTS: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers. CONCLUSIONS: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.

Survey on infectious disease telephone hotlines in primary care: General practitioners' satisfaction and compliance with advice.

OBJECTIVES: Infectious disease (ID) advice is a major part of antimicrobial stewardship programs. The objective of this study was to assess general practitioners' (GPs)' opinions and compliance with advice given by ID hotlines. PATIENTS AND METHODS: This multicenter survey was based on the 7-day assessment of initial advice requested by GPs to a hotline set up by volunteer hospital ID teams to record advice for 3 years. The primary endpoint was the GPs' satisfaction with the advice given by ID specialists. RESULTS: Ten ID teams participated in the study and recorded 4138 requests for advice, of which 1325 requests included a proposal for antibiotic therapy and justified a follow-up call at seven days. Only 398 follow-up calls (30%) were carried out because many GPs were not reachable. GPs were very satisfied with ID hotlines: 58% considered them indispensable and 38% very useful. The recommendations provided by ID specialists were followed by GPs in more than 80% of cases. The two main motivations for GPs to call the hotline were to get quick advice (86%) and to receive help in managing a patient (76%). CONCLUSIONS: The ID telephone consultations and advice systems for GPs are highly appreciated and are effective in terms of following the recommendations.

Strengthening primary care for diabetes and hypertension in Eswatini: study protocol for a nationwide cluster-randomized controlled trial.

BACKGROUND: Diabetes and hypertension are increasingly important population health challenges in Eswatini. Prior to this project, healthcare for these conditions was primarily provided through physician-led teams at tertiary care facilities and accessed by only a small fraction of people living with diabetes or hypertension. This trial tests and evaluates two community-based healthcare service models implemented at the national level, which involve health care personnel at primary care facilities and utilize the country's public sector community health worker cadre (the rural health motivators [RHMs]) to help generate demand for care. METHODS: This study is a cluster-randomized controlled trial with two treatment arms and one control arm. The unit of randomization is a primary healthcare facility along with all RHMs (and their corresponding service areas) assigned to the facility. A total of 84 primary healthcare facilities were randomized in a 1:1:1 ratio to the three study arms. The first treatment arm implements differentiated service delivery (DSD) models at the clinic and community levels with the objective of improving treatment uptake and adherence among clients with diabetes or hypertension. In the second treatment arm, community distribution points (CDPs), which previously targeted clients living with human immunodeficiency virus, extend their services to clients with diabetes or hypertension by allowing them to pick up medications and obtain routine nurse-led follow-up visits in their community rather than at the healthcare facility. In both treatment arms, RHMs visit households regularly, screen clients at risk, provide personalized counseling, and refer clients to either primary care clinics or the nearest CDP. In the control arm, primary care clinics provide diabetes and hypertension care services but without the involvement of RHMs and the implementation of DSD models or CDPs. The primary endpoints are mean glycated hemoglobin (HbA1c) and systolic blood pressure among adults aged 40 years and older living with diabetes or hypertension, respectively. These endpoints will be assessed through a household survey in the RHM service areas. In addition to the health impact evaluation, we will conduct studies on cost-effectiveness, syndemics, and the intervention's implementation processes. DISCUSSION: This study has the ambition to assist the Eswatini government in selecting the most effective delivery model for diabetes and hypertension care. The evidence generated with this national-level cluster-randomized controlled trial may also prove useful to policy makers in the wider Sub-Saharan African region. TRIAL REGISTRATION: NCT04183413. Trial registration date: December 3, 2019.

Semantic segmentation for fully automated macrofouling analysis on coatings after field exposure.

Biofouling is a major challenge for sustainable shipping, filter membranes, heat exchangers, and medical devices. The development of fouling-resistant coatings requires the evaluation of their effectiveness. Such an evaluation is usually based on the assessment of fouling progression after different exposure times to the target medium (e.g. salt water). The manual assessment of macrofouling requires expert knowledge about local fouling communities due to high variances in phenotypical appearance, has single-image sampling inaccuracies for certain species, and lacks spatial information. Here an approach for automatic image-based macrofouling analysis was presented. A dataset with dense labels prepared from field panel images was made and a convolutional network (adapted U-Net) for the semantic segmentation of different macrofouling classes was proposed. The establishment of macrofouling localization allows for the generation of a successional model which enables the determination of direct surface attachment and in-depth epibiotic studies.

Measurements of pulse rate using facial video cameras from smart devices in patients diagnosed with atrial fibrillation.

Clinical applications of passive long-term heart rate (HR) monitoring in patients with cardiac arrhythmias include adequate drug titration of atrioventricular (AV) nodal drugs and assessment of medical compliance with treatment. A majority of patients treated with beta-blockers, especially patients with atrial fibrillation (AF), require some degree of drug titration during the first 6 months of treatment to ensure that adequate HR control and medicine compliance has been achieved. Failing to achieve adequate rate control in patients with AF can lead to worsening symptoms, heart failure exacerbations, and potentially tachycardia-induced cardiomyopathy. Enabling video-based monitoring during telehealth patient visits could facilitate providers to measure heart rate (HR) without the need for a dedicated home device (smartwatch, SPO2 device, or others). Videoplethysmography (VPG) is a monitoring technology that measures pulse rate by utilizing front-facing cameras embedded in smart devices. VPG provides a remote and contactless cardiac monitoring solution. We conducted a clinical experiment to evaluate the accuracy of VPG in measuring HR while running on two portable devices: Samsung S10 smartphones and S3 tablets. We used a single­lead ECG to measure the heart rate at the time of the VPG recordings in AF patients. We employed the Bland-Altman method to measure the level of agreement between videoplethysmography and ECG-based measurements of HR. The findings reveal that the mean difference in videoplethysmography and ECG-based heart rate was inferior to 1 bpm across the 2 devices with confidence intervals ranging from 3 to 12 BPM. Our facial video-based HR monitoring solution could assist providers in measuring heart rates in their patients with AF during remote telehealth visits.

Study of "ALS reversals": LifeTime environmental exposures (StARLiTE).

We previously reported on a series of patients diagnosed with ALS whom had an extraordinary course defined by substantial and sustained improvement in weakness and function. For this study, twenty-five of these "ALS Reversals" completed extensive environmental exposure questionnaires. These responses were then compared to a large database of prior responses from patients with typically progressive ALS (n = 6187). The results demonstrated that the "Reversal" participants have had a diverse number of exposures with substantial heterogeneity. In general, this was similar to the control group; however, there were a few specific differences that could be further explored in future research.

Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

Accelerating the Front End of Medicine: Three Digital Use Cases and HCI Implications.

Digital applications in health care are a concurrent research and management question, where implementation experiences are a core field of information systems research. It also contributes to fighting pandemic crises like COVID-19 because contactless information flow and speed of diagnostics are improved. This paper presents three digital application case studies from emergency medicine, administration management, and cancer diagnosis with AI support from the University Medical Centers of Münster and Göttingen in Germany. All cases highlight the potential of digitalization to increase speed and efficiency within the front end of medicine as the crucial phase before patient treatment starts. General challenges for health care project implementations and human-computer interaction (HCI) concepts in health care are derived and discussed, including the importance of specific processes together with user analysis and adaption. A derived concept for HCI includes the criteria speed, accuracy, modularity, and individuality to achieve sustainable improvements within the front end of medicine.

ESMO Congress 2021: highlights from the EORTC gastrointestinal tract cancer group's perspective.

There has been no major change of practice in gastrointestinal oncology at the European Society for Medical Oncology (ESMO) symposium 2021, but confirmation that immunotherapy in combination with chemotherapy has become standard of care in several indications. The European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Track Cancer Group has selected important phase II and III trials presented during the symposium across all gastrointestinal cancers as well as early reports on new drugs or new combinations that may change practice in the future.

Pharmacologic profiling reveals lapatinib as a novel antiviral against SARS-CoV-2 in vitro.

The emergence of SARS-CoV-2 virus has resulted in a worldwide pandemic, but effective antiviral therapies are not widely available. To improve treatment options, we conducted a high-throughput screen to uncover compounds that block SARS-CoV-2 infection. A minimally pathogenic human betacoronavirus (OC43) was used to infect physiologically-relevant human pulmonary fibroblasts (MRC5) to facilitate rapid antiviral discovery in a preclinical model. Comprehensive profiling was conducted on more than 600 compounds, with each compound arrayed across 10 dose points. Our screening revealed several FDA-approved agents that can attenuate both OC43 and SARS-CoV-2 viral replication, including lapatinib, doramapimod, and 17-AAG. Importantly, lapatinib inhibited SARS-CoV-2 RNA replication by over 50,000-fold. Further, both lapatinib and doramapimod could be combined with remdesivir to improve antiviral activity in cells. These findings reveal novel therapeutic avenues that could limit SARS-CoV-2 infection.

A patient-centred web-based adverse drug reaction reporting system identifies not yet labelled potential safety issues.

PURPOSE: Reporting of adverse drug reactions (ADRs) by patients is essential for a comprehensive risk-benefit evaluation of drugs after marketing, but only few data are available regarding patient-centred web-based ADR reporting systems. Hence, we aimed to analyze ADRs reported by patients with a particular emphasis on novel drugs and serious ADRs not yet labelled in the respective summary of product characteristics (SPC). METHODS: All ADR reports received by a web-based, patient-centred platform ( www.nebenwirkungen.de ) between April 1, 2019, and September 1, 2020, were descriptively analyzed. ADRs and drugs were coded automatically according to MedDRA and ATC classification system. SPC labelling of reported ADRs for novel drugs marketed since 2015 was checked manually. RESULTS: In total, 13,515 patient reports including 29,529 ADRs were received during the study period (serious ADRs [SADRs] n = 1,318; 4.5%). Women were affected in more than two-thirds of ADR reports. The most common patient-reported ADRs were nausea, dizziness and headache, whereas arrhythmia, intestinal obstruction and erectile dysfunction were the most frequent SADRs. Ciprofloxacin, levothyroxine and venlafaxine were the compounds most frequently suspected for causing both ADRs and SADRs. Regarding novel compounds, 289 reports including 739 ADRs were received (mainly fatigue, headache and myalgia). Three hundred thirty-one (44.8%) out of those ADRs were not yet labelled in the respective SPC, whereof twelve were SADRs. CONCLUSION: The majority of patient-reported ADRs were non-serious. However, a relevant number of non-labelled even serious ADRs was reported for novel compounds by patients. Despite well-known limitations of patient-reported ADRs, this web-based ADR reporting system contributes to the identification of new ADRs and thus can help to improve patients' safety complementing other pharmacovigilance instruments.

The diagnostic value of the neurological examination in coma of unknown etiology.

BACKGROUND: Identifying the cause of non-traumatic coma in the emergency department is challenging. The clinical neurological examination is the most readily available tool to detect focal neurological deficits as indicators for cerebral causes of coma. Previously proposed clinical pathways have granted the interpretation of clinical findings a pivotal role in the diagnostic work-up. We aimed to identify the actual diagnostic reliability of the neurological examination with regard to identifying acute brain damage. METHODS: Eight hundred and fifty-three patients with coma of unknown etiology (CUE) were examined neurologically in the emergency department following a predefined routine. Coma-explaining pathologies were identified retrospectively and grouped into primary brain pathology with proof of acute brain damage and other causes without proof of acute structural pathology. Sensitivity, specificity and percentage of correct predictions of different examination protocols were calculated using contingency tables and binary logistic regression models. RESULTS: The full neurological examination was 74% sensitive and 60% specific to detect acute structural brain damage underlying CUE. Sensitivity and specificity were higher in non-sedated patients (87/61%) compared to sedated patients (64%/59%). A shortened four-item examination protocol focusing on pupils, gaze and pyramidal tract signs was only slightly less sensitive (67%) and more specific (65%). CONCLUSIONS: Due to limited diagnostic reliability of the physical examination, the absence of focal neurological signs in acutely comatose patients should not defer from a complete work-up including brain imaging. In an emergency, a concise neurological examination should thus serve as one part of a multimodal diagnostic approach to CUE.

Validation of 3D fluoroscopy for image-guidance registration in depth electrode implantation for medically refractory epilepsy.

BACKGROUND: Frame registration is a critical step to ensure accurate electrode placement in stereotactic procedures such as stereoelectroencephalography (SEEG) and is routinely done by merging a computed tomography (CT) scan with the preoperative magnetic resonance (MR) examination. Three-dimensional fluoroscopy (XT) has emerged as a method for intraoperative electrode verification following electrode implantation and more recently has been proposed as a registration method with several advantages. METHODS: We compared the accuracy of SEEG electrode placement by frame registration with CT and XT imaging by analyzing the Euclidean distance between planned and post-implantation trajectories of the SEEG electrodes to calculate the error in both the entry (EP) and target (TP) points. Other variables included radiation dose, efficiency, and complications. RESULTS: Twenty-seven patients (13 CT and 14 XT) underwent placement of SEEG electrodes (319 in total). The mean EP and TP errors for the CT group were 2.3 mm and 3.3 mm, respectively, and 1.9 mm and 2.9 mm for the XT group, with no statistical difference (p = 0.75 and p = 0.246). The time to first electrode placement was similar (XT, 82 ± 10 min; CT, 84 ± 22 min; p = 0.858) and the average radiation exposure with XT (234 ± 55 mGy*cm) was significantly lower than CT (1245 ± 123 mGy*cm) (p < 0.0001). Four complications were documented with equal incidence in both groups. CONCLUSIONS: The use of XT as a method for registration resulted in similar implantation accuracy compared with CT. Advantages of XT are the substantial reduction in radiation dose and the elimination of the need to transfer the patient out of the room which may have an impact on patient safety and OR efficiency.

Layer-by-Layer Deposited Hybrid Polymer Coatings Based on Polysaccharides and Zwitterionic Silanes with Marine Antifouling Properties.

Polyelectrolyte multilayer (PEM) assembly is a versatile tool to construct low-fouling coatings. For application in the marine environment, their structure needs to be stabilized by covalent linkage. Here, we introduce an approach for spin coating of silane-based sol-gel chemistries using layer-by-layer assembly of polysaccharide-based hybrid polymer coatings (LBLHPs). The silane sol-gel chemistry allows the films to be cross-linked under water-based and mild reaction conditions. Two different silanes were used for this purpose, a conventional triethoxymethyl silane and a de novo synthesized zwitterionic silane. The polysaccharide-silane hybrid polymer coatings were thoroughly characterized with spectroscopic ellipsometry, water contact angle (WCA) goniometry, attenuated total reflection-Fourier transform infrared spectroscopy, and atomic force microscopy. The coatings showed good stability in seawater, smooth surfaces, a high degree of hydration, and WCAs below or close to the Berg limit. LBLHPs showed low-fouling properties in biological assays against nonspecific protein adsorption, attachment of the diatom Navicula perminuta, and settlement of zoospores of the macroalga Ulva linza.

Fully Convolutional Neural Network for Detection and Counting of Diatoms on Coatings after Short-Term Field Exposure.

While the use of deep learning is a valuable technology for automatic detection systems for medical data and images, the biofouling community is still lacking an analytical tool for the detection and counting of diatoms on samples after short-term field exposure. In this work, a fully convolutional neural network was implemented as a fast and simple approach to detect diatoms on two-channel (fluorescence and phase-contrast) microscopy images by predicting bounding boxes. The developed approach performs well with only a small number of trainable parameters and a F1 score of 0.82. Counting diatoms was evaluated on a data set of 600 microscopy images of three different surface chemistries (hydrophilic and hydrophobic) and is very similar to counting by humans while demanding only a fraction of the analysis time.

The accuracy of 3D fluoroscopy (XT) vs computed tomography (CT) registration in deep brain stimulation (DBS) surgery.

BACKGROUND: Stereotactic registration is the most critical step ensuring accuracy in deep brain stimulation (DBS) surgery. 3D fluoroscopy (XT) is emerging as an alternative to CT. XT has been shown to be safe and effective for intraoperative confirmation of lead position following implantation. However, there is a lack of studies evaluating the suitability of XT to be used for the more crucial step of registration and its capability of being merged to a preoperative MRI. This is the first study comparing accuracy, efficiency, and radiation exposure of XT- vs CT-based stereotactic registration and XT/MRI merging in deep brain stimulation. METHODS: Mean absolute differences and Euclidean distance between planned (adjusted for intraoperative testing) and actual lead trajectories were calculated for accuracy of implantation. The radiation dose from each scan was recorded as the dose length product (DLP). Efficiency was measured as the time between the patient entering the operating room and the initial skin incision. A one-way ANOVA compared these parameters between patients that had either CT- or XT-based registration. RESULTS: Forty-one patients underwent DBS surgery-25 in the CT group and 16 in the XT group. The mean absolute difference between CT and XT was not statistically significant in the x (p = 0.331), y (p = 0.951), or z (p = 0.807) directions. The Euclidean distance between patient groups did not differ significantly (p = 0.874). The average radiation exposure with XT (220.0 ± 0.1 mGy*cm) was significantly lower than CT (1269.3 ± 112.9 mGy*cm) (p < 0.001). There was no significant difference in registration time between CT (107.8 ± 23.1 min) and XT (106.0 ± 18.2 min) (p = 0.518). CONCLUSION: XT-based frame registration was shown to result in similar implantation accuracy and significantly less radiation exposure compared with CT. Our results surprisingly showed no significant difference in registration time, but this may be due to a learning curve effect.